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PHASE 1 Medicine > IMMS > Flashcards

IMMS Flashcards

1
Q

What is the structure of DNA?

A

Double helix

Complimentary base pairs (A-T {2 H-bonds} & C-G {3- H bonds})

Coils around nucleosomes (made of protein histones)
Complex supercoils to form chromosomes

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2
Q

How many chromosomes (pairs?) are there in a normal human somatic cell?

A

46 chromosomes

23 pairs
22 pairs are autosomes (anything that isn’t sex- determining)
1 pair is the sex chromosomes (XY- male & XX- female)

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3
Q

What is a Karyotype?

A 
Number and appearance of chromosomes in a cell
Spreads are arranged in size order:
* Biggest pair is 1
* Smallest pair is 22
* Sex pair is 23
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4
Q

How many genes does a human have in total?

A

30,000 genes

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5
Q

What does each chromosome consists of?

A

P arm- short arm (petit)
Q arm- long arm
Two arms separated by a centromere

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6
Q

What is Mitosis?

A

Type of cell division where a single cell divides into two genetically identical daughter cells with 46 chromosomes

2n parent cell –> 4n parent cell –> 2n daughter cells X2

Parent cell is destroyed in the process

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7
Q

What are the stages of mitosis?

A 
(I pee mostly at trees C)
Interphase
Prophase
Metaphase
Anaphase
Telophase
Cytokinesis
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8
Q

What is the purpose of mitosis?

A

Producing two daughter cells that are genetically identical to the parent cell.

Growth
Replacement of dead cells

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9
Q

Chromatin .VS. Chromosomes .VS. Chromatids

A

Chromatin is cell not in replication

Chromosome is cell during replication

Chromatids is cell after replication

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10
Q

For mitosis to occur, what must happen?

A

Cell must be in cell cycle- Interphase

If cell is in G0, outside cell cycle mitosis can’t occur

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11
Q

What happens in Interphase? (MITOSIS)

A

Longest phase…

  • G1: (no visible activity)

Rapid cell growth (becomes larger)
Organelle synthesis
Protein synthesis of proteins involved in spindle formation
Normal metabolic function

  • S phase: (Synthesis)

DNA doubles through DNA replication
Histone proteins double through protein synthesis (2X as much DNA at end of S)
Centrosome replication

  • G2:

Chromosomes condense
Energy stores accumulate
Mitochondria and centrioles double

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12
Q

What happens in Prophase? (MITOSIS)

A
  • Chromatin condenses into chromosomes

* Centrosomes nucleate microtubules and move to opposite poles of nucleus

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13
Q

What happens in Prometaphase and Metaphase? (MITOSIS)

A

PROMETAPHASE
* Nuclear membrane breaks down

  • Microtubules invade nuclear space
  • Chromatids attach to microtubules
  • Cell no longer has a nucleus

METAPHASE
* Chromosomes line up along equatorial plane (metaphase plate)

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14
Q

What happens in Anaphase? (MITOSIS)

A
  • Sister chromatids separate, and are pushed to opposite poles of the cells, centromere first as spindle fibres contract
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15
Q

What happens in Telophase? (MITOSIS)

A
  • Nuclear membrane reforms
  • Chromosomes unfold into chromatin
  • Cytokinesis begins
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16
Q

What happens in Cytokinesis? (MITOSIS)

A
  • Cell organelle become evenly distributed around each nucleus
  • Cell cytoplasm splits and divides into 2 daughter cells with a nucleus in each and 46 chromosomes
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17
Q

What is Down’s syndrome caused by?

A

1 extra chromosome at 21

Trisomy 21

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18
Q

In histology, how can you tell if a cell is undergoing mitosis?

A
  • If the nucleus is dark (chromatin has condensed to chromosomes)
  • If nuclei aren’t the same size
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19
Q

How do you know if something is malignant?

A

If there are too many mitotic figures

Lots of dark nuclei of different sizes

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20
Q

How do you determine how bad the cancer is?

A

By the number of mitotic figures

The more mitotic figures, the worse it is

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21
Q

How is MEIOSIS different to MITOSIS?

A
  • Only in gametes
  • Recombination of genetic material results in genetic diversity
  • 2 cell divisions
  • 4 haploid (23 chromosomes) cells produced, which are genetically distinct from each other and the parent cell
  • Meiosis isn’t a cycle
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22
Q

What happens during Meiosis 1

A

Chromosome number is halved

Interphase-
* Cell growth, Organelle synthesis, Protein synthesis, DNA replication, Chromosomes condense

Prophase-
* Crossing over occurs between non- sister chromatids at the Chiasmata (Genes switch independently)= GENETIC DIVERSITY

Metaphase-
* Random assortment of homologous chromosomes occurs on metaphase plate= GENETIC DIVERSITY

Anaphase-
* Sister chromatids are pulled apart

Telophase and cytokinesis-

  • Sister chromatids end up in separate poles
  • Chromosomes decondense
  • Nuclear envelope forms and cytoplasm splits
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23
Q

What happens during Meiosis 2?

A
  • Sister chromatids separate

* Haploid cells produced

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24
Q

What is Gametogenesis?

A
  • The first stage is the proliferation of primordial (undifferentiated) germ cells (developing gametes) by mitosis
  • The timing of mitosis in germ cells differs greatly in males and females
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25
Q

What is Gametogenesis in males?

A
  • Primordial germ cell –> lots of mitoses –> spermatogonia (mature sperm)
  • Some mitosis occurs in embryonic stages to produce primary spermatocytes present at birth
  • Mitosis really begins during puberty and continues throughout life
  • Meiotic division commence at puberty
  • Cytoplasm divides evenly
  • After meiosis 2 –> 4 equal sized gametes
  • Millions of mature sperm continually produced
  • Process takes 60-65 days
  • 100/200 million sperm per ejaculate
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26
Q

What is Gametogenesis in females?

A
  • Primordial germ cell –> 30 mitoses –> oogonia
  • Oogonia enter prophase 1 of Meiosis 2 by 7th month of intrauterine life
  • Process suspended
  • Cells enter ovulation 10-50 yrs later
  • Cytoplasm divides unequally- 1 egg & 3 Polar bodies ( that apoptose)
  • Meiosis 1 is completed at ovulation ( then cells remain in suspended animation)- at this point there is 1 big cell, 1 small cell each with diploid DNA. then go on to divide again ( after fertilisation) to form 1 big cell (egg) and 3 small cells (polar bodies)
  • Meiosis 2 is only complete if fertilisation occurs
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27
Q

Problems with Meiosis

A
  • Non- disjunction

* Gonadal mosaicism

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28
Q

What is non- disjunction, name 2 examples?

A
  • Failure of chromosome pairs to separate in Meiosis 1 or sister chromatids to separate properly in Meiosis 2
  1. Down syndrome (Trisomy 21- RISK INCREASES WITH AGE FOR MALES AND FEMALES
    75% maternal meiosis I,
    25% maternal meiosis II,
    3-5% paternal non disjunction
  2. Turners syndrome (Monosomy {loss of a chromosome}- Only 1 X chromosome)
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29
Q

What is Gonadal Mosaicism, which inheritance patterns is it commonly observed with and give 2 conditions?

A
  • Occurs when precursor germline cells to ova or spermatozoa are a mixture of two or more genetically different cell lines (due to errors in mitosis)
  • One cell line is normal, the other is mutated
  • Incidence increases with advancing paternal age
  • Parent is healthy ( since genetic change is only in germline so all other cells are unaffected- have usual genetic components), but the foetus may have genetic diseases
  • More common in males
  • Can be observed with any inheritance pattern, but most commonly autosomal dominant and x- linked
  • Observed in a number of conditions, including osteogenesis imperfecta (brittle bones) and duchenne muscular dystrophy
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30
Q

Name the three causes of disease?

A

Genetic
Multifactorial
Environmental

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31
Q

What is genetic cause of disease and give examples of some diseases?

A
  • Individually rare but cumulatively enough to have regional genetic services
  • Down Syndrome, Cystic Fibrosis, Huntington disease, Haemophilia
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32
Q

What is multifactorial cause of disease and give some examples?

A
  • Main cause of disease in developed countries

* Spina bifida, Cleft lip, Diabetes, Schizophrenia

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33
Q

What is environmental cause of disease and give some examples?

A
  • Main cause of disease in 3rd world countries and A&E (genetics play a small role)
  • Poor diet
  • Infection
  • Drugs
  • Accidents
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34
Q

Definition of AUTOSOMAL

A

Chromosomes 1-22, all chromosomes except the sex chromosomes (XY)

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35
Q

Definition of LOCUS

A

The position of a gene/DNA on the genetic map.

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36
Q

Definition of GENOTYPE

A

Genetic constitution of an individual

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37
Q

Definition of PHENOTYPE

A

Appearance of an individual which results from the interaction of the environment and the genotype

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38
Q

Definition of ALLELE
What is normal allele referred to as?
What does diseased allele carry?

A

One of several alternative forms of a gene at a specific locus

Normal allele is also referred to as wild type

Disease allele carries the pathogenic mutation

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39
Q

Definition of POLYMORPHISM

A

Frequent hereditary variations at a locus.

Doesn’t cause problems (thats mutations).

Polymorphisms can be you more/less efficient or make you more/ less susceptible to disease.

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40
Q

Definition of CONSANGUINITY

A

Reproductive union between two relatives

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41
Q

Definition of AUTOZYGOSITY

A

Homozygous by descent i.e. inheritance of the same mutant allele through two branches of the same family

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42
Q

Definition of HOMOZYGOUS

A

Both alleles are the same at a locus

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43
Q

Definition of HETEROZYGOUS

A

Alleles at a locus are different

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44
Q

Definition of HEMIZYGOUS

A

Describes genes that are carried on an unpaired chromosome. Refers to a locus on an X chromosome in a male

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45
Q

Definition of PENETRANCE

What are the two types?

A

Proportion of people with a gene/genotype who show the expected phenotype

  • Complete: gene or genes for the trait are expressed in all the population
  • Incomplete: the genetic trait is only expressed in parts of the population
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46
Q

Definition of VARIABLE EXPRESSION

A

Variation in clinical features (type and severity) of a genetic disorder between individuals with the same gene alteration

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47
Q

Definition of SEX LIMITATION

A

Expression of a particular characteristic limited to one of the sexes

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48
Q

Definition of MULTIFACTORIAL CONDITION

A

Diseases due to a combination of genetic and environmental factors.

If the condition is more common in one particular sex, the relatives of an affected individual of the less frequently affected sex will be a higher risk than relatives of an affected individual or the more frequently affected sex

i.e if a boy has the condition then female relatives are more at risk and vice versa.

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49
Q

Definition of LATE- ONSET

A

Condition not manifested at birth (where it does this is called congenital).

Classically adult-onset e.g Huntington’s

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50
Q

What is AUTOSOMAL DOMINANT INHERITANCE?

A

MENDELIAN
* A disease that only manifests in the heterozygous state

  • Affects both males and females in equal proportions.
  • Affected individuals in multiple generations
  • Transmission by individuals of both sexes to both sexes
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51
Q

Why are parents sometimes unaffected in autosomal dominant inheritance?

A
  • They don’t have the genes for it- Gonadal Mosaicism
  • Mother has reduced penetrance/ variable expression

*Only one defective gene is needed. (50% chance of offspring having condition with 1 affected and 1 unaffected parent)
E.G. HUNTINGTONS. only way to pass on disease is from male to male, so must be autosomal dominant

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52
Q

What is autosomal recessive inheritance?

A

MENDELIAN

  • A disease that manifests in the homozygous state
  • 2 defective genes required
  • If both parents are carriers, 25% chance of offspring having condition, 50% of offspring being carrier. *
  • Healthy siblings have 2/3 chance of being carriers. the affected child is disregarded in the ratio
  • Male and females affected in equal proportions
  • Affected individuals only in a single generation
  • Parent can be related (consanguineous)- recessive disorders most common in these types of families
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53
Q

What is Cystic fibrosis?

A
  • Most common autosomal recessive condition affecting whites in the UK
  • Chronic condition affecting mainly the lungs and gut, variable presentation
  • Incidence of 1 in 25,000
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54
Q

What is X linked inheritance and give 2 examples?

A

MENDELIAN

  • caused by mutation in genes on X chromosome, E.G. haemophilia and duchenne muscular dystrophy
  • X linked can never be passed from father to son because sons always get their X chromosome from their mother (No male-to-male transmission)
  • All daughters from affected male are carriers and all sons are unaffected.
  • All sons from affected male and unaffected female are unaffected female are unaffected
  • Usually males are affected, they can never be carriers
  • Usually transmitted through unaffected females
  • Examples=
    X linked dominant= Alport’s syndrome
    X linked recessive= Duchenne’s muscular dystrophy
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55
Q

What is Lyonisation?

A
  • Process of X chromosome inactivation
  • One of 2 X chromosomes in every cell in a female is randomly inactivated early in embryonic development
  • only one functional copy of X chromosomes
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56
Q

What is Barr body?

A

Inactive X chromosome since packaged in heterochromatin (cannot be transcripted)

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57
Q

What is Imprinting?

A

NON-MENDELIAN

  • For some genes, only 1 out of the 2 alleles is active. The other is inactive.
  • For particular genes it is always the paternal or the maternal allele.
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58
Q

What is Knudson’s 2 hit Hypothesis?

A

Gene mutations may either be inherited or acquired during a person’s life

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59
Q

What is sporadic and hereditary cancer?

A

Sporadic= 2 acquired mutations

Hereditary= 1 inherited mutation + 1 acquired mutation

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60
Q

What is an ideogram?

A

Diagrammatic form of chromosome bands, bands are numbered according
to distance to centromere

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61
Q

What are the classifications of genetic disease?

A
  • Chromosomal
  • Mendelian- Autosomal dominant/ recessive or X linked
  • Non traditional- Mitochondrial, Imprinting, Mosaicism
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62
Q

In genetic pedigrees, what are the squares, circles and highlighted shapes?

A 
Square= Male
Circle= Female
Highlighted= Affected
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63
Q

When is DNA most risk of mutation?

A

S phase- DNA replication occurs here

Checkpoints check the DNA, mutated DNA triggers apoptosis

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64
Q

Where is DNA found?

A

95% Nucleus

5% Mitochondria (from ovum)

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65
Q

Types of tissues

A 
Epithelia
Supporting tissues
Muscle
Nerves
Germ cells
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66
Q

What is Epithelia and its purpose?

A
  • One of more layers of cells that line a body cavity

* Protection, absorption, secretion

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67
Q

What is the purpose of supporting tissue and give some examples?

A
  • Structure and protection

* Cartilage, bones, tendons and blood

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68
Q

Give the three types of muscle?

A

Smooth, Skeletal, Cardiac

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69
Q

What types of nerves are there?

A

Brain, Peripheral, Visceral

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70
Q

What are the two types of Germ cells?

A

Ova and Sperm

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71
Q

What does Haematoxylin stain?

A
  • Stains acidic things BLUE

* Stains Cell nuclei and RNA BLUE

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72
Q

What does Eosin stain?

A
  • Stains alkaline things PINK
  • Stains cytoplasm and colloidal proteins (e.g. plasma) PINK
  • Stains Keratin ORANGE
  • Many extra cellular fibres (e.g. collagen and elastin) also stain PINK
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73
Q

What does H&E not stain?

A

Watery extra cellular jelly (GAG) and fat, so appear as white spaces

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74
Q

What does Alcian Blue stain?

A

Stains following BLUE:
* Glycosaminoglycan (GAG) rich structures (found in all connective tissue and extracellular matrix)

  • Mucous goblet cells
  • Mast cell granules
  • Cartilage matrix
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75
Q

What does iron haematoxylin stain?

A

Stains nuclei and elastic fibres black

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76
Q

What does Periodic Acid Schiff (PAS) stain?

A

Stains Hexose sugars (esp. those in complex carb containing structures including goblet cell mucins, cartilage matrix, glycogen, basement membranes and glycocalyx- MAGENTA (DARK PINK)

Useful to detect goblet cells in SI, or GAG in intestinal brush border

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77
Q

What does Toluidine blue stain?

A
  • Stains nuclei, ribosomes, cytoplasm- DARK BLUE
  • Cartilage matrix, mast cell granules- PALE BLUE
  • GAG rich components- BRIGHT PURPLE
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78
Q

Which size cells are more active and why?

A
  • Small cells tend to be more dormant

* Larger cells are active due to mitosis and abundance of organelles

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79
Q

Cell ultra structure of the NUCLEUS

A
  • Brain of cell
  • Double nuclear membrane
  • Houses DNA 95% (in form of chromatin) within the nucleolus (site of ribosomal RNA formation. e.g. DNA transcription. Bigger it is, more metabolically active the cell)
  • Euchromatin- lighter areas due to different densities, decondenses sometimes (DNA needs to decondense in order to transcribe)
  • Heterochromatin- Darker, permanently condensed
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80
Q

Cell ultra structure of MITOCHONDRIA

A
  • Site of oxidative phosphorylation
  • Double membrane, inner membrane is highly folded (cristae)
  • Outer membrane: lipid synthesis and FA metabolism
  • Inner membrane: Resp. chain (ETC), ATP production
  • Matrix: Tricarboxlic acid (Krebs’) cycle- Cells arranged in clusters, some singletons. Chondrocytes continue to divide after solid matrix begins to form, thickened matrix restricts migration of daughter cells, so they stay in clusters
  • Intramembranous space: Nucleotide phosphorylation (ADP to ATP)
  • Contains 5% of DNA (maternal)- likely were initially bacteria that fomred symbiotic relationships with animals
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81
Q

Cell ultra structure of ROUGH ENDOPLASMIC RETICULUM

A
  • Site of protein synthesis

* Highly folded flattened membrane sheets

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82
Q

Cell ultra structure of SMOOTH ENDOPLASMIC RETICULUM

A
  • Site of membrane lipid synthesis
  • Processes and stores synthesised proteins
  • Highly folded flattened membrane sheets without ribosomes
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83
Q

Cell ultra structure of GOLGI APPARATUS

A
  • Parallel stacks of membrane - processes and modifies macromolecules synthesised in the endoplasmic reticulum
  • Cis (first) golgi (nuclear facing - near nucleus) - receives SMOOTH ENDOPLASMIC RETICULUM vesicles, protein phosphorylation occurs here
  • Medial golgi (in the middle, central part) - modifies products by adding sugars - forms complex oligosaccharides by adding sugars to lipids and peptides
  • Trans golgi network (last, this transfers) - proteolysis of peptides into active forms and sorting of molecules into vesicles which bud from the surface
  • Located close to the nucleus of the cell
  • In most cells the golgi apparatus cannot be seen, HOWEVER it can be seen clearly in plasma cells [exam question??] - seen as perinuclear hoff (lighter area) in a plasma cell
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84
Q

What are VESICLES?

A

Very small, spherical membrane-bound organelles which transport & store material and exchange cell membrane between compartments

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85
Q

There are many types of VESICLES, name some?

A

Cell-surface derived (pinocytotic and phagocytotic vesicles)

Golgi- derived transport vesicles

ER - derived transport vesicles

Lysosomes

Peroxisomes

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86
Q

What are LYSOSOMES?

A

Site of breakdown for most molecules

Contain digestive enzymes

Derived from Golgi

H+- ATPase on membrane, pumps H+ ions into cell, creating low PH to enable acid hydrolases to function

Breakdown debris from dead cells and bacteria and damaged cell organelles

Formed when two vesicles fuse:

  • Hydrolase contains enzymes that degrade proteins at low PH
  • Endosomes which has hydrogen atpase on membrane which pumps H+ into lysosomes to lower PH
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87
Q

What are Peroxisomes?

A

Small membrane bound organelles containing enzymes which oxidase long chain Fatty acids

Such as Long chain FAD-amino oxidase, catalase, urate oxidase-

The above are involved in process by which FA are broken down into two- carbon fragment which the cell can use as a source for generating ATP (BETA OXIDATION)

Also produce Hydrogen peroxide as byproduct of the breakdown of FA which can be used to destroy pathogens etc… (as its toxic to cells, but also peroxisomes can destroy H2O2 thus protecting body)

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88
Q

What is CYTOSKELETON and are they visible in light microscopy?

A

Filamentous proteins which brace the internal structure of the cell

Helps maintain their shape and internal organisation

They’re not visible in light microscopy

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89
Q

What is Microfilament made of and where is it?

A

Smallest diameter
Made of Actin (Present in cells as globular Gprotein that polymerises into filamentous F actin) forming a bracing mesh (cell cortex) on inner surface of cell membrane to maintain cell shape

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90
Q

What do intermediate filaments do?

A

Anchored transmembrane proteins which can spread tensile force through tissues

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91
Q

What are the 6 types of Intermediate filaments (10nm diameter) and where are they found?

A

Cytokeratin- epithelial cells

Desmin- myocytes

Glial fibrillary acidic protein (supports neurones in the brain)- astrocytic glial cells

Neurofilament protein- neurones

Nuclear laminin- Nuclei of all cells

Vimentin- mesodermal cells

They have a diagnostic utility in immunohistochemistry. Stains can show diff types of filaments, diff cells have diff types of filament

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92
Q

What are microtubules?

A

Tubulin (alpha and beta) arranged in groups of 13 to form hollow tubes

Arise from centrosome (comprises of 2 centrioles)

Found in all cells except erythrocytes (they have no nucleus, so microtubules not needed for cell division)

Act as scaffold for when cells divide

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93
Q

What is Lipofuscin?

A

Membrane-bound orange-brown pigment

Peroxidations of lipids (degradation of lipids) in older cells

Common in heart and liver, found in older people - sign of wear and tear

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94
Q

What is Lipid?

A

Non-membrane-bound vacuoles

Appears as empty space in histology since dissolved in processing

Stored in adipocytes and liver

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95
Q

What is Glycogen?

A

CHO polymer in cytoplasm

Normally seen on electron microscopy

May accumulate in some cells and in some diseases

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96
Q

What is G-banding?

A

Technique used to stain chromosomes using Giemsa, to show visible patterned banding on karyotype.

Helps to identify specific chromosomes

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97
Q

Why do cells in the liver stay in G0?

What other cells also do this?

A

They don’t grow, unless damaged (then they enter the cell cycle)

Myocytes and brain cells (so with age functions less well)

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98
Q

How can you tell the difference between benign and malignant tumours in histology?

A

Benign= too many cells, abnormal growth

Malignant= more mitotic figures at all levels

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99
Q

How to treat cancer with mitosis?

A

Using chemotherapeutic agents to block mitosis at different stages

E.g. 
Mitotic spindle (scaffold)= Taxol

Spindle poles (destroy)= Ispinesib

Anaphase (block)= Colchicine= like drugs

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100
Q

Three ways to prepare tissues?

A

Thin slices
Smear
Thick slices

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101
Q

How do you prepare a tissue into thin slice?

A

Preserve it by fixing in formalin (aq sol. of gas formaldehyde)- PREVENTS ROTTING

Embed sample in paraffin- EXTRACTS WATER AND OTHER SUBSTANCES

Very fine slices (4 microns thick) are made, mounted and stained

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102
Q

Why can thin tissue slices be problematic?

A

Can be difficult to imagine the 3D of a cell, because a slice can be thinner than a cell

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103
Q

Why are some tissues prepared as smears?

A

To see whole cells such as blood/ other fluids/ solid tissues

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104
Q

How do you prepare bone for looking under a microscope?

A

Too hard to be a smear or slice

Sample is demineralised to produce thin sections

Or mineralised sections grind down to produce a thick slice.

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105
Q

What does Val Gieson stain?

A

Stains elastic tissue with wavy brown detail

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106
Q

What does Trichrome stain?

A

Consists of 3 types of cell

Stains a variety of different tissues different colours in the same section

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107
Q

Give an example of a small cell and a large cell?

A

Small= lymphocytes (10um DIAMETER)- nucleus, very little cytoplasm, enclosed by cell membrane. They circulate in the blood and are found in large numbers in organs such as in lymph nodes, the tonsils and the thymus gland. Many tissues also have lymph nodules full of lymphocytes within their fabric.

Large= Motor neurons (70-100 um DIAMETER)= axons up to 1 metre

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108
Q

Name the shapes of cells?

A

Rounded- e.g. biconcave discs

Polygonal- Irregular shaped cells

Fusiform- Elliptical shaped

Squamous- E.g. Fibroblasts Flattened, appear to have thin plates, cells towards centre of cell of polygonal and mature into squamous cells

Cuboidal- E.g. Thyroid, roughly square

Columnar- E.g. cells lining gallbladder, more rectangular

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109
Q

If a cell is metabolically active, what is its cell size and content like?

A

Dormant cells are generally smaller, as they don’t need to maintain an elaborate cellular mechanical machinery.

When challenged, they differentiate further increasing the amount of cytoplasm and become more metabolically active.

Metabolically active cells often have a nucleoli, and have an abundance of cellular organelles so are larger

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110
Q 
Give examples of things in the body with these lifespans:
Days-
Months-
Years-
Nearly whole life-
Whole life-
A

Days- Lining of the SI (gut) (4-5 days)

Months- Lots of tissues- blood (120 days), skin, connective tissue

Years- Bones and tendons

Nearly whole life- (limited regeneration) skeletal muscle

Whole life- Nerves and brain, cardiac muscle, stem cells and germ cells (almost no capacity to regenerate)

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111
Q

What is there between cells?

A

Interstitial fluid:

  • Water
  • Salts in solution
  • Peptides and proteins (e.g. plasma proteins, hormones etc.)

Extracellular material:

  • Fibrillar proteins- e.g. collagen, elastin, or tendons
  • GAG jelly
  • Inorganic salts as solids (e.g. calcium in bone)
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112
Q

What colour do nerve cells stain with a silver stain?

A

Brown

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113
Q

What are the basic molecular building blocks?

A

CHONSP

Carbon
Hydrogen
Oxygen
Nitrogen
Sulfur 
Phosphate
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114
Q

Living organisms:

A
  • Made of one or more cells
  • Capable of reproduction
  • Responding to the environment
  • Adapting and changing
  • Requiring a source of energy
  • Growing and or developing
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115
Q

Difference between Atoms, Molecules and Macro molecules in chemistry

A

Atoms are the simplest levels

Two or more atoms make a molecule

Macro molecules are large, biologically important molecules inside cells

Organelles are aggregates of macro molecules used to carry out a specific function in the cell

ORGANELLES, CELLS, TISSUES, ORGANS, ORGAN, ORGAN SYSTEM AND ORGANISM

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116
Q

What are Macromolecules?

A

Simple molecules such as sugars, lipids and amino acids, can form complex large molecules

They have osmotic, structural, optical, enzymatic and other complex functions

Examples include: Haemoglobin, DNA, glycogen, rhodopsin and collagen

Structures of macromolecules are very heterogenous

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117
Q

Molecules to macromolecule examples

A

Monosaccharide to Polysaccharide with glycosidic bond

Nucleotide to Nucleic acid with phosphodiester bond

Amino acid to Protein with peptide bond

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118
Q

Describe carbohydrates:

General formula, examples of types of carbohydrates

A

General formula: Cn(H20)n

E.g. monosaccharides, disaccharides, oligosaccharides, polysaccharides

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119
Q

Glucose + galactose =
Glucose + fructose =
Glucose + glucose =

A

Lactose
Sucrose
Maltose

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120
Q

Monosaccharides

A

Chain of carbons, hydroxyl groups and one carbonyl group

An aldose has an aldehyde

A ketose has a ketone group

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121
Q

What is a chiral carbon (D&L monosaccharides) ?

A

Carbon with 4 different groups attached

D & L monosaccharides have the same chemical properties but different biological ones (isomers)

There will be Two optically active and different forms

Most sugars living in organisms are D, when not indicated its the D form

Under polarised light- D shifts it right, L shifts it left

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122
Q

Cyclized (ring) structures:

A

By the reaction of the aldehyde or ketone groups with a hydroxyl group of the same molecule, monosaccharides generally exist as ring structures.

There are chair forms, zig-zag. Don’t lie on same plane

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123
Q

What is a glycosidic bond and give the types what is alpha and beta ?

A

The hydroxyl group of a monosaccharide can react with an OH or an NH group to form a glycosidic bond.

O- glycosidic bonds- (oxygen i.e. hydroxyl) form disaccharides, oligosaccharides and polysaccharides

N- glycosidic bonds- (nitrogen i.e. amine (NH) are found in nucleotides and DNA

Alpha- hydroxyl groups on the same side

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124
Q

Sugar derivatives?

A

Aminosugars: containing an amino (NH2) group. Often acetylated. e.g. Glucosamine

Alchohol- sugars. e.g. Sorbitol

Phosphorylated: containing Phosphate groups, e.g. G6P

Sulfated: Sulfate groups, e.g. Heparin chondroitin sulphate

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125
Q

Oligosaccharides

A

Disaccharides contain 2 monosaccharides (MS) joined by an O-glycosidic bond.

Oligosaccharides contain 3-12 MS.

Oligosaccharides are the product of digestion of polysaccharides, or part of complex protein/lipids

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126
Q

Polysaccharides-1

A

Formed by thousands of MS joined by glycosidic bonds e.g. Starch - storage in plants, made of amylose (glucose alpha 1,4) and amylopectin (glucose alpha 1,4 and alpha 1,6 glycosidic bonds)

Proteoglycans

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127
Q

Proteoglycans?

A

Long, unbranched polysaccharides radiating from a core protein [found in animals]

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128
Q

Polysaccharides- 2

A

GLYCOGEN - storage in animals, is a branched polysaccharide formed of glucose residues.

Linkage is both alpha 1,4 (between carbons) and alpha 1,6 (between side chain and main chain) - branching is at regular intervals.

Core protein is glycogenic, amino linked to the only reducing end of the inner chain

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129
Q

Lipids: Fatty acids

A

Triglyceride= 3 FA bound to glycerol

Straight carbon chains (mostly 16-20) with a methyl group (CH3) and a carboxyl gorup (C=OOH) at the ends.

Melting point decreases with the degree of unsaturation (fluidity).

Some of the C-C bonds can be unsaturated (i.e. have double bonds) tend to be hydrophobic and contain no oxygen in main chain.

In unsaturated FA, double bonds are commonly cis and spaced at 3C intervals

Many natural sources and many functions. Such as cooking oils

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130
Q

Steroids

A

Cholesterol is a naturally occurring fat

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131
Q

Eicosanoids

A

Derivatives of Arachidonic acid.

Synthesised from 20 C atoms

Major biological functions,metabolised to form prostaglandin, thromboxane etc…

Cell signalling molecules

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132
Q

What are nucleotides?

A

Building blocks of DNA,

Made from Nitrogenous base, sugar and phosphate
In DNA=
* Adenine- thymine (2 CARBON NITROGEN RINGS=Purines),
* Cytosine- guanine (1 CARBON NITROGEN RING=Pyrimidines)
* Deoxyribose sugar

In RNA=

  • A-U
  • C-G
  • Ribose sugar
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133
Q

What are the bonds in a DNA/RNA?

A

Between bases= hydrogen bonds

Between phosphate and sugar are phosphodiester bonds

Phosphate bonds in nucleotides are a source of energy

Nucleotide has N-glycosidic bond between base and sugar, and Ester bond between Phosphate ester and sugar

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134
Q

Amino acids

A

Building blocks of proteins- 20 in total

Carbon with amino group, carboxyl group and side chain

Charge is determined by all three components. charge changes somewhat with the PH of the solution

Side chain often determines polarity (hydrophillic) non polarity (hydrophobic) of the amino acid

E.g glutamic acid- net negative charge since two carbon groups, 1 amino group

Carboxyl groups= negative

Amino group= positive

Most natural amino acids are in the L form, in contrast to that of sugar whose natural form is D

At different PH carboxyl and amino groups are ionised (charged). Some amino acids also have ionisable side chains (can associate and dissassociate)

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135
Q

Peptide bonds

A

Formed by condensation reaction (water released) between carboxyl group and amino group

Amino group first then carboxyl group at the end

Protein are formed by linked amino acids which are bonded together by peptide bonds

These linear chain fold in different shapes to form 3D structures

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136
Q

What is folding of a protein and its identity determined by?

A

Charged interactions, flexibility and physical dimensions

Sequence of amino acids, also determines folding and structure

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137
Q

Properties of peptide bonds

A

Very stable
cleaved by proteolytic enzymes

Cleaved (broken down bye) by proteolytic enzymes or extreme temperatures- Proteases or peptidases

Can have partial double bonds

Flexibility around C atoms not involved in bond thus allows multiple conformations

There is usually one preferred confirmation (i.e. R1 AND R2 (residual group) on the same side of chain or on different side) determined mainly by the type of side chain and their sequence in the polypeptide

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138
Q

Protein structure and function

A

Large polypeptide usually formed from 10s to 1000s of amino acids

Functions is totally dependent on structure (huge variety of functions arise from huge number of different shapes)

Function is dependent on structure

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139
Q

Protein vs peptide

A

Protein= functional and synthesised by a cell (50= AA)

Peptide= Bit of protein broken off (less than 50 AA long)

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140
Q

Primary structure of a protein?

A

Linear sequence of amino acids, held together by covalent bonds

Sequence of AA in protein determine where bonds will form thus structure and thus function

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141
Q

Secondary structure of a protein?

A

Formation of either alpha helix (H-bonds between each carbonyl group and the H attached to the N which which is 4 AA along the chain. Side chains look outwards. Proline breaks the helix (ring + no H)

Or beta pleated sheets (formed by H bonds between linear regions of polypeptide chains, chains from 2 proteins or same protein, if the chain is folding back, structure is usually a 4 AA turn, called a hairpin loop or beta turn due to hydrogen between amino acids- determined by a local interactions between the side chains and sequence of AA

Super- secondary structures: Combination of secondary structures. Structures and functional units of folded proteins often consists of combinations of alpha and beta structures=
Helix-turn-helix
B a B unit
Leucine zipper
zinc finger
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142
Q

Tertiary structure of Protein

A

Overall 3D confirmation of a protein
Bonding involved is electrostatic, H bonds and covalent bonds. Folding of the secondary structure into a globular structure due to bonds such as ionic bonds, disulphide bridges and Van der Waal forces. Confirmation can change with temperature or pH.

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143
Q

Quaternary structure of proteins

A

3D structure of protein composed of multiple subunits. Same non- covalent interactions as tertiary structures. 2 or more tertiary structures joined together to form a protein e.g. haemoglobin

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144
Q

Forces that hold proteins together

A

Van der waals

Hydrogen bonds

Hydrophobic forces

Ionic bonds

Disulphide bonds

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145
Q

Van der waals

A

Weak/attractive force between all atoms due to fluctuating electrical charge- only important when 2 macromolecular surfaces fit closely in shape. Can also be repulsive at very short distance

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146
Q

Hydrogen bonding

A

Weak interaction between polar bonds (dipoles). IMPORTANT IN AMINO ACID SIDE CHAINS, oxygen and nitrogen in main chain and water

Partial negative charges on negative atoms, O and N.
Partial positive charge on H

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147
Q

Hydrophobic forces

A

As uncharged and non-polar side chain are repelled by water, these hydrophobic side chains tend to form tightly packed cores in the interior of proteins, excluding water molecules.

This attraction is the ‘hydrophobic force’

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148
Q

Ionic bonds

A

Between fully partiallly charged groups. Weakened in aqueous systems by shielding by water molecules and other ions in solution

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149
Q

Disulphide bonds

A

Very strong covalent bonds between sulphur atoms

Lots of Cysteine= stronger stability, cell surface receptors, antibody

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150
Q

Factors affecting rate of reaction

A 
Temperature
PH
Conc. of reactants
Catalyst
Surface area of a solid reactant 
Pressure of gaseous reactants or products
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151
Q

Enzymes

A

Powerful biological catalyst

Enzymes bind the reactants (substrates) and convert them to products. Then they release the products and return to their original form

Not only they speed-up the reactions, but provide a way to regulate the rate of reactions

Can be used for diagnostic purposes because since they control metabolism they can be used as disease markers e.g. when released in bloodstream, when they should be present. A lot of drugs work by inhibiting the actions of enzymes

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152
Q

Regulation of enzymes

A

Enzymes can be regulated by altering the concentration of substrates, products, inhibitors or activators, they can also be regulated by modifying the enzyme itself by phosphorylation.

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153
Q

Isoenzyme

A

Enzyme that have a different structure and sequence but catalyse the same reaction

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154
Q

Why are enzymes only effective in a narrow range of temperatures?

A

As T increases, the stability of the enzyme structure decreases- bonds weaken, eventually leading to denaturation and thus lower reaction speed

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155
Q

Coenzymes

A

They cannot in them self catalyse a reaction but can help enzymes to do so. They can bind with the enzyme protein molecule to form the active enzyme

Complex organic structures which help to maximise the repertoire of enzymes functional groups, they can be metal ions (Fe 2+, Mg 2+, Zn 2+) or organic (usually derived from vitamins) or both (e.g. Fe 2+ and heme)

Activation-transfer coenzymes

Oxidation-reduction enzymes

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156
Q

Activation- transfer coenzymes

A

Form a covalent bond and are regenerated at the end of the reaction

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157
Q

Oxidation- reduction enzymes

A

Involved in reactions where electrons are transferred from one compound to the other. E.g. NAD + transfers electrons with hydrogen and is important in energy processes including the generation of ATP.

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158
Q

Haemoglobin and Myoglobin

A

Haemoglobin- found in red blood cells, oxygen carrier in blood
Myoglobin- found in muscle, serves as a reserve supply of oxygen and also facilitates the movement of O2 in muscles

Both Haemoglobin and myoglobin are structurally related proteins with some common elements- have the same tertiary structure

At the core of both molecules

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159
Q

What structure is at the core of both haemoglobin and myoglobin?

A

Porphyrin ring which holds an iron atom.
An iron containing porphyrin is termed a heme.

This iron atom is the site of oxygen binding- the name haemoglobin in the combination go heme and globin.

Thus haemoglobin can be regarded as an enzyme that binds and releases o2 thus Fe can be seen as a coenzyme since its the site of o2 binding (when o2 binds, haemoglobin molecule changes shape slightly)

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160
Q

Factors influencing haemoglobin saturation

A

Partial pressure of o2 in blood, as it increases so does haemoglobin saturation

Temperature, H+ and partial pressure of CO2 (PCO2)= all modify the structure of haemoglobin and alter its affinity for O2. Increase in these results in; haemoglobin decreased affinity for O2 and enhanced unloading of O2 from the blood. Decrease acts in opposite manner. All these parameters are high in peripheral capillaries where O2 unloading is the target

Sickle cell anaemia
Genetic disorder that is characterised by the formation of hard, sticky sickle shaped red blood cells

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161
Q

Immunoglobulins

A

Antibodies
Main function is to bind to antigens on toxins and proteins. these targets are consequently labelle dfor destruction by cells of the immune system by lysis or thorugh complement system
Many different types : IgG, IgM, IgA. Antibody- antigen binding is very specific- one antibody only matches one antigen

Antigens are bound by a portion of the antibody called the variable domain (THUS SPECIFICITY OF ANTIBODIES DETERMINED BY THE VARIABLE REGION). Amino acid in the variable domain can be varied to produce a potentially infinite variety of 3D shapes to recognise an infinite variety of foreign antigens

162
Q

Structure of antibodies

A

Disulphide bonds define loops characteristics of Ig
Light chains, heavy chains
Variable regions have light chains and heavy chains (Vl, Vh) and constant regions (Cl, Ch)

Specific antigen binding sites and bind to other antibodies

163
Q

What are prokaryotes?

A

Less compartmentalisation

No nuclear membrane

DNA arranged often in single chromosome

In E. Coli it is circular

164
Q

What are Eukaryotes?

A

More compartmentalisation

DNA is in the nucleus, bound to proteins (chromatin complex).

Different appearance according to functional moment e.g. looks large and dark in mitosis since chromatin condense into visual aggregates- CHROMOSOMES

Each chromosome is made of 2 identical strands of (chromatids) joined in teh centre (centromere). some DNA is found in mitochondria (purely maternal DNA)

165
Q

DNA in medicine

A

DNA in physiology: DNA, RNA, protein

DNA in pathology: Genetic disease, viruses, cancer

DNA in diagnostics: Mutation analysis, microbiology, forensic medicine

DNA in therapy: DNA as drug target, gene therapy, risk assessment

DNA in biotechnology: Production of biomedicines, delivery vectors, gene products

166
Q

Functions of DNA

A

DNA is a template and regulator for transcription and protein synthesis.

DNA is the genetic material thus the structural basic of hereditary and genetic diseases.

167
Q

Structure of nucleic acids

A

Nucleotides are the building blocks to make new DNA

Free phosphate groups provide energy for the reaction to go through

168
Q

DNA polymerase

A

DNA polymerase reads the template strands from 3’ to 5’ thus DNA is synthesised on the daughter strand from 5’ to 3’ since DNA runs antiparallel, the daughter strand is synthesised from 5’ to 3’ since phosphate at the 5’ is used by enzyme as a source of energy for reaction to occur (ACTIVATION ENERGY)- reason why DNA CAN ONLY BE SYNTHESISED FROM 5’ to 3’

From diagram , at one end of the molecule is an unreacted oxygen (3’) whereas at 5’ end there is a phosphate group thus DNA can only be synthesised from 5’ to 3’ since if it was 3’ to 5’ there would be no phosphate group available to provide the energy for the reaction to occur
Unreacted oxygen at 3’ thus DNA polymerase must start at 5’ with phosphate as energy source

DNA strands run antiparallel to each other i.e one runs 5’ to 3’ whereas the other runs 3’ to 5’

169
Q

Enzymes and proteins involved in DNA replication

A

Topoisomerase: Unwinds the double helix by relieving the supercoils

DNA helicase: Separates the DNA apart, by breaking hydrogen bonds between bases, exposing nucleotides

DNA polymerase: Reads 3’ to 5’ and synthesises DNA on daughter strand 5’ to 3’ - creates DNA by working in paris to make 2 new strands of DNA. Starts at a primer

Primer- short strand of DNA that is the start point for DNA synthesis as DNA polymerases can only add nucleotides on to an existing strand of DNA

Single strand binding protein (SSB) - keeps two strands of DNA apart whilst synthesis of new DNA occurs - prevents annealing to form double stranded DNA

Primase enzyme: RNA polymerase that synthesises the short RNA primers needed to start the strand replication process

RNAse H: removes the RNA primers that previously began the DNA strand synthesis

170
Q

Process of DNA replication

A
  1. Prior to cell division, topoisomerase unwinds DNA and DNA helicase separates DNA
    apart to expose two single DNA strands and create two replication forks. DNA replication takes place simultaneously at each fork.
  2. SSB’s (single-strand binding protein) coat the single DNA strands to prevent re-
    annealing or ‘snapping back together’.
  3. The primate enzyme then uses the original DNA sequence on the parent strand to synthesise a short RNA primer. Primers are necessary since DNA polymerase can only extend a nucleotide chain, not start one
  4. DNA polymerase begins to synthesise a new DNA (via complementary base pairing using free floating nucleotides) strand by extending an RNA primer in the 5’ to 3’ direction. Each parental strand is copied by one DNA polymerase.
  5. As replication proceeds,
    RNAse H recognises RNA primers bound to the DNA template and removes the primers by hydrolysing the RNA
  6. DNA polymerase can then
    fill the gap left by RNAse H
  7. DNA replication process
    completed when the ligase enzyme joins the short DNA pieces (Okazaki fragments) together into one continuous strand.
171
Q

What are the 3 types of RNA?

A

(Single stranded unlike DNA which is double stranded)
mRNA (messanger)
rRNA (ribosomal)
tRNA (transfer)

Unlike DNA, aren’t present in the cell at all times
Many mRNA species only accumulate following cell stimulation

172
Q

What do transcription factor do and what is a promoter region?

A

Proteins that bind to promoter regions find their way to specific sequences on the 5’ of the 1st exon (region called the promoter)

Promoter has a specific sequence of nucleotides- they do not code fro proteins but instead act as binding sites- found at the 5’ end

Transcription complex forms around the TATA box (reads thymine, adenine, thymine, adenine etc…) on the 5’ axon of the 1st exon

173
Q

DNA transcription process

A

Topoisomerase unwinds double helix, relieving the supercoils

DNA helicase then separates the DNA apart exposing nucleotides

SSB’s coat the single DNA strans to prevent DNA re-annealing

Free mRNA nucleotides line up next to their complementary bases on the template strand (U-T & C-G)

RNA polymerase (specifically RNA polymerase 2) joins the mRNA nucleotide (catalysing phosphodiester bonds between them to form an antiparallel mRNA strand (5’ CAP head and a 3’ Poly A tail starting at a promoter (specific sequence that RNA polymerase binds to- initiation of transcription. Transcription is stopped at the stop codon)

mRNA leaves the nucleus and attaches to an 80s ribosome

At ribosome the mRNA (bases on mRNA are read in 3- codon) sequence is used as a template to bind to complementary tRNA molecules at their anticodon (3 bases complementary to codon on mRNA). Ribosome reads mRNA codon by codon, one codon will code for a particular amino acid. This amino acid is brought by a specific tRNA molecule (carried on it 3’ end) since tRNA molecules are attached to specific amino acids. BASES ARE READ 5’ TO 3’

Enzymes remove amino acid from tRNA and amino acids are linked together by a peptide bond (created by a condensation reaction), creating a polypeptide chain - a protein

174
Q

Useful properties of DNA

A 
Heat denaturation (melting T) (outside DNA)
Alkali dissociation (outside of humans)
Hybridisation (the longer the strands become the easier it is to separate using enzyme Helicase)
175
Q

DNA replication

A

Prior to cell division DNA opens at the replication fork.

Base sequence on each parent strand is copied into a complementary daughter strand.

The two parental strands separate in front of the fork.

New DNA is made behind the fork, composed of a new and an old strand: replication is semi conservative.

Many proteins are involved in DNA replication, binding proteins and enzymes.

176
Q

Prokaryotes DNA replication

A

A binding protein (DNAa) starts the process at a single point of origin (oriC)

The parental strands separate, and form a bubble.

Both strands are copied simultaneously and in opposite direction. Sequences are proof-read.

Replication ends at a termination point. DNA is circularised by ligases.

Cell division

177
Q

DNA polymerase

A

DNA polymerase reads 3’ to 5’, prints 5’ to 3’

Substrates are deoxyribonucleotides triphosphates

Enzyme stays on the strand, at the same times extends and proof-reads

178
Q

How is DNA strand opened?

A

Helicase opens the strand
SSb protein keeps it open
Topoisomerase unwinds it (relieves supercoil)

179
Q

DNA POLYMERASE 5’ to 3’

A

One strand is done normally 5’ to 3’

The other strand is done using Okazaki fragments which are joined together by ligase

180
Q

Mutations of DNA

A

DNA damage: chemicals, UV, radiation, chance

DNA repair: base or nucleotide excision
mismatch repair
transcription-couple repair

181
Q

What is PCR?

A

DNA replication in test tube

Isolate DNA and use heat stable DNA polymerase with primers to amplify DNA

Using heating and cooling

182
Q

Messanger RNA

A

Printed as a long linear transcript

Processed to the mature form (in proximity of the nuclear membrane). It has a 5’ CAP and a 3’ Poly A tail

Ribosomes are abundant in eukaryotic cytoplasm, and four main types of rRNA combine with proteins to form 80s ribosomes

183
Q

rRNA?

A

Ribosomes print transcript mRNA with help from transfer RNA

184
Q

tRNA?

A

tRNA carry aminoacids to ribosomes, and check that they are incorporated in the right position.

Each tRNA only carries one aa &raquo_space;> at least 20 tRNA types

Very small molecules

At the anticodon, a triplet sequence pairs with mRNA &raquo_space;> right aa for the right triplet ( = CODON).

185
Q

Give examples of start codon and stop codons

A 
START= AUG
STOP= UGA, UAG, UAA
186
Q

The global picture of DNA transcription

A

Primary transcript, mRNA is made in the nucleus from DNA after signals that protein synthesis is needed

Leaves the nucleus via nuclear pore where it is edited to PolyA-RNA, mRNA

Ribosome (RER) recognises mRNA from its CAP on the 5’ end

Ribosome is responsible for translation VIA tRNA carry AA

Polypeptide is formed , edited in Goglgi apparatus to form final protein product

187
Q

Regions of the gene

A

Exons contain the coding sequence.

Introns are non coding

Promoter region is what RNA polymerise recognises and where it starts

mRNA primary transcript - mRNA strand is a complementary copy of original DNA

Primary > Mature - Non-coding (introns) are removed and exonic regions are joied

188
Q

What is exon shuffling?

A

Exon shuffling (where exons are not in the same order) allows new proteins to be made e.g. the immune system. Thus exon shuffling enable huge variants of antibodies etc… to be produced

189
Q

Genetic code?

A

Degenerate but ambiguous- Many AA specified by more than one codon, but each codon specifies only 1 AA

Almost universal- all organism uses same code- fewer that 10 exception

Non overlapping and without punctuation- codons don’t overlap. each nucleotide is only read once

190
Q

How does tRNA bind to a codon on the mRNA

A

tRNA contains an aminoacid

at its 3’ end corresponding to the codon on mRNA to which the anticodon of the tRNA can base pair.

191
Q

Factors initiating gene expression

A

Protein called ‘transcription factors’ find their way into specific sequences 5’ of the 1st exon (region called ‘promotor’)

A transcription complex forms around the TATA box 5’ of the 1st exon

Hellix opens, DNA strand separation
RNA pol 11 starts building mRNA
etc….

192
Q

Factors turning off expression

A

Activation of repressors (inhibitors of RNA polymerase binding)

Each step of RNA transcription or processing finds no longer actively produced transcription and processing proteins.

Complexes do not form anymore for lack of phosphorilation.

Enzymes no longer activated

RNA stability

Many other unknown mechanisms

193
Q

Silencing genes?

A

DNA can be chemically altered to the methylated form i.e turned on or off (silenced)

In a macrophage, where immunoglobulins are not produced, but still has normal DNA, the gene for producing immunoglobulins will be in the heterochromatin (can remember as h = hiding i.e. not active) state - since its not needed to be synthesised thus in the heterochromatin state no transcription of these gene can occur

Whereas in a B cell, that needs to produce immunoglobulins, that gene will be in the euchromatin state - so it can be transcripted and thus immunoglobulins (proteins) can be synthesised z

194
Q

Types of DNA mutation

A

Duplications of genes or part of a gene (of a single base or whole gene)

Deletions (whole gene or some exons)- Inframe, or out of frame

Mutations of regulatory sequence (coding sequence still intact, but gene itself is switched on or off etc…)

DNA damage: from chemicals, UV, and radiation

DNA repair issues: Base nucleotide excision, mismatch repair or transcription- coupled repair

Mis-sense mutation

Non- sense mutation

Splice site mutation

Expansion of a Tri-nucleotide repeat

195
Q

What is an inframe deletion?

A

Can be an in frame deletion- whereby a complete codon is removed thus only 1 AA is lost. This is less catastrophic. Known as in frame deletion since the reading frame is not altered. Results is a milder disease- later onset death typical

196
Q

What is an out of frame deletion?

A

Can be out of frame deletion which clearly disrupts the protein e.g. deletion causing the absence of dystrophin in duchenne muscular dystrophy. If C is lost the sequence shifts to the right once, so the reading frame is changed. Can cause quite catastrophic effects- early mortality

197
Q

What is a misense mutation?

A

A point mutation in which a single nucleotide change results in a codon that codes for a different amino acid (substittion). This can have varied affect and can result in a silent mutation and a non functional protein. e.g. Sickle cell disease where CAG is replaced by CTG

May or may not be pathogenic could be a polymorphism or of no functional significance

198
Q

What is a non sense mutation?

A

Point mutation that produces a stop codon - results in an incomplete, usually non-functional protein. E.g. Duchenne’s muscular dystrophy

199
Q

What is a splice site mutation?

A

Affects the accurate removal of an intron
Enzyme recognises CGAT as cutting site. A changes to C and then enzyme no longer recognises the sequence, so excision doesnt occur thus sequence of intron is translated and proteins are synthesised

200
Q

What is expansion of a tri nucleotide repeat?

A

Huntingtons disease= CAG
Triple repeat is repeated several times in the first part of the coding sequence.

The normal rnage of repeats is 15-20

If repeats are larger than 36, the patient will develop Huntington’s. If repeats is larger, onset will be earlier. If repeats is less that 36, then no disease

201
Q

What is anticipitaion in diseases?

A

In diseases such as Huntington’s, repeats get bigger when they are
transmitted to the next generation resulting in earlier symptoms of greater severity - this process is called anticipation

202
Q

What is the aim of PCR?

A 
Polymerase chain reaction 
To synthesise fragments of DNA
Its the basis for forensic testing
Uses primers: short synthetic pieces of DNA that have complementary bases to DNA you are trying to synthesise/amplify
One cycle takes 5-20 mins
203
Q

What is loss of function variants?

A

Only one allele functioning. Most loss of function variants are recessive.

If a pathway is very sensitive to the amount of gene product so that if only half is produced it cannot function this will cause a problem.

Haplo-insufficiency

204
Q

What is Gain of function variants?

A

Increased gene dosage e.g. PMP22 duplication on 1 allele in hereditary motor and sensory neuropathy type 1A

Increased protein activity e.g. a variant may occur at the recognition site for protein degradation leading to an accumulation of undegraded protein within the cell

205
Q

What is dominant-negative variants?

A

Where the protein from the variant allele interferes with the protein from the normal allele.

E.g. a dimer where one variant and one normal allele would result in only 25% normal dimers

206
Q

What is diagnostic testing?

A

Patient has signs and symptoms suggesting a particular diagnosis

A molecular genetic test will confirm a diagnosis

In this context a genetic test is being used to confirm a clinical diagnosis

Issues informed consent

207
Q

What is predictive testing?

A

Testing health at-risk family members for a previously identified familial variant – often dominant

HD No intervention

BRCA1/2 some intervention

208
Q

What is carrier testing?

A

Autosomal recessive and X-linked disorder

Testing an individual in isolation not particularly helpful – couple testing

Reproductive decision making

209
Q

What is prenatal testing?

A

Genetic test performed in pregnancy where there is a increased risk of a specific condition affecting the fetus

Chorionic villous sample or amniocentesis

Often chromosomal or DNA if specific variant in the family has been identified

Counselling issues

210
Q

What is preimplantation genetic diagnosis?

A

8 cell embryo

Under gentle suction pipette removes one cell

Single cell free for analysis

211
Q

What is genetic screening?

A

Target population, not high risk families

E.g. Newborn screening for Cystic fibrosis

It may be the same test but the context is different

212
Q

What is susceptibility testing?

A

Increased or decreased risk for a multifactorial condition

This issue is only just emerging

213
Q

Types of genetic tests?

A

Testing for genetic conditions – offered in Clinical Genetics

  • Diagnostic
  • Carrier
  • Predictive
  • Prenatal tests incl. NIPT

Testing to clarify familial relationships – usually done in private sector or a forensic laboratory
* Paternity testing

Genetic testing to determine identity – usually done in a forensic laboratory
* Genetic finger printing

214
Q

What is FISH?

A

Fluorescence in situ hybridisation

DNA probes labelled with fluorophores

They are hybridised directly to the chromosome preparation or interphase nuclei

You can count the chromosomes in interphase, look for submicroscopic deletions using locus specific probes, interpret abnormalities more clearly, we can look for specific rearrangements such as gene fusions etc, in acquired abnormalities

FISH is routine and can provide quick results without the need to look at chromosomes or provides more “detailed” information.

215
Q

What is cytogenetics? (constitutional, acquired)

A

Used to look at chromosomes both constitutionally and as acquired changes.

Confirm malignancy, classification of a disease type, prognosis, monitoring

Constitutional changes occur at gametogenesis, affects all cells of body and are heritable. These changes are associated with abnormal mental and physical abnormality in the patient.

Acquired changes occur during lifetime, restricted to malignant tissue, not heritable.

216
Q

What is fusion gene and deregulation gene?

A

Breakpoints occur in two genes and fuse to form hybrid gene

Translocation gene

217
Q

What is microarray?

A

New technology that improves the resolution for detecting cytogenic abnormalities

218
Q

During Mitosis, Chromosomes attach themselves to microtubules that propagate from chromosomes. What are these microtubules made of?

  • Actin
  • Cytokeratin
  • Desmin
  • Tubulin
  • Vimentin
A

Tubulin

Microtubules are tubular polymers of alpha- and beta-tubulin and have a diameter of 25nm.
Actin is a microfilament, 5nm in diameter
Cytokeratin, desmin and vimentin are all intermediate filaments

219
Q

Examining a histological section, a pathologist sees a cell undergoing mitosis. The chromosomes are moving towards opposite poles of the cell and there are no nuclear membranes. Which phase of mitosis is this?

  • Anaphase
  • Metaphase
  • Pro-metaphase
  • Prophase
  • Telophase
A

Anaphase

This is a description of anaphase, during which the chromosomes are pushed to either pole of the cell.
The nuclear membrane forms around the nuclear material in telophase.

220
Q

The morphology of epithelial cells varies according to their function. Which of the following structures is lined by a stratified squamous epithelium?

  • Trachea
  • Duodenum
  • Pleural cavity
  • Ureter
  • Vagina
A

Vagina

The skin (keratinised), oral cavity, tongue, oesophagus and vagina (non-keratinised) are all lined by stratified squamous epithelium.
The trachea is lined by a pseudostratified columnar epithelium (respiratory epithelium)
The duodenum is lined by a simple columnar epithelium.
The pleural cavity is lined by a simple squamous epithelium (mesothelium).
The ureter is lined by a complex epithelial type known as urothelium.
221
Q

Some epithelial cells bear cilia on their luminal surface. Which of the following is lined by a ciliated epithelium?

  • Bronchus
  • Gallbladder
  • Jejunum
  • Renal tubule
  • Urethra
A

Bronchus

Cilia are microscopic motile projections on the luminal surface of some epithelial cells. They function to move material across the surface of the epithelium. Cilia are found on the epithelial cells lining the fallopian tubes and conducting airways.
Do not confuse them with microvilli, which are present on cells lining the gut. Microvilli serve to increase surface area for absorption.
Renal tubules are lined by non-ciliated cuboidal cells.
The urethra is lined by non-ciliated urothelium.

222
Q

Simple molecules can join together to form macromolecules. Which of the following is a macromolecule?

  • Adenine
  • Adenosine triphosphate
  • Glyceraldehyde
  • Glycogen
  • Lysine
A

Glycogen

Simple molecules such as sugars, amino acids and nucleotides can join together to form large complex macromolecules.
Examples of macromolecules include DNA, glycogen, haemoglobin, rhodopsin and collagen.
Glyceraldehyde is a 3-carbon carbohydrate (that you will meet again in glycolysis)
Lysine is a positively-charged amino acid
Adenine is a nitrogenous base
Adenosine triphosphate is a nucleotide

223
Q

Amyloidosis is a condition in which proteins with secondary structure conformation are deposited in tissues. Which of the following is an example of a secondary protein structure?

  • Beta-alpha-beta unit
  • Beta-pleated sheet
  • Helix-turn-helix
  • Linear chain
  • Zinc finger
A

Beta pleated sheet

In amyloidosis, proteins are deposited in tissues in a beta-pleated sheet conformation. This is an example of a secondary protein structure (the alpha helix is the other.)
The linear chain is a protein’s primary structure.
Beta-alpha-beta units, helix-turn-helix conformation and zinc fingers are all supersecondary protein structures.

224
Q

The two helices in deoxyribonucleic acid (DNA) are held together by hydrogen bonds that form between complimentary nitrogenous bases. Which of the following base pairings is correct in DNA?

  • Adenine : Adenine
  • Adenine : Cytosine
  • Adenine : Guanine
  • Adenine : Thymine
  • Adenine : Uracil
A

Adenine: Thymine

In DNA, Adenine always pairs with thymine and guanine always pairs with cytosine.
Adenine does not pair with itself!
The distractor was option E – adenine DOES pair with uracil, but in RNA, not DNA! (There is no uracil in DNA.)

225
Q

Some inherited diseases, such as hypertrophic cardiomyopathy can be caused by mutations in different genes. The correct term for this is:

  • Allelic heterogeneity
  • Allelic homogeneity
  • Allelic polymorphism
  • Locus heterogeneity
  • Mutational heterogeneity
A

Locus heterogenity

An allele is one of a number of alternative forms of the same gene found at the same genetic locus.
Hypertrophic cardiomyopathy is an example of a disease with locus heterogeneity – mutations in different genes give the same clinical condition.
Allelic heterogeneity (also known as mutational heterogeneity) is when lots of different mutations in one gene cause a condition (such as cystic fibrosis).
Allelic homogeneity is when all individuals with a disease have the same mutation (e.g. Huntingtons).
Allelic polymorphism is when more than one allele can be found for a given gene within the normal population.
Expansion of tri-nucleotide repeats is found in conditions such as Huntingtons, Myotonic dystrophy and Fragile X syndrome.

226
Q

Which inheritance is this?
Disease is present in several generations

Transmitted by men to men and women

Huntingtons disease

A

Autosomal dominant

227
Q

Which of the following most accurately describes an individual with the karyotype: “45,X”

  • Normal female
  • Normal male
  • Female with Down syndrome
  • Female with Edwards syndrome
  • Female with Turner syndrome
A

Females with Turner syndrome

The normal karyotype is 46, XX for females and 46, XY for males.
The karyotype 45, X denotes a female lacking one of the two X chromosomes. This is Turner syndrome.
A female with Down syndrome would have the karyotype 47, XX, +21 (as Down syndrome is due to trisomy 21)
A female with Edwards syndrome would have the karyotype 47, XX, +18 (as this is due to trisomy 18).

228
Q

What inheritance is this?
Mutation inherited from an affected father to daughters (who are carriers)

One daughter transmits the mutation to a son (who is affected) and a daughter (who is a carrier)

A

X linked inheritance

Recessive mutation
Female carriers
Males with one copy of the gene are affected

229
Q

Which of the following statements concerning autosomal recessive inheritance is true?

  • They affect heterozygotes
  • They affect males and females in equal proportions
  • They are less common following consanguinuity
  • They only affect White families
  • They typically affect individuals in multiple generations
A

They affect males and females in equal proportions

Autosomal recessive diseases occur with equal frequency in males and females. (Unlike X-linked which are more common in males)
Homozygotes have the disease, while heterozygotes are asymptomatic carriers of the mutation. (Unlike dominant diseases, which occur in homozygotes and heterozygotes)
Consanguinuity (reproductive union between related individuals) increases the risk that offspring will have an autosomal recessive disease.
However, autosomal recessive diseases can manifest in any family (irrespective of race).
Typically, when the pedigree is constructed, the disease has manifested in only one generation of the family.

230
Q

How do you identify that a condition has a genetic component?

A

By clinical observations:
Family studies- In a multifactorial condition, risk of condition in relatives of an affected individual is dramatically higher than in the general population. Risk varies with degree of genetic relationship, risk varies with severity and number of relatives affected.
Twin studies- compare Genetically identical and non identical twins. Higher risk in genetically identical twins
Adoption studies- Adopted children of a parent with a multifactorial condition have high risk of developing the disease. Low risk of adoptees and normal biological parents. Higher in biological families

231
Q

What is homeostasis?

A

Maintenance of constant internal environment
Property of a system in which variable are regulated so that internal conditions remain stable and relatively constant

E.g. Temperature, Blood pressure, PH, glucose and oxygen concentration

Cells must communicate with each other to achieve homeostasis, major communication systems include: endocrine (hormones), nervous (currents and neurotransmitters) and immune (antibodies, cytokines and interleukin_

232
Q

What is autocrine communication?

A

Chemical is released from cell into the
extracellular fluid and then acts upon the very cell that secreted it

Cell talking to themselves

233
Q

What is paracrine communication?

A

Chemical messengers involved in the
communication between cells, released into extracellular fluid - travel short distances, local communication. E.g Acetylcholine at neuromuscular junction

Cell talking to neighbouring cells a short distance away

234
Q

What is endocrine communication and give examples of organs involved?

A

Secretion into blood

Produce and secrete hormones, communication between cells, travel much longer distance, systemic communication, can affect the whole body.

E.G. acetylcholine at neuromuscular junctions

235
Q

What is Exocrine communication?

A

Secretion into ducts then into organ

Cells talking to other cells elsewhere in body

236
Q

Key differences between endocrine and paracrine?

A

Hormones travel in blood in endocrine whereas in paracrine chemical messangers only travel in extracellular fluid.
Endocrine affects more things and travel further than paracrine

237
Q

What is a positive feedback loop?

A

Amplification of signal. E.g. clotting cascade & oxytocin
release during childbirth

238
Q

What is a negative feedback loop?

A

Centre of homeostasis, main way endocrine hormones are controlled. E.g. blood sugar regulation, temperature regulation, blood pressure regulation, thyroid regulation - thyroxin, as well as going to target cell, is also sensed by the pituitary, if there is too much thyroxine in the blood then the high thyroxine levels will stimulate the pituitary to stop producing thyroid stimulating hormone (TSH)

239
Q

Problems with feedback

A

Can get primary hypothyroidism: that is the thyroid is
producing too little thyroxine to induce negative feedback, meaning TSH levels in the blood keep increasing since pituitary doesn’t think there is enough thyroxine in the blood.

Can also get primary hyperthyroidism: whereby the thyroid produces too much thyroxine and keeps producing regardless of the presence of TSH produced by the pituitary, TSH levels fall but thyroxine levels rise.

Primary - means the problems is with the endocrine gland e.g. the thyroid.

Secondary - means the problem is with the pituitary or hypothalamus e.g secondary hypothyroidism - whereby both TSH and thyroxine levels are low (indicative of secondary hypothyroidism) since the pituitary is not producing enough TSH thus little thyroxine is produced meaning target cells are not being induced.

240
Q

Organs involved in Endocrine communication

A

Organs involved: Hypothalamus (hypothalamic hormones include dopamine)

Pituitary (anterior pituitary hormones and posterior pituitary hormones include oxytocin and ADH/ vasopressin)

Thyroid (front of neck),

Parathyroid (directly behind neck)

Adrenals (above kidneys)

Pancreas

Ovaries

Testes

241
Q

What are the 6 main Hypothalamic (releasing hormones) hormones?

A

Gonadotrophin-releasing hormone (GnRH)

Growth hormone-releasing hormone (GHRH)

Somatostatin (SS)

Thyrotropin-releasing hormone (TRH)

Corticotropin-releasing hormone (CRH)

Dopamine (DA)

242
Q

What are the 6 main Anterior pituitary (stimulating) hormones?

A
  • Folicle stimulating hormone (FSH)
  • Lutenising hormone (LH) (TWO ABOVE ARE GONADOTROPHIC HORMONES)
  • Growth hormone (GH)
  • Thyroid stimulating hormone (TSH)
  • Prolactin
  • Arendocorticotrophic hormone (ACTH)
243
Q

What are the two main posterior pituitary hormone?

A 
Oxytocin- released during child birth 
Antidiuretic hormone (also known as Vasopressin, ADH)- (in brain, master endocrine organs),
244
Q

What is a hormone?

A

Moleucle that act as a chemical messanger
Classifies according to structure: Peptide, amino acid derivatives (from tyrosine/tryptophan), Steroid (from cholesterol)

245
Q

Peptide hormones?

A

Made from short chain amino acids, vary in size from few amino acids to
small proteins, some have carbohydrate side chains (glycoproteins)

They are large, hydrophilic charged molecules that cannot diffuse across a membrane.

They bind to receptors on membranes.

Peptide hormone is pre-made and stored in cell, then released and dissolved into blood when needed. Binds to receptor on membrane then chemical reaction produces a quick response from the cell and a 2nd messenger is released in the cell - VERY FAST (minutes) (signal transduction cascade).

Examples; Insulin, growth hormone, thyroid stimulating hormone (TSH) and ADH/vasopressin

246
Q

Amino acid hormones?

A

Synthesised from tyrosine, acts in same way to peptide.

Examples;
adrenaline, thyroid hormones (thyroxine (T4) and triiodothyronine (T3))

247
Q

Steroid hormones?

A

Synthesised from cholesterol,water
insoluble & lipid soluble - can cross membranes BUT requires transport proteins in blood, targets an intracellular receptor.

Steroid hormone is made by cell and diffuses out once made (not stored), transported in blood bound to transport proteins as it cannot dissolve in water.

Binds to receptor inside cell. SLOW RESPONSE (hours/days) since it directly affects DNA.

Examples; Testosterone, oestrogen and cortisol (long term stress hormone)

248
Q

How much of total body water is ICF, ECF (intracascular and interstitial)?

A

Total body water= 60%, 42L

ICF= 40% of body weight, 28L

ECF= 20% of body weight, 14L

Intravascular= 3L

Interstitial= 11L

249
Q

What is Intracellular fluid predominant electrolyte?

A

Predominant electrolyte is potassium

250
Q

What is Extracellular fluid predominant electrolyte?

A

Predominant electrolytes are sodium (main contributor to ECF osmolarity and volume), chloride and bicarbonate (anions) and Ca2+ (especially in heart and muscle), protein= colloid osmotic pressure, glucose and urea especially in heart and muscle

251
Q

What is interstitial?

A

Surrounds the cells, but doesn’t circulate

252
Q

What is plasma?

A

Circulates as the extracellular component of blood

Change in plasma osmolality pulls or pushes water across cell membranes

253
Q

What is transcellular?

A

Makes up the CSF, digestive juices and mucus

254
Q

Fluid compartments in the body are in osmotic equilibrium, Water is freely permeable between ICF & ECF. What is the gradient determined by?

A

Osmotically active substances (solutes)= Potassium, sodium, chloride, glucose and urea

If there is any change in the solute continent of a compartment- there is a shift in water

Always equal= isotonic

Any change in solute content of a compartment= Shift in water

255
Q

Water intake?

A

Drink, diet, IV fluid

256
Q

Water loss?

A

Kidneys

Insensible losses: sweat, breath, vomiting & faeces

257
Q

Why don’t we give water intravenously?

A

It is hypo-osmolar/hypotonic vs cells

Water enters blood cells causing them to expand and burst: haemolysis

However, this only occurs in the vicinity of the intravenous cannula

If you could achieve instantaneous mixing it wouldn’t occur

258
Q

Water Homeostasis

ECF Osmolality

A

Tightly regulated

Changes in ECF osmolality lead to a rapid response

Water deprivation or loss will lead to a chain of events

Water deprivation/increased in solutes= Increased ECF osmolality :

  • Change detected by osmoreceptors in hypothalamus= Release of ADH from posterior pituitary- Renal water retention
  • Stimulation of thirst centre in hypothalamus- Increased water intake
  • Movement of water from ICF to ECF
259
Q

3 Regulating hormones?

A

ADH, Aldosterone, atrial natriuretic peptide

260
Q

Osmosis definition?

A

net movement of solvent molecules through a semipermeable membrane to a higher solute concentration (i.e. lower water conc.)

261
Q

Osmolality definition?

A

measure of the number of dissolved particles per kg of fluid

262
Q

Osmolarity definition?

A

measure of the number of dissolved particles per L of fluid

263
Q

Osmotic pressure definition?

A

pressure applied to a solution, by a pure solvent, required to prevent inward osmosis, through a semipermeable membrane

264
Q

Oncotic pressure definition?

A

form of osmotic pressure exerted by protein that tends to pull fluid into its solution - water moves from interstitial fluid into plasma

265
Q

Hydrostatic pressure definition?

A

Pressure difference between capillary blood(plasma) and interstitial fluid - water and solutes move from plasma into interstitial fluid

266
Q

How does ADH work?

A

Acts to increase water reabsorbtion in collecting ducts of the kideny in order to dilute the solute and return water in ECF to normal

267
Q

What happens when there is a decreased renal blood flow?

A

Decrease in water in ECF= decrease in effective circulating volume= decrease in renal blood flow

Results in release of renin from the juxtaglomerular kidney cells in the kidneys

Renin converts angiotensinogen to angiotensin 1, Angiotensin converting enzyme (ACE) then converts angiotensin 1 into 2 which in turn triggers the release of aldosterone from the adrenal cortex above the kidneys

Angiotensin 2 and aldosterone increase na + reabsorption in the kidenys in exchange for potassium or hydrogen secretion

Also stimulate ADH release

Sodium reabsorption brings water with it to return water in ECF to normal

Osmolality (sodium) is controlled by changing water, Water is controlled by changing osmolality (sodium)

268
Q

Causes of dehydration?

A

water deprivation, vomiting, diarrhoea, burns, heavy sweating, diabetes insipidus (literally pee bucket loads since too little ADH produced), diabetes mellitus & drugs

269
Q

Consequences of dehydration?

A

thirst, dry mouth, inelastic skin, sunken eyes, raised haematocrit (viscosity of blood), weight loss, confusion & hypotension

270
Q

Causes of water excess?

A

High intake/ decreased loss of water, excess ADH

271
Q

Consequences of water excess?

A

Hyponatraemia (low sodium levels), cerebral over- perfusion (due to high blood volume and thus pressure) - causes headaches, confusion & convulsions

272
Q

What is serous effusion?

A

Excess water in a body cavity

273
Q

What is Oedema and the types?

A

Excess water in the Intracellular tissue space or distruption of the filtration and osmotic forces of circulation fluids

  • Inflammatory (leakage)=proteins leak out due to increased vascular permeability - they bring in water, thereby diluting the toxins - fibrinogen polymerises to form a fibrin mesh and immunoglobulins collect
  • Venous (increased end pressure)- due to increased venous pressure or venous
    obstruction from a thrombus
  • Lymphatic (blocked)- Obstructions from a tumour/parasite
  • Hypolabuminaemic- Lower oncotic pressure
274
Q

What is transudate?

A

Fluid pushed through the capillary due to high pressure within the capillary
Low protein content

275
Q

What is exudate?

A

Fluid that leaks around the cells of the capillaries caused by inflammation &↑permeability of pleural capillaries to proteins.

High protein content

276
Q

What can cause volume overload?

A

ECF volume expansion (Heart, Kidney failure, Cirrhosis with ascites)

Loss of Intravascular fluid into interstitial space

Low effective circulating volume stimulates RAAS and ADH

Renal sodium retention, plus water retention

Oedema

277
Q

What is a pleural effusion?

A

10ml of fluid- Normal pleural space

Balance between hydrostatic and oncotic forces in the visceral and parietal pleural vessels and lymphatic drainage

PLEURAL EFFUSIONS= result from disruption of this balance

Diff. fluids can enter the pleural cavity.
Transudate, exudate

Pleural fluid protein is measured to differentiate between Transudate (Cirrhosis, Hypoalbimunaemia, Peritoneal dialysis) and Exudate (High protein levels compared to transudates, Malignancy, Pneumonia)

May also contain cells, bacteria and enzymes)

278
Q

What is Hypernatraemia?

A

High sodium.

Causes: renal failure, mineralocorticoid excess (sodium excess), osmotic diuresis (increased urine rate due to high amount of water) and diabetes insipidus.

Consequences: cerebral intracellular dehydration - high sodium = low H2O which then dehydrates the brain as there is a lower water concentration since H2O leaves intracellular to go extracellular as solute concentration increases - osmosis

279
Q

What is Hyponatraemia?

A

Low sodium.

Causes: diuresis (increase urine rate), Addison’s disease, excess IV fluids & oedema.

Consequences: Intracellular over hydration - hypotension since H2O goes intracellular as solute concentration increases - osmosis

280
Q

What is potassium excretion controlled by?

A

Excretion from kidneys is controlled by aldosterone as it controls the
Na/K pump

281
Q

What is Hyperkalaemia?

A

High potassium.

Causes: renal failure, diuretics/ACE inhibitors, Addison’s, Acidosis.

Consequences: Risk of myocardial infarction since high potassium levels mess with resting potential generated in heart for heart contraction

282
Q

What is Hypokalaemia?

A

Low potassium.

Causes: diarrhoea, vomiting, alkalosis, hypomagnesaemia (low magnesium levels).

Consequences: weakness & cardiac dysrhythmia (abnormal heart beat - again since K is necessary for resting potentials and thus action potential generation etc.)

283
Q

What is Hypercalcaemia?

A

High calcium.

Causes: primary hyperparathyroidism (parathyroid gland producing too much parathyroid hormone meaning calcium is leached from bone to increase blood calcium levels), skeletal metastases, vitamin D toxicity and tuberculosis.

Consequences: metastatic calcification (deposition of calcium salts in otherwise normal tissues - resulting in stones) and kidney stones (renal calculi)

284
Q

What is Hypocalcaemia?

A

Low calcium

Causes: Vitamin D deficiency, magnesium deficiency, renal disease, parathyroidectomy (no parathyroid hormone released) & intestinal malabsorption.

Consequences: tetany (spasms of the hands, feet & voice box)

285
Q

What is the cell membrane composed of?

A

Lipid, protein and carbohydrate that exist in a fluid state

286
Q

What does a phospholipid bilayer consists of?

A

Contains
Glycolipids: communication, joins cells to form tissues and stability

Glycoproteins: for cell to cell recognition and acts as receptors

Cholesterol: maintains fluidity in membrane

287
Q

What are all lipid in cell membranes?

A

Amphipathic- both hydrophilic and phobic

288
Q

Function of cell membranes?

A

Acts as selective barrier to the outside environment and compartmentalise cells

Cell membrane is semipermeable; absorbs nutrients and expels waste and maintains intracellular balance

Helps cells respond to signals via receptors

Has molecules on it for inter cellular adhesion

Can act as an insulator i.e. myelin sheath

289
Q

Properties of cell membranes?

A

Occluding: tight junctions help seal cells together in an epithelial sheet to prevent leakage of molecules between them

Anchoring:
* ACTIN filaments; enable cell to cell adhesion through adherens junctions (ADHERENS JUNCTION JOINS ACTIN BUNDLE IN ONE CELL TO A SIMILAR BUNDLE IN ANOTHER CELL - HELPS KEEP CELLS TOGETHER) & cell to matrix (external to cell) adhesion through adherens junctions too.

  • INTERMEDIATE FILAMENTS; enable cell to cell adhesion through desmosomes (cell surface adhesion proteins + intracellular keratin cytoskeletal filaments - they resist shearing forces & JOIN THE INTERMEDIATE FILAMENTS IN ONE CELL TO THOSE IN A NEIGHBOUR) & cell to matrix adhesion through focal adheren junctions. HEMIDESMOSOMES; anchor intermediate filaments in a cell to the basal lamina

Communicating: gap junctions- allows the passage of small water soluble ions and molecules

290
Q

What is endocytosis?

A

Energetic process to absorb/engulf molecules into a cell. Some extracellular fluid is usually engulfed too along with the molecule etc. - a portion of the membrane is invaginated to form a membrane bound vesicle called an endosome

Receptor mediated - specific, found in depressed areas (coated pits) - allows the cell to get the molecules it needs. Ligands bind to receptor, this complex is engulfed - releasing the ligand into the cytosol (fluid portion of the cytoplasm outside the cell organelles)

Pinocytosis (drinking) - bringing in dissolved solutes

291
Q

Where does endocytosis occur?

A

Occurs in neutrophils & macrophages - they implement phagocytosis (eating) whereby they engulf entire cells/macromolecules to form a phagosome

292
Q

What is exocytosis?

A

Vesicle from the golgi apparatus, fuse with the plasma cell membrane, resulting in the expulsion of waste or the secretion of enzyme/hormones

293
Q

Movement across membranes?

A

Facilitated diffusion
Passive diffusion
Active transport

294
Q

What is facilitated diffusion?

A

the movement of solutes from a region of their high concentration to a region of their low concentration through protein channels (WITHOUT CARRIER PROTEINS).

This continues until dynamic equilibrium is reached. e.g. Glucose - protein assisted which is regulated by insulin.

Voltage gate channels activated by action potentials

295
Q

What is passive diffusion?

A

Passive diffusion e.g. gaseous exchange along chemical gradient

296
Q

What is Active transport?

A

The movement of solutes from a region of low concentration to a region of high concentration against the concentration gradient.

Both transmembrane carrier protein and ATP is required. e.g Na/K ATPase pump - going against chemical and electrical gradients

297
Q

What are receptors and give an example?

A

Gateway to intracellular signals: Examples; open a channel, activate a intracellular enzyme, induce second messenger (peptide hormone binds to receptor) & migrate nucleus to receptor-ligand complex

Examples: enzyme linked receptor e.g. tyrosine kinase - transfers a phosphate group from ATP to a protein in a cell thus acts like an on/off switch, ion channel linked receptor - participate in rapid signalling events found in electrically active cells like neurons, also referred to as ligand gated ion channels, G-protein coupled receptors - sense molecules outside the cell and activate inside signal transduction pathways to ultimately illicit a cellular response

298
Q

Dietary energy sources, which gives the most energy per gram?

A

Carbohydrates (4kcal/g)
Protein (4kcal/g)
Alcohol (7kcal/g)
Lipid (9kcal/g - gives the most energy per gram)

299
Q

What is a Protein?

A

Amino acids in chains, contain carbon, hydrogen, oxygen & nitrogen (maintains nitrogen balance- when starving/dieting, there is a decrease in proteins thus decrease in nitrogen and that affects cell functions

300
Q

What is a lipid?

A

3 fatty acids esterified to one glycerol mostly - most efficient energy source

301
Q

What is alcohol in metabolism?

A

typically ethanol, highly energetic

302
Q

What is metabolism?

A

chemical reactions that occur in a living organism

303
Q

What is basal metabolic rate? (BMR)

A

amount of energy needed to keep the body alive in the rest state.

It is the energy needed to keep the heart pumping, the brain working and the liver and kidneys functioning -

BMR = 1kcal/kg body mass/hr (24kcal/kg/day), an adult requires approximately 0.8g/kg ideal body weight protein per day

304
Q

Factors that increase BMR?

A

High BMI

Hyperthyroidism

Low ambient temperature

Fever/infection

Pregnancy (due to increase in weight and thyroid hormone)

Exercise

305
Q

Factors that decrease BMR?

A

Age (as you get older, BMR decreases)

Gender (female have lower BMR since they have less metabolically active tissues)

Starvation

Hypothyroidism (less thyroid hormone = lower BMR)

306
Q

What is daily energy expenditure? (DEE)

A

Energy to support our BMR and our physical

activity + energy required to process food we eat (diet induced thermogenesis)

307
Q

Storage of excess energy?

A

Stored as triglycerides (excess lipid) (approx 15kg)

Stored as glycogen (excess glucose) (approx 200g in liver & 150g in muscle)

Stored as protein (approx 6kg)

Carbohydrates account for 30% of ATP production at rest

Lipids account for 70% of ATP production at rest

Proteins are often used in longer periods of starvation

308
Q

What is ATP?

A

Energy utilisation

biosynthesis or macromolecules, muscle contraction, active ion transport and thermogenesis

309
Q

What is ADP and pi used in?

A

Respiration (energy production from carbs, lipids and proteins, 02 in C02 out= ATP

310
Q

Structure of ATP?

A

Three main parts;
Adenine- Base found in nucleotides in DNA/RNA also a component part in NAD/ FAD. adenine forms adenosine when attached to ribose

Ribose- Simple 5C sugar (monosaccharide) also found in RNA, forms adenosine (nuceloSide) with adenine

Phosphate- Three phosphate groups (hence triphosphate)

311
Q

What bonds does ATP have?

A

Two phosphoanhydride bonds, when first hydrolysed it produced ADP and when the second is hydrolysed it produces AMP

High energy bonds

312
Q

How does ATP provide energy?

A

When the phosphate bonds are broken energy is released BUT to ‘break’ bonds an input of energy is required.

As bonds reform in the products of the reaction of the hydrolysis of ATP energy is released. The energy released making the new bonds is greater than the energy required to hydrolyse the bonds (since they are relatively weak) thus meaning the hydrolysis of ATP gives out energy

313
Q

Methods of generating ATP?

A

Glycolysis

Kreb’s cycle

Oxidative phosphorylation

Substrate level phosphorylation

Electron transport chain

Beta oxidation

314
Q

Where does glycolysis take place?

A

In the Cytosol

315
Q

What is the glycolysis equation?

A

1 glucose + 2ADP + 2 NAD+ > 2
x pyruvate + 4 x ATP + 2NADH + 2H+ + 2H20

SIMPLIFIED: Glucose + 2ADP + 2Pi + 2NAD+ > 2 Pyruvate + 2ATP + 2NADH + 2H+ + 2H20

316
Q

What is kinase?

A

enzyme that adds/removes phosphate group to things from an ATP

317
Q

What is Isomerase?

A

enzyme that rearranges structure of substrate without changing the molecular formula. (Similar to a mutase)

318
Q

What is aldolase?

A

enzyme that creates or breaks carbon-carbon bonds

319
Q

What is dehydrogenase?

A

enzyme that moves hydride ion (H-) to an electron acceptor e.g. (NAD+ of FAD+)

320
Q

What is Enolase?

A

enzyme that produces a carbon=carbon double bond by removing a hydroxyl group (OH)

321
Q

Process of glycolysis?

A

From the diagram above; the NAD+ and H+ released in step 6 of glycolysis, is used in the conversion of pyruvate to lactate which releases NAD+ which can once again be used in step 6.

Pyruvate > Lactate: In anaerobic conditions, the pyruvate produced cannot enter the
Kreb’s cycle or undergo Oxidative Phosphorylation since these processes require oxygen, instead, the pyruvate can be converted to lactate: Glucose + 2 ADP + 2 Pi > 2 Lactate + 2 ATP + 2 H2O

Fate of lactate: some of the lactate that is formed is released into the blood and
taken up by the heart & brain where it is converted back to pyruvate and used as an energy source.

Another portion is taken up by the liver where it is used as a precursor for the formation of glucose, which is then released into the blood where it becomes available as an energy source for cells.

322
Q

Can some cells be supplied ATP by only glycolysis?

A

Yes
For example, in
erythrocytes (e.g. red blood cells), they contain the enzymes for glycolysis but do not have mitochondria (thus cannot use the Kreb’s cycle or oxidative phosphorylation). All their ATP production therefore occurs by anaerobic glycolysis. Also in some skeletal muscles there are considerable amounts of glycolytic enzymes but few mitochondria - thus a lot of ATP production is done by glycolysis. Despite this the majority of cells do not have sufficient amounts of glycolytic enzymes or enough glucose to provide for glycolysis to meet the energy requirement of the cell using glycolysis alone

323
Q

Why is glycolysis inhibited in acidosis?

A

PHOSPHOFRUCTOKINASE-1 (PFK-1) IS PH DEPENDENT AND IS

INHIBITED BY ACIDIC CONDITIONS

324
Q

Regulators of glycolysis?

A

AMP (adenosine monophosphate)- allosteric activator (modifies the AS of the enzyme so that the affinity for the substrate increases) of Phosphofruktokinase-1 (PFK-1).

AMP binds to PFK-1 resulting in a conformational change increasing affinity for fructose-6- phosphate

Adenosine triphosphate (ATP) is an allosteric inhibitor (modifies the active site of 
the enzyme so that the affinity for the substrate decreases) for PFK-1

Thus at low ATP levels = fast reaction speed of PFK-1 > fructose 1,6 bisphosphate, and at high ATP levels = slow reaction speed of PFK-1 > fructose 1,6 bisphosphate

AMP opposes the allosteric inhibition of ATP

325
Q

Where does the Krebs/TCA cycle take plase?

A

Mitochondrial matrix

326
Q

What is the formula for Krebs

A

Acetyl CoA + 3NAD+ + FAD + GDP + ADP + Pi + 2H2O > 2CO2 + CoA + 3 NADH + 3H+ + FADH2 + GTP + ATP

327
Q

What is the primary molecule entering the Kreb’s cycle

A

Acetyl coenzyme A. it is derived from the B vitamin pantothenic acid and functions primarily to transfer acetyl groups (2C) from one molecule to another

328
Q

How can Acetyl CoA be made?

A

From pyruvate or beta oxidation of fatty acids or from amino acid breakdown

329
Q

Why can the Krebs cycle only take place in aerobic conditions?

A

Since oxidative phosphorylation is required to covert NADH & FADH2 back to NAD+ and FAD to be used in the conversion of Isocitrate to a-Ketoglutarate and a-Ketoglutarate to Succinyl coenzyme A & Succinate to Fumarate & Malate to Oxaloacetate.

330
Q

Process of Krebs cycle

A

Can I Keep Selling Socks For Money, Officer?

Citrate, Isocitrate, a-Ketoglutarate, Succinyl CoA, Succinate, Fumarate, Malate, Oxoloacetate

331
Q

What is Beta oxidation?

A

Fatty acid is oxidised
Aerobic only

Dependent on oxygen

Good blood supply

Adequate numbers of mitochondria

332
Q

How can Acetyl CoA be derived from oxidation of Fatty acids?

A

FA is just a carboxylic acid group with lots of carbons attached

FA must be activated in the cytoplasm before being oxidised in the mitochondria

Process: FA + ATP + CoA= Acycl CoA + PPI (pyrophosphate) + AMP.

Adenosine is taken from ATP and used to make Acyl Coenzyme A

Occurs in the mitochondria (but most FA (>12C long)cant get through outer mitochondrial membrane on their own

333
Q

What is the Carnitine shuttle?

A

Acyl CoA –> Enzyme Carnitine acyltransferase 1 (resides in the outer mitochondrial membrane)
–> Acyl Carnitine

Coenzyme is is remove for Acyl CoA and recycled. the molecule Carnitine is added, so can be transported into the mitochondria through the outer mitochondrial membrane.

Once inside the mitochondria another enzyme Carnitine acyltransferase 2 converts Acyl Carnitine back to Acyl CoA

Coenzyme A is re-added and the carnitine is ripped off to regenerate Acyl CoA. the carnitine can then diffuse through the outer mitochondrial membrane to be used again to covery Acyl CoA to Acyl Carnitine

334
Q

Do fatty acids of carbohydrates yield more energy during oxidation?

A

Fatty Acid oxidation yields more energy per carbon than the oxidation of carbohydrate. The net result of the oxidation of one mole of oleic acid (an 18C FA) will be 146 moles of ATP compared to 38 moles of ATP produced from 1 mole of glucose

335
Q

Why can’t fatty acids act as a fuel source for the nervous system?

A

They can’t get through the blood-brain barrier

336
Q

How much does each round of b-oxidation produce?

A

1 MOL:
NADH
FADH2
Acetyl CoA

337
Q

What is NADH AND FADH2 produced from beta oxidation and Kreb’s cycle used in?

A

Oxidative phosphorylation

338
Q

When are fatty acids principally used as fuels?

A

When hormones signal fasting or increased deman

339
Q

Give some examples of Fatty Acid

A

Linoleic acid (18C), Oleic acid (18C), Palmitic acid (16C) Arachidonic acid (20C)

340
Q

Where does oxidative phosphorylation occur?

A

Inner mitochondria membrane

341
Q

Name some of the structures embedded in the inner mitochondrial membrane surface that form the components of the electron transport chain

A

Cytochromes (contain iron and copper co-factors, structure resembles the red iron- containing haemoglobin)

Associated proteins embedded in the inner mitochondrial membrane surface

342
Q

Process of oxidative phosphorylation?

A

2 electrons from 1 Hydrogen atom are initially transferred either from NADH + H+ or FADH2 to one of the protein in the ETC

These electrons are then successively transferred to other compounds in the chain redox reactions, until the electrons are finally transferred to molecular oxygen, which then combines with hydrogen ions (protons) to form water

343
Q

Where do the hydrogen ions and electrons in ETC come from?

A

free hydrogen ions and the hydrogen-bearing coenzymes (NADH and FADH2), that had been released earlier in the electron transport chain when the electrons from the hydrogen atoms were transferred to the cytochromes.

344
Q

How is the hydrogen free forms of coenzymes (NAD+ & FAD) regenerated to accept two more hydrogens from intermediates in the Kreb’s cycle, glycolysis or beta- oxidation?

A

Coenzyme hydrogens transferred to water

345
Q

At certain steps along the ETC, small amounts of energy are released, when electrons are transferred from one protein to another along the chain. What is the energy used for?

A

Pump cytochromes to pump hydrogen ions from the matrix into the intermembranal space

Creates another source of potential energy in the form of Hydrogen/ion conc. grad. across the membrane

Embedded in the inner mitochondrial membrane are enzymes called ATP synthase. This enzyme forms a channel in the membrane allowing H ions to flow back into the matric via chemiosmosis- moving from an area of high conc. of H ions to an area of low conc.

During this process, the energy of the concentration gradient is converted into chemical bond energy by ATP synthase, which then catalyses the formation of ATP from ADP and Pi.

The transfer of electrons to oxygen produces on average around 2.5 and 1.5 molecules of ATP for each molecule of NADH + H+ & FADH2 respectively.

346
Q

Overall reaction of respiration?

A

C6H12O6 + 6O2 + 38 ADP + 38 Pi –> 6CO2 + 6H20 + 34-38 ATP

(There is debate to how much ATP is produced from glycolysis, Kreb’s cycle and Oxidative phosphorylation but its roughly between 34-38 ATP molecules (38 is theoretical and assumes all NADH produced in glycolysis and Kreb’s enter oxidative phosphorylation and all the free H ions are used in the chemiosmosis for ATP)

347
Q

What is Ketogenesis?

A

During high rates of fatty acids oxidation, primarily in the liver (hepatocytes), large amounts of acetyl-CoA are generated. These exceed the capacity of the Kreb’s/TCA cycle, and one result is the synthesis of ketone bodies.

348
Q

What are Ketone bodies?

A

Ketone bodies (acetone, acetoacetate & B-hydroxybutyrate) are synthesised in the mitochondrial matrix from Acetyl CoA generated from b-oxidation

349
Q

What happens to the level of Oxaloacetate when Carbohydrate utilisation is low or deficient?

A

When carbohydrate utilisation is low or deficient, the level of oxaloacetate will also be low resulting in a reduced flux through the Kreb’s cycle - leading to an increased release of ketone bodies from the liver to be used as fuel by other tissues

350
Q

What happens to b-hydroxybutyrate and acetoacetate when glycogen in the liver is high?

A

When the glycogen in the liver is high the production of b-hydroxybutyrate increases. Another fate of the acetoacetate is that it can spontaneously be converted to acetone. Since acetone is volatile it is rapidly expired by the lungs

351
Q

How can Acetoacetate and b-hydroxybutane be oxidised as fuels in most tissues?

A

Cells transport the acetoacetate and b-hydroxybutyrate from the blood into the cytosol then into the mitochondrial matrix.

Here b-hydroxybutyrate is oxidised back to acetoacetate.

Acetoacetate can then be activated to Acetoacetyl CoA which can then be cleaved into two molecules of Acetyl CoA by the thiolase enzyme (same enzyme involved in b-oxidation).

Then the Acetyl CoA can be used in the Kreb’s cycle to produce ATP

352
Q

The liver has no enzyme Succinyl CoA: Acetoacetate CoA (enzyme used to convert acetoacetate to acetoacetyl CoA) IN SUFFICIENT CONCENTRATIONS). What does this mean?

A

THUS CANNOT UTILISE KETONE BODIES AS FUEL since they cannot be converted to Acetyl CoA in the liver - this ensure that extrahepatic tissues have access to ketone bodies as a fuel source during prolonged starvation

353
Q

What happens in early stages of starvation?

A

The last remnants of fat are oxidised, the heart and skeletal muscle will consume primarily ketone bodies in order to PRESERVE GLUCOSE FOR USE BY THE BRAIN -

when glucose in the brain decreases then the brain CAN use ketone bodies for energy

354
Q

Control in the releases of free fatty acids from adipose tissue directly affects what?

A

Level of ketogenesis in the liver

355
Q

Clinical significance of Ketogenesis?

A

Production of ketone bodies occurs at a relatively slow rate during normal feeding
and under normal physiological status

Normal physiological responses to carbohydrate shortages cause the liver to increase production of ketone bodies from the acetyl-CoA generated from fatty acid oxidation.

This allows the heart and skeletal muscles primarily to use ketone bodies for energy, thereby preserving the limited glucose for use by the brain.

The most significant disruption in the level of ketosis occurs in untreated insulin- dependent diabetes mellitus

356
Q

What is Diabetic Ketoacidosis?

A

Results from reduced supply of glucose (since there will be a significant decline in circulating insulin) and an increase in fatty acid oxidation (due to an increase in circulating glucagon).

The increased production of Acetyl-CoA leads to ketone body production that exceeds the ability of peripheral tissues to oxidise them.

Ketone bodies are relatively strong acids (pH 3.5), and their increase lowers the pH of blood.

This acidification of the blood can have many consequences but most critical is the fact that it IMPAIRS THE ABILITY OF HAEMOGLOBIN TO BIND TO OXYGEN - note if a patient is in diabetic ketoacidosis, the excess ketones in the blood will result in their BREATH SMELLING OF PEAR DROPS (KETONES).

357
Q

Oxygen?

A

Oxygen: favours reduction in single electron steps, two unpaired electrons, parallel spin, permits combustion, cellular respiration (electron transport chain), formation of free radicals & is highly reactive

358
Q

What is the reactive oxygen species?

A

highly reactive oxygen containing compounds that are free radicals (have a single unpaired electron in their orbital) or compounds that are readily converted to oxygen free radicals in the cell

  • these compounds contribute to ageing, homeostasis and some cancers.
359
Q

What is the reactive oxygen species?

A

highly reactive oxygen containing compounds that are free radicals (have a single unpaired electron in their orbital) or compounds that are readily converted to oxygen free radicals in the cell

  • these compounds contribute to ageing, homeostasis and some cancers.

Reactive free radical extract electrons (usually as hydrogen atoms) from other
compounds to complete their own orbitals, thereby initiating free radical chain reactions.

  • The hydroxyl radical is probably the most potent of the ROS
360
Q

Exogenous sources of ROS?

A

UV radiation, tobacco and drugs

361
Q

Endogenous sources of ROS

A

NADPH & the electron transport chain

362
Q

Formation of ROS?

A

Formation occurs through the reduction of oxygen in 4 steps:
- Firstly oxygen is reduced by a single electron to form superoxide (O2•–) [free
radical]

Then the superoxide is reduced further to form hydrogen peroxide (H2O2) [not a free radical]

H2O2 is reduced further to produce hydroxyl radical (OH•) [free radical]

Then lastly its further reduced to water (H2O)

363
Q

Is Hydrogen peroxide a Radical?

A

Not a radical, but it is a ROS since it is readily converted to the hydroxyl radical (OH•) in cells.

Its also lipid soluble so can cause damage away from site of formation.

Transition metals such as Fe2+ or Cu2+, catalyse the formation of the hydroxyl radical from hydrogen peroxide in the nonenzymatic Fenton reaction (the iron dependent generation of a hydroxyl radical from hydrogen peroxide) by donating a single electron

364
Q

What is the Fenton reaction?

A

H2O2 + Fe2+ > Fe3+ + OH- + OH•

365
Q

What is the Haber- Weiss reaction?

A

O2•– + H2O2 + H+ > O2 + H2O + OH• -

The hydroxyl radical can also be formed by the Haber-Weiss reaction involving
superoxide (O2•–)

Combines with the Fenton reaction to form the Haber- Weiss cycle (4 Reactions to produce an OH• and consume H202

366
Q

Haber- Weiss cycle reactions

A

Fe2+ + H2O2 > Fe3+ + OH- + OH• [Fenton reaction]

OH• + H2O2 > H2O + O2•– + H+

O2•– + H+ + H2O2 > O2 + OH• + H2O [Haber-weiss reaction]

Fe2+ + OH• + H+ > Fe3+ + H2O

367
Q

Hydroxyl radical (OH•)

A

Most potent of ROS

Radical characteristics- lipid soluble (thus can cause superoxide damage away from site of hydrogen O2·- Produced by electron transport chain. Generates other radicals locally formation as well as damaging peroxide H2O2 Generates radicals with transition metals. Lipid soluble lipid bilayers)

Hydroxyl OH· Most reactive radical

Initiator of chain reactions that form lipid peroxides and organic radicals

368
Q

Cellular damage by free radicals

A

Proteins, lipids, carbohydrates and nucleic acid

Damage membranes of: cells, nucleus, mitochondria and endoplasmic reticulum

Cell membrane damage results in the increased permeability of the membrane resulting in an influx of calcium, water and sodium

Diseases: Emphysema, Parkinson’s, Acute renal failure and Diabetes

DNA can also be damaged by hydroxyl radial- results in strand breaks and base alterations- Mutations

369
Q

What is the respiratory burst?

A

Immune system defence against bacteria

Sudden release of ROS by immune cells (Neutrophils, macrophages and monocytes) during phagocytosis

Immune cells utilise NADPH oxidase to reduce oxygen to superoxide

Superoxide is released (which is then reduced to hydrogen peroxide, which in turn can be reduced to hydroxyl radical etc.), which then generates other reactive oxygen species

Neutrophils & monocytes use myeloperoxidase to further combine H2O2 with Cl- to produce hypochlorite (which plays a role in destroying bacteria by damaging bacterial cell membranes) (ClO-) [H2O2 + Cl- > H2O + NADP+ O2- Cl-]

370
Q

Absence or impairment of function of NADPH oxidase prevents formation of what and causes what ?

A

Prevents the formation of ROS

Causes chronic granulomatous disease (X-linked) (build up of pathogens in phagocytes since they can engulf but NOT kill them - leads to severe skin infections with bacteria or fungi)

371
Q

Protection against oxygen toxicity?

A

Antioxidant enzymes:

Antioxidant vitamins:
Vitamin E - found in liver, free radical scavenger, protects
against lipid peroxidation and terminates free radical propagation in membranes, Vitamin C - e.g ascorbic acid, reacts with superoxide & hydroxyl radical and regenerates reduced vitamin E

Cellular compartmentalisation:
Respiratory burst taking place in phagosomes so
harmful chemicals don’t get out and damage healthy tissue

372
Q

Give examples of antioxidant enzymes?

A

Superoxide dismutase - converts superoxide to hydrogen peroxide (non toxic unless converted to another ROS) & oxygen

Catalase - catalyses conversion of hydrogen peroxide to water & oxygen and protects white blood cells against own respiratory burst

Glutathione Peroxidase - catalyses the reduction of hydrogen peroxide to water and a disulphide (GSSG)

373
Q

What is an acid?

A

Proton/H+ donor

HA (acid) H+ + A- (conjugate base)

374
Q

What is a base?

A

Proton/H+ acceptor:

B (base) + H+ BH+ (conjugate acid)

375
Q

What is a strong acid?

A

A compound that ionises completely in solution to form hydrogen ions and a base

376
Q

What is a weak acid and base?

A

Compounds that are only partially ionised in solution

377
Q

What are bufferS?

A

ALL ARE WEAK ACIDS OR BASES WITH THE CONJUGATE BASE OR ACID RESPECTIVELY.

Solution which resists changes in pH when small quantities of strong acids or base are added.

It limits the change in hydrogen ion concentration (and thus pH) when hydrogen ions are added or removed from the solution.

When hydrogens are in excess the extra ions are taken up and when hydrogens are in short supply more hydrogen ions are released.

378
Q

What is the Henderson Hasselbalch equation?

A

pH = pKa + log([HCO3 -] / [CO2])

379
Q

What is the ideal Ph

A

7.4

380
Q

What is normal Ph range?

A

7.35-7.45

381
Q

How are hydrogen ions produced?

A

The process of metabolism generates hydrogen ions.

Small amounts are from the oxidation of amino acids and the anaerobic
metabolism of glucose to lactic and pyretic acid

Far more hydrogen ions and thus acid are produced as a result of carbon dioxide (CO2) release from oxidative (aerobic) metabolism. Although CO2 doesn’t contain hydrogen ions it rapidly reacts with water to form carbonic acid (H2CO3), which further dissociates into hydrogen & bicarbonate ions (HCO3 -):

This reaction occurs throughout the body and in certain circumstances is speeded up by the enzyme carbonic anhydrase. Carbonic acid is a weak acid and with bicarbonate (its conjugate base) forms the MOST IMPORTANT BUFFERING SYSTEM IN THE BODY

382
Q

How is the hydrogen ion concentration controlled?

A
  • Blood & tissue buffering
  • Excretion of CO2 by the lungs
  • Renal excretion of H+ and regeneration of HCO3 -

Buffers are able to limit changes in hydrogen ion concentrations - this prevents the large quantities of hydrogen ions produced by metabolism resulting in dangerous changes in blood or tissue pH

383
Q

What are body buffer systems?

A

Bicarbonate
Proteins
Haemoglobin

384
Q

What is the bicarbonate buffer?

A

this is the most important buffer system in the whole body
(equation above). Despite the fact that bicarbonate is not an efficient buffer, its efficiency is improved because CO2 is removed at the lungs & bicarbonate is regenerated by the kidneys.

385
Q

How is protein a buffer?

A

Many proteins, notably albumin, contain weak acidic and basic groups
within their structure. Thus, plasma and other proteins form important buffering systems.

Intracellular proteins limit pH changes within cells, whilst the protein matrix of bone can buffer large amounts of H+ ion in patients with chronic acidosis

386
Q

Haemoglobin as a buffer?

A

Its not only important in the carriage of oxygen to the tissues but
also in the transport of CO2 and in buffering hydrogen ions.

Haemoglobin binds both CO2 & H+ and is thus a powerful buffer.

Deoxygenated haemoglobin has the strongest affinity for both CO2 & H+; thus its buffering effect is strongest in the tissues.

387
Q

Buffering of CO2?

A

Little CO2 is produced in red cells thus CO2 produced by tissues passes easily into the cell down a concentration gradient.

CO2 then either combines directly with haemoglobin or combines with water to form carbonic acid.

The CO2 that binds directly with haemoglobin combines reversibly with terminal amine groups on the haemoglobin molecule to form carbaminoheamoglobin .

In the lungs the CO2 is released and passes down the concentration gradient in to the alveoli - THIS IS THE BUFFERING OF CO2

388
Q

How are H+ ions buffered?

A

In tissues, dissolved CO2 passes into the red blood cells down the concentration gradient where it combines with water to form carbonic acid.

This reaction is catalysed by the enzyme carbonic anhydrase.

Carbonic acid then dissociates into bicarbonate and H+ ions.

The H+ ions bind to reduced haemoglobin to form HHb.

BICARBONATE IONS (HCO3 -) GENERATED BY THIS PROCESS PASS BACK INTO THE PLASMA IN EXCHANGE FOR CHLORIDE IONS (CL-) - this ensures that there is no net loss or gain of negative ion in the red blood cell.

In the lungs this process is reversed and H+ ions bound to haemoglobin recombine with bicarbonate to form CO2 which passes into the alveoli.

In addition, reduced Hb (haemoglobin) is reformed to return to the tissues.

389
Q

Carbon dioxide elimination?

A

CO2 is responsible of the majority of H+ ions produced by metabolism.

Thus, the RESPIRATORY SYSTEM forms the single most important organ involved in the control of hydrogen ions.

In the lungs, the arterial partial pressure of CO2 (PaCO2) is INVERSELY
PROPORTIONAL to alveolar ventilation - i.e. if alveolar ventilation falls the PaCO2 rises.

Thus, relatively small changes in ventilation can have a profound effect on hydrogen ion concentration and thus pH.

Ideal pH = 7.4:
• pH > 7.45 - ALKALOSIS
• pH < 7.35 - ACIDOSIS

Alkalosis and acidosis can be respiratory or metabolic

390
Q

Disorders of Hydrogen ion homeostasis?

A

Disturbances of the body’s acid base balance results in the plasma contains either too many hydrogen ion (acidaemia - condition related to this is acidosis) or too few hydrogen ions (alkalaemia - condition related to this is alkalosis).

The the pH is too low in acidaemia (less than 7.35) whilst in alkalaemia the pH is too high (greater that 7.45) - these disturbances may be due to respiratory causes (i.e. changes in PaCO2) or non-respiratory (METABOLIC) causes.

391
Q

What is respiratory acidosis

A

Results when the PaCO2 is above the upper limit of normal (>6kPa).

Respiratory acidosis is most commonly due to decreased alveolar ventilation causing decreased excretion of CO2.

Less commonly, it is due to excessive production of CO2 by aerobic metabolism
- this may occur in syndromes such as malignant hyperpyrexia (fever with an extreme elevation of body temperature)

392
Q

What is Respiratory alkalosis?

A

Results from the excessive excretion of CO2, and occurs when the PaCO2 is less than 4.5kPa - this is commonly seen in hyperventilation due to anxiety

In more serious diseases, such as severe asthma or moderate pulmonary
embolism, respiratory alkalosis may occur

In both respiratory acidosis & alkalosis the compensation time is VERY QUICK, MEANING THERE CAN BE A RAPID RESPONSE TO COUNTER THE ACIDOSIS/ ALKALOSIS THUS IT HAS A LIMITED EFFECT

393
Q

What is metabolic acidosis and its commonest cause?

A

May result from either an excess of acid due to increased production of organic acids or reduced buffering capacity due to low concentration of bicarbonate

Excess H+ production is the most commonest cause of metabolic acidosis and results form the the excessive production of organic acids (usually lactic or pyretic acid) as a result of anaerobic metabolism. This may result from local or global tissue hypoxia (deficiency in the amount of oxygen reaching the tissues).

394
Q

Why might tissue hypoxia occur?

A

Reduced arterial oxygen content: for example because of anaemia or reduced PaCO2

Hypoperfusion (low perfusion) - for example, any cause of reduced cardiac output may result in metabolic acidosis (e.g hypovolaemia (low blood volume), cardiogenic shock etc.). Also local hypoperfusion in conditions like ischaemic bower or ischaemic limb may cause acidosis

Reduced ability to use oxygen as a substrate - e.g. in conditions like severe sepsis and cyanide poisoning anaerobic metabolism occurs as a result of mitochondrial dysfunction

395
Q

What is diabetic ketoacidosis?

A

Cells are unable to use
glucose to produce energy due to the lack of insulin.

Fats form a major energy source and result in the production of ketone bodes (acetoacetate and 3- hydroxybutyrate) from acetyl coenzyme A.

Hydrogen ions are released during the production of ketones resulting in metabolic acidosis

396
Q

Is inadequate excretion of H+ another cause of metabolic acidosis

A

This results from
renal tubular dysfunction and usually occurs in conjunction with inadequate reabsorption of bicarbonate.

Any form of renal failure may result in metabolic acidosis.

397
Q

Some endocrine disturbances can result in inadequate excretion of H+ ions e.g. hypoaldosternonism. How?

A

Aldosterone regulates sodium reabsorption in the distal renal tubule.

As sodium reabsorption and H+ excretion are linked, a lack of aldosterone (e.g in Addison’s disease) tends to result in reduced sodium reabsorption and thus a reduced ability to excrete H+ into the tubule resulting in reduced H+ loss.

398
Q

How does excessive loss of bicarbonates cause metabolic acidosis?

A

Intestinal secretions are high in sodium bicarbonate.

The loss of small bowel contents or excessive diarrhoea results in the loss of large amounts of bicarbonate resulting in metabolic acidosis - this can occur in Cholera or Crohn’s disease.

399
Q

What is metabolic alkalosis? (rare)

A

May result from the excessive loss of H+ ions, the excessive reabsorption of bicarbonate or the ingestion of alkalis

Excess H+ loss - since gastric secretions contain large quantities of hydrogen
ions, the loss of gastric secretions will result in metabolic alkalosis - this occurs in prolonged vomiting or pyloric stenosis

Excessive reabsorption of bicarbonates - since bicarbonate and chloride
concentrations are linked, if chloride concentration falls or chloride losses are excessive the bicarbonate will be reabsorbed to maintain electrical neutrality. Chloride can be lost from the gastro-intestinal tract, thus in prolonged vomiting it is not only the loss of hydrogen ions that results in alkalosis but also the chloride losses which in turn results in bicarbonate reabsorption.

Chloride losses may also occur in the kidneys as a result of diuretic drugs - the thiazide and loop diuretic are a common cause of metabolic alkalosis. These drugs cause increased loss of chloride in the urine resulting in excessive bicarbonate reabsorption

In both metabolic acidosis & alkalosis COMPENSATION CAN TAKE TIME TO COME INTO AFFECT RESULTING IN A DELAYED RESPONSE MEANING THAT THE ACIDOSIS OR ALKALOSIS HAS A GREATER EFFECT THAN IF IT WAS RESPIRATORY

400
Q

What is the anion gap?

A

The difference in serum concentration of cations (positive) and anions (negative) e.g. Cl-, HCO3 -, Na+, K+ - Equation: (Na+ + K+) - (HCO3- + Cl-)

Not all ions are included e.g. K+, PO4 -, SO4 -

Normal value is between 3-11mEq/mol

Can be used to help diagnose cause of metabolic acidosis - if there is a high
anion gap or normal anion gap - can be used to see if cause is excessive loss of bicarbonate or excess H+ production etc.

401
Q

Summary of alkalosis/acidosis

A

Lungs/respiratory:

Alkalosis: hyperventilate and blow off CO2

Acidosis: slow down, retain CO2

Rapid response, limited effect

Kidneys/metabolic:

Alkalosis: excrete H+, retain HCO3-

Acidosis: retain H+, Excrete HC03-

Delayed response, greater effect

PHASE 1 Medicine (5 decks)

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