Growth Flashcards
What are the 3 cell types?
Labile, stable, permanent
Which cell type are continously cycled?
Labile
What can cause toomuch growth?
- Developmental
- Hamartoma
- Reactive/adaptive
- Hyperplasia
- Hypertrophy
What is a hamartoma?
• tumour-like overgrowth • grows in patient’s growth period • stops growing • tissues are normal for site, but excessive • e.g. pigmented naevi (“moles”) haemangioma
What is hyperplasia?
increase in cell numbers
• response to stimulus
• regression once stimulus removed
• increased size and function
What is normal physiological endocrine hyperplasia?
normal growth and development
puberty and pregnancy
What is pathological endocrine hyperplasia?
parathyroid/thyroids
chronic irritation/inflammation
What is hypertrophy?
increase in cell size • often occurs with hyperplasia • pure hypertrophy • muscle – mechanical stimulus skeletal - exercise smooth - pregnancy cardiac – LVH in hypertension
What is neoplasia?
growth which is uncontrolled and does
not stop and which persists after the
stimulus is removed
What happens in too little growth?
Developmental • agenesis • does not develop at all • aplasia • fails to develop normal structure • hypoplasia • less tissue formed
What is atrophy?
Decrease in size after growth • size and number of cells • can be physiological – in embryology Mechanisms • Imbalance of cell loss and production • apoptosis • not necrosis (mostly) • reduction in structural components of the cell – esp proteins
What is generalised atrophy?
nutritional – e.g. in starvation
• senile
• endocrine
• bone - osteoporosis
What is localised atrophy?
- ischaemic
- pressure
- disuse
- neuropathic/denervation
- immune mediated (autoimmune)
- idiopathic
What is metaplasia?
Abnormal differentiation
• change from one differentiated tissue to another
• within the same germinal layer
• result from changes in environmental demands
- epithelium
- mucous
- squamous
• mesenchymal
What is dysplasia?
abnormal growth and differentiation in a
tissue, with abnormal cells and tissue
architecture
• may be premalignant
What is ectopia?
• developmental
abnormality
• normal tissue
• abnormal site
What is a neoplasm?
• an abnormal mass of tissue
• growth of which is excessive
• and is unco-ordinated with that of normal
tissues
• and persists after the provoking stimulus is
removed
What is invasion?
unconfined growth into CT – the defining feature of
malignant tumours
What is metastasis?
spread distant from the primary tumour
What is cytology?
features of individual cells – often very abnormal
How can we classify neoplasms?
by clinical behaviour
• benign
• malignant
by histogenesis – tissue of origin
• epithelial – lining or glandular
• mesenchymal – various types
What is stroma?
supporting connective tissue of cancer cells
What are the effects of benign tumours?
pressure • obstruction • function – esp hormone secretion these vary by site and tumour • effect is not always “benign”
What is the pathology of malignant tumours?
– invade underlying tissues – cytologically abnormal – differentiation varies – well, moderate, poor – anaplasia
• stroma
– angiogenesis
– immune response
What is the cytology of malignant tumours?
variation in cell shape and size • variation in nuclear shape and size • odd mitoses • altered differentiation
What are 90% of tumours classified as?
Benign …
Which epithelial cancers are odd?
melanoma: melanocytes malignant • lymphoma • leukaemia bone marrow precursors • teratoma germ cell tumours most in testes, most malignant (ovarian tend to be benign) can mimic ANY tissue
Why do tumours arise?
• benign tumours
little known, many be inherited factors
genetic susceptibility to cancer
• inherited cancer syndromes
• single mutant genes, often tumour suppressor genes
• retinoblastoma, some colon cancers.
What is the defining feature of malignant tumours?
Invasion - unconfined growth into CT
What is direct growth by?
Surface apposition (bone added on surface by osteoblasts) and resorption (Bone being removed by osteoclasts)
What is sutural directed growth?
Sutures in membranous bones are growth centres and expression of growth at these sites changes shape
What is cartilage directed growth?
Cartilages are primary factor in craniofacial growth - growing cartilage replaced by bone
Suggested that this growth is genetically determined
Examples - spheno-occipital and spheno-ethmoidal synchondroses, nasal septum, condyle
What is the functional matrix theory?
Bone growth takes place in response to growth of surrounding tissues. Craniofacial growth as a response to functional needs that is mediated by adjacent soft tissue growth
2 matrices:
Periosteal matrix
Capsular matrix
Function of jaw changed to influence growth - orthodontics
What is the growth of the head dictated by in the early years?
Growth of the brain
What are facial changes in the early years 0-12 related to?
Synchondroses
What does post natal growth of the maxilla occur by?
Surface and sutural deposition
What is the change in position of bone called?
Drift
What does growth in length of the mandible occur by?
Cartilage replacement in the secondary growth cartilage at the condylar head
How does the mandible grow in height and length?
Resorption from the anterior surface and deposition on the posterior surface
Mandibular growth in height?
K
Condylar cartilage is not a true cartilage ..
.
Where are the existing stable anatomical locations of the mandible?
Mandibular canal
Retromoalr region
Mandibular symphysis
What are the two types of rotation of the mandible?
Matrix rotation - around the condyle
Intra-matrix rotation - within body of mandible
What happens to the face with backward rotation?
Gets longer with time, matrix rotation centred on the condyle
What can cause an anterior open bite?
Mandible growing downwards and backwards
What happens to the face in forward rotation?
Becomes shorter with time
What do children with adenoidal fancies have?
Increases in lower and total face height, narrow upper arches, retroclined incisors, difficulties in nasal breathing etc
What are the 2 phases of facial soft tissue growth during puberty?
Phase 1 ..
What are the 5 ways of assessing growth timing and rate of growth of the craniofacial structures?
Measurement of change in height. Secondary sexual characteristics Hand-wrist radiographs Radiographic assessment of cervical spine maturation Average growth increment s
Wha is a scammons growth curve?
Shows growth patterns of most systems of the body including the skeleton and muscle mass - height
What is the neural curve?
Graph of the growth of the brain, nervous system and associate structures
What is the atlas technique?
Ulnar sesamoid bone ossified at the start of pubertal growth spurt - looking for this bone on hand-wrist radiograph - comapred with the reference atlas
What is a cephalogram?
x ray of the craniofacial area
Assesses growth spurt in body height and mandibular size
3 cervical vertebrae examined on radiograph
What is the growth pattern and determinant of growth in infancy?
Rapid foetal growth
In infancy deceleration of the foetal growth rate
nutrition is determinant
What is the growth pattern and determinant of growth in Childhood?
Slow deceleration except mid childhood adrenal spurt
Growth hormone is determinant
What is the growth pattern and determinant of growth in puberty?
Pubertal growth spurt
sex steroids and growth hormone is determinant
What are 3 ways to measure bone growth?
- Growth charts - height/weight
- Bmi
- Bone age
What is the equation for BMI?
Mass (kg)/ height (m))^2
How is bone age used to measure growth?
Uses standardised x-rays to measure the maturity of each epiphyseal centre of the left hand wrist to derive a score
the age at which the score is on the 50th centile is the bone age of the individual
What is the name of one of the standard systems of bone age calculations?
Tanner and Whitehouse - quantify how much growth has occurred and how much is to come
What are the common causes of short stature or failure to thrive?
under nutrition, malabsorption - intestinal infection, CF, Crohns, Coeliac
individual and familial short stature
damage by alcohol, drugs, genetic e.g. downs
systemic disease - heart, lung, renal, haematological, diabetes mellitus, endocrine - hypothyroid/hypopituitary
iatrogenic - steroid excess
inherited - acondroplasia, hypophosphatasia, Noonan’s syndrome
What are environmental factors that can affect growth?
Drugs/Chemicals -
Thalidomide, Epanutin, Warfarin, Alcohol, Fluoride (teeth)
Radiation Infection Metabolic defects Hyperthermia Vascular Amniotic bands
What are some examples of multiple defects?
Associations
Sequences
Field complexes
Syndromes
What type of defect is common and often multifactorial?
Single system defect e.g. abnormal failed completion of embryonic process
What are associations?
Combinations of anomalies which are associated
statistically but underling mechanism not clear
What does VATER stand for? (association)
V Verterbral
anomalies
A Anal atresia
T Tracheo –
E Esophageal
atresia
R Radial and Renal anomaliesWhat does atresia mean?
Abscence or abnormal narrowing of a normal opening or passage in the body?
What is Potter’s sequence?
atypical physical appearance of a baby due to oligohydramnios experienced when in the uterus. It includes clubbed feet, bowed limbs, joint contractures, squashed faces. pulmonary hypoplasia and cranial anomalies related to the oligohydramnios (deficiency of amniotic fluid).
What is Pierre-Robin sequence?
a set of abnormalities affecting the head and face, consisting of a small lower jaw (micrognathia), failed palatal closure, a tongue that is placed further back than normal (glossoptosis), and blockage (obstruction) of the airways
What is a sequence?
a series of ordered consequences due to a single cause. It differs from a syndrome in that seriality is more predictable: if A causes B, and B causes C, and C causes D, then D would not be seen if C is not seen
What areas will need to be managed in Pierre Robin sequence
Breathing difficulties Feeding difficulties Cleft Palate Speech therapy Dental care Possible learning disability
What is a field complex?
Insult to a localised part of an embryo resulting in abnormalities in adjacent structures of disparate embryonic origin
What is an example of a field complex?
Eg Stapedial artery interruption in rodents hemifacial microsomia
What is an example of a syndrome?
Trisomy 21 - Downs’
What are some symptoms of trisomy 21?
Learning delay Cardiac Defects (70%) Relatively short neck, unstable atlanto-axial joint Short stature Increased risk of Leukaemia Hypotonia Hypothyroidism Epilepsy, Alzheimers Large, fissured tongue Periodontal disease Hypodontia Microdontia Enamel Defects Class 3 malocclusion due to maxillary retrognathia
What is williams syndrome?
- deletion of genes chromosome 7 Fault in calcium metabolism leading to xs calcium Failure to thrive in infancy Highly verbal and overly sociable Characteristic facial appearance “Elfin” Short stature Delayed growth Variable learning delay & behavioural problems Heart defects Susceptible to loud noise Renal calculi
Give some examples of general disorders of growth and development? (from lecture)
Osteogenesis imperfecta Down’s syndrome X-linked Vitamin D resistant rickets Cleidocranial dysostosis Achondroplasia Gigantism Acromegaly
Give some examples of dental disorders of growth and development? (from lecture)
Dentinogenesis imperfecta
amelogenesis imperfecta
What can DI be associated with?
Osteogenesis imperfecta
What are the three types of DI?
1) Mutation in Type I collagen. Associated with OI, Chromosome 7 and 17
2) Mutation in Dentine Sialophosphoprotein I Gene, Chromosome 4
3) Brandywine Isolate, Maryland Chromosome 4
DSPP mutation affecting non-collagenous proteins (DSP, DPP, DGP); variation in severity of presentation
What does DD stand for?
dentin dysplasia
What is DD type II a mild form of and what is DI type III a severe form of?
DI
What are the dental features of DI?
Amber, grey to purplish discolouration
Pulpal obliteration
relatively bulbous crowns, short narrow roots
enamel may be lost following tooth eruption, exposing soft dentine which wears rapidly
normal mantle dentine
affects primary> permanent
What are some of the signs of OI?
Bone fragility Multiple fractures Unstable vertebral column Blue sclera Progressive hearing loss Bisphosphonates- risk of osteonecrosis Dentinal changes
What are the signs and symptoms of X -linked vitamin D-resistant rickets?
Aka Hypophosphatemic rickets Rachitic changes in long bones Failure of distal tubular phosphate reabsorption Short stature Bowing of legs ↓Serum phosphate, ↑Alkaline phosphatase Large pulp chambers and elongated pulp horns Abscesses in the absence of caries
What defect causes achondroplasia?
defect in FGFR3 gene
Sporadic mutation in 75% and AD
What are the signs of achondroplasia?
Shortened arms and legs. Upper arms & thighs > than forearms and lower legs
Large head size, frontal bossing
Flattened nasal bridge
Crowding due to small jaws especially maxilla
What is cleidocranial dysotosis?
Defective development of intramembraneous ossification Short in stature Delayed closure of sutures Absent clavicles - can touch each shoulder together Frontal & parietal bossing Hypoplastic maxilla & zygoma Multiple unerupted teeth Multiple supernumeraries
What is gigantism caused by?
Overproduction of pituitary growth hormone
Usually due to adenoma - a benign tumour formed from glandular structures in epithelial tissue
What happens if there is overproduction of the pituitary growth hormone before and after fusion of the epiphyses in gigantism?
results in gigantism of whole skeleton
after - results in acromegaly
What is gigantism called in adults?
Acromegaly
What are the signs and symptoms of acromegaly?
Continued growth at the mandibular condyle Gross prognathism Macroglossia Spacing of the dentition Thickening of the facial soft tissues Overgrowth of hands and feet
What is a pseudogene?
section of a chromosome that is an imperfect copy of a functional gene
What are some functions of junk DNA?
used to produce noncoding RNA components such as transfer RNA, regulatory RNA and ribosomal RNA.
Landing spots for proteins that influence gene activity
Strands of RNA with myriad roles
Places where chemical modifications silence stretches of
chromosome
What is a promoter sequence?
Short sequence of bases upstream of the start of each gene where RNA polymerase recognises and binds to
What are the three types of RNA polymerase found in eukaryotes and what do they do?
Polymerase I - nucleolar region of nucleus, transcribes
large ribosomal RNA
Polymerase II - mRNA precursors
Polymerase III - small RNAs (tRNA), 5S ribosomal RNA
and other small DNA sequences
What is the importance of TFIID?
TFIID is the first protein to bind to DNA during the formation of the pre-initiation transcription complex of RNA polymerase II (RNA Pol II). Binding of TFIID to the TATA box in the promoter region of the gene initiates the recruitment of other factors required for RNA Pol II to begin transcription
where do most POL II genes have a TATA box?
25 – 35 bases upstream
of initiation site
What promotor contains the TATA box?
basal promoter
What are enhancers?
DNA sequences which can control efficiency
and rate of transcription. Regulate expression of genes in
specific cell type and control timing of gene expression
Why are promoter sand enhancers ‘cis’ acting elements?
they are on the same molecule of DNA as the gene they regulate
How can tumour promoting viruses and translocations cause cancer?
Tumour promoting viruses transform healthy cells by inserting strong promoters in vicinity of growth-stimulating genes, while translocations in some cancer cells place genes that should be “turned off” in the proximity of strong promoters and enhancers
Which end of the strand is transcription started?
5’
how can enhancers be brought closer to promoters?
Looping of the DNA due to interactions between proteins bound to the enhancer and those bound to the promoter
these proteins are called activators and the proteins that inhibit the looping are called repressors
What do enhancers contain?
binding site sequences for
transcription factors (TF)
and enhance/upregulate
transcription.
Active enhancers are bound by activating TF and brought into proximity of target promoters by looping.
Where do transcription factors bind?
bind to promoter and enhancer sequences
and recruit RNA polymerase. Basal transcription factors are
required at every promoter site for RNA polymerase interaction
(TFIID).
Why are transcription factors ‘trans’ acting elements?
they are encoded by a different gene to that they are regulating
What does RNA polymerase catalyse?
the sugar-phosphate bond between 3’-OH of ribose and 5’ PO4
What allows RNA molecules to have structural and catalytic functions?
The ability to fold into complexthree-dimensional shapes
What causes POL I to pause and release transcript? (transcription strand)
Termination of pol I genes by a termination factor = hair pin loop
What is the sequence AAUAAA required for?
The sequence AAUAAA is found near the polyadenylation site of eucaryotic mRNAs. This sequence is required for accurate and efficient cleavage (needed for release of polymerase from DNA template) and polyadenylation of pre-mRNAs in vivo
At which end are mature pol II mRNA’s polyadenylated?
3’ end
What 3 things happen as RNA polymerase moves down the strand?
- CAP on 5’ end - to stabilize the pre-mRNA,
essential for transport of RNA out of nucleus - Alternative splicing
- Poly(A) tail on 3’ end - cleavage at AAUAAA
(stop codon) by endonuclease then multiple adenosine
added, up to 250. This step needed for release
of polymerase from DNA template
Why does pre-mRNA need to be capped?
Protects from degradation
Serves as assembly point for proteins needed to recruit
small subunit of ribosome to begin translation
What is alternative splicing?
A mechanism by which different forms of mature mRNAs (so different proteins) (messengers RNAs) are generated from the same gene
- different splicing sites are selected - splicesomes
- plasticity allows for diseae development
What is an exon?
a segment of a DNA or RNA molecule containing information coding for a protein or peptide sequence.
What are the two types of spliceosome?
Major – removes 99.5% of introns
Minor – removes remaining 0.5%
What are the two main functions of a spliceosome?
- Recognition of intron/exon boundaries
- Catalysis of cut and paste reactions which remove non-coding introns and stitch flanking exons back together
spliceosome contains both proteins and RNA’s
How are spliceosomes linked to disease?
Mis-splicing = rapid degeneration of mRNA
Mis-regulation of splicing factor levels = cancer
What are the 7 types of RNA?
- mRNA
- rRNA
- tRNA
- Non-coding RNA (ncRNA)
- Small nuclear RNA (snRNA)
- small nucleolar RNA (snoRNA)
- micro RNA (miRNA)
What does rRNA do?
Build ribosomes
What are the 4 kinds of rRNA?
18S - one of these along with other proteins
make the small subunit of the ribosome.
28S, 5.8S and 5S - one each of these, along with 45 other
proteins used to make the large subunit of the ribosome.
S = (Svedberg unit) sedimentation rate, related to mass and shape
What does tRNA do?
Each kind carries, at 3’ end, one of 20 amino acids
i.e. most amino acids have more than one tRNA
What does small nuclear RNA do?
RNA biogenesis and processing
several are part of spliceosomes
What does snoRNA do?
Participate in making ribosomes by helping to cut large precursor of 28S, 18S and 5.8S.
Modify many nucleotides in rRNA, tRNA and snRNA e.g. can add methyl groups to ribose
Implicated in alternative splicing of pre-mRNA
Template for synthesis of telomeres
What do miRNA do?
Tiny RNA molecules regulate gene function post-transcriptionally - estimated more than one third of protein
18-25 nucelotides long
Bind to mRNA and cause degradation – inhibits protein synthesis
what does DNA fingerprinting use to differentiate?
variable number of tandem repeats (VNTRs)
Repeating nucleotides (15 -100) 1kb to 20kb. Number of repeats and loci are inherited from your parents. Large variation of number of these regions between individuals
repeat regions bounded by specific restriction enzyme sites - restriction enzymes can cut the DNA at specific sequences - cuts the VNTR’s out
How is cDNA produced for PCR?
RNA is used to make cDNA from mRNA, then cDNA is multiplied by PCR , DNA can then be detected
What 5 things do you need for PCR?
template - DNA/cDNA nucelotides - A,C, G, T primers Taq buffer
What are the 3 steps of PCR?
- denaturation to break the cDNA double bonds - 94 degrees
- annealing - temperature lowered to 54 degrees to allow the primers to bond to the DNA template (45 seconds)
- Extending - when the temperature is raised and the new strand of DNA is made by the Taq polymerase enzyme. (2 mins 72 degrees)
Why does PCR detect the accumulation of DNA during the reaction?
Different amounts of DNA in starting sample and if measurements taken
at plateau the data would not truly represent the starting material.
Exponential phase is optimal point for analyzing data.
What does SYBR green bind to?
Any double stranded DNA
What are the advantages of real-time PCR?
Traditional measure at end-point and real-time collects data in
exponential growth phase
Increase in reporter fluorescence directly proportional to number of
amplicons generated
Increased dynamic range of detection
No post-PCR processing
Detection down to 2-fold change
What does in situ hybridisation detect?
localization technique for the detection of a gene product (RNA) in tissues
What is the transcriptome?
The transcriptome is the set of all RNA molecules in one cell or a population of cells.
What is proteomics?
– large scale study of proteins, particularly their structures and functions, includes post-translational modifications
What is metabolomics?
comprehensive characterization of small molecule metabolites in biological systems
What is a single nucleotide polymorphism?
DNA sequence variations when single nucleotide in genome sequence is altered
Many have no effect on cell function, others predispose to disease, influence response to drugs or environmental insults (bacteria, viruses, toxins, chemicals).
What specific gene is associated with periodontal disease?
An increase in a specific genotype of IL-1 gene
What molecule could control the inflammatory periodontal response caused by increased IL-1?
IL-1RA - interleukin-1 receptor antagonist is similar in structure to IL-1α and IL-1β and so competes with these for the surface receptor. It doesn’t cause ”normal” signaling ie acts as competitive inhibitor and could control the inflammatory response.
How many repeats of VNTRs is associated with perio?
2 repeats
What are the phases of the cell cycle?
S phase - replication of DNA G2 - cell prepares to divide M phase - cell division and cytokineses G0 - cells leave cell cycle that cease division G1 - cell grows S phase
Which phases of the cell cycle are collectively known as interphase?
G1, S, G2
What are the stages of the M phase?
Prophase - condensation of chromatin and disappearance of nucleolus
prometaphase - the nuclear membrane breaks apart into numerous “membrane vesicles”, and the chromosomes inside form protein structures called kinetochores. Kinetochore microtubules emerging from the centrosomes at the poles (ends) of the spindle reach the chromosomes and attach to the kinetochores, throwing the chromosomes into agitated motion.
metaphase - These chromosomes, carrying genetic information, align in the equator of the cell
anaphase - replicated chromosomes are split and the daughter chromatids are moved to opposite poles of the cell.
telophase -During telophase, the effects of prophase and prometaphase (the nuclear membrane and nucleolus disintegrating) are reversed. As chromosomes reach the cell poles, a nuclear envelope is re-assembled around each set of chromatids, the nucleoli reappear, and chromosomes begin to decondense back into the expanded chromatin that is present during interphase. The mitotic spindle is disassembled and remaining spindle microtubules are depolymerized
How is the cell cycle regulated? (3 places)
Extra & Intracellular signals
G1 checkpoint – growth & environment
G2 checkpoint – DNA replication
M checkpoint – chromosome alignment on spindle
What are cyclins?
Proteins that control the cell cycle
Where is cyclin D present?
G1 - cdk 4 and 6
Where is cyclin E and A present?
S phase
Where is cyclin B and A present?
M phase
What molecule has to associate with cyclin for it to carry out its task? What controls its activity?
Cyclin dependent kinases - phosphorylate cyclins to activate them
activity controlled by cdk inhibitors
Give some examples of cells that enter G0 phase?
Neuron, epithelial cell, red blood cells - specialised cells
How is the g0 phase activated?
Active repression of genes
Which protein blocks the cell cycle if DNA is damaged? (G2 checkpoint)
p53 (mutated in approx 50% of cancers including oral- hence tumour forms as cell cycle continues)
Which protein with reduced levels predicts a poor outcome in breast cancer?
p27 - less of an aid to cyclins if reduced levels
What type of genes are many cell regulatory genes?
Tumour suppressor genes
Why does apoptosis occur?
Destroys cells that may be a threat - virus infected, immune after inflammation has been dealt with, DNA damaged cells
What signals can trigger apoptosis?
Withdraw of positive signals such as growth factors, hormones
or if the cell receives negative signals e.g. UV, death activators, hypoxia
What processes happen to the cell in apoptosis?
Mild convulution chromatin compaction and margination condensation of cytoplasm breakup of nuclear envelope blebbing cell fragentation apoptotic bodies are phagocytosed
What are the differences in apoptosis and necrosis?
Apoptosis Controlled Energy dependent cells shrink Membrane intact Non-inflammatory No scarring Indiv. or small cell groups Nuclear fragmentation Physiological (or Pathol.)
Necrosis Uncontrolled No ATP required Cells swell No membrane integrity Inflammatory Scarring Large cell groups Nuclear dissolution Pathological
What is the intrinsic pathway of apoptosis?
Mitchondria senses various apoptotic stimuli
releases cytochrome C - involved in electron transport chain
binds to Apaf-1 protein
forms complex that initiates a cascade of proteolytic enzyme reactions - carry out degradation processes = apoptosis
What does bcl-2 bind to?
oncogene that binds to Apaf-1 protein - prevents complex formation with cytochrome C, which prevents apoptotic cells dying, this allows DNA damaged cells etc to stay alive
What is the intrinsic pathway of apoptosis?
Ligand binds to membrane receptor e.g. FasL to Fas
intiates cascade of phosphorylation reactions within cell transducing signal to activate enzyme cascade that carry out apoptosis
What are caspases?
Family of proteolytic enzymes - affectors of apoptosis (do the digesting)
- present as inactive proenzymes as don’t need them all the time
activated by proteolytic cleavage which activates another enzyme etc = cascade (all enzymes have different substrates and controlled by different mechanisms)
What does caspase 9 activate?
caspase 2, 3, 6, 7, 8, 10
Example of disease where apoptosis goes wrong
Treacher Collin’s syndrome, cleft palate/lip
What virus can inactivate p53?
HPV
What virus protein is similar to bcl-2 - prevents cells from apoptosing?
Epstein Barr Virus protein - nasopharyngeal cancer
What cancer inhibits expression of Apaf-1?
Melanoma
What do some tumours produce to block T cell cytotoxicity?
Fas antagonists
Examples of autoimmune conditions in which apoptosis does not occur
SLE, rheumatoid arthiritis
Examples of conditions where there is an increase in apoptosis causing disease
Neurodegenerative
Hiv
In what condition is it common to view apoptotic bodies under H&E?
Lichen Planus
Name some examples of epigenetic changes
DNA methylation, histone modification, nucleosome location or non-coding RNA (micro RNA)
What is the most common transepigenetic signal?
transcription factor –
activates its own
transcription so epigenetic state is self-sustaining
Give some examples of some cis epigenetic signals
DNA methylation or
changes in histones
How can methylation prevent transcrption of a gene?
Blocks the bind of transcription factors to the promoter region
What is Zebularine?
DNA methylation inhibitor
What chemical marks the future of tooth forming regions?
pax9
What is mutation of pax9 associated with?
Oligodontia
What is GREM2 mutations associated with?
Isolated tooth agenesis, microdontia, short tooth roots, taurodontism, sparse and slow growing hair, dry and itchy skin
What type of RNA is expressed less of in molars compared with incisors?
miRNA
What causes teeth to develop into a single row?
Antagonistic Actions of Msx1 and Osr2 Pattern
What is Riegers syndrome?
Hypodontia with malformations of anterior chamber of the eye
What is holoprosencephaly?
abnormalities in forebrain cleavage and midface development
Which is the most abundant enamel matrix protein?
Amelogenin
What are the advantages of using salivary glands for a method of gene therapy?
Well-encapsulated, limiting undesirable spread of vector.
Luminal membranes of virtually every epithelial cell in SGs are easy to
access in a relatively non-invasive manner.
Ductal access of SGs uses a limited fluid volume that is not diluted or
disseminated following delivery, enabling use of low vector doses.
Salivary epithelial cells are well differentiated and very slowly dividing,
providing a relatively stable cell population for non-integrating vectors.
SGs normally make large amounts of protein for export, both exocrine
and endocrine
A single SG is not crucial for life and can be removed in event of
unexpected adverse effect with relatively little morbidity, cf liver or lung!!!
What are the 2 general pathways for protein secretion\/
Predominant leading to saliva (mucosal; across apical
membrane).
Constitutive leading mainly towards interstitium and bloodstream
(serosal; across basolateral membrane).
What gene could potentially restore salivary flow after radiation?
human aquaporin-1 (cDNA)
What are exosomes?
durable, cell-specific lipid microvesicles
can migrate through the vasculature
reside in a number of biofluids, eg urine, blood, breast milk, bronchial
lavage fluid, CSF and saliva
true functions not known
but suggested could range from immune
response regulators to tumour invasion promoters.
What suggested that saliva may show biomarkers of tumours elsewhere in the body?
Breast cancer-derived exosomes could activate transcription in salivary gland
cells and alters the salivary gland-derived exosomes in terms of their
proteome and transcriptome
This suggests that tumour-derived exosomes could function as a shuttle
between distal tumour and oral cavity – resulting in discriminatory salivary
biomarkers.
Pancreatic tumour exosomes function in this way too.
What is hyperplasia?
increase in cell number
What is metaplasia?
the abnormal transformation of one differentiated cell type to another differentiated cell type within the same germinal layer- not cancer
What is dysplasia?
the presence of cells of an abnormal type within a tissue, which may signify a stage preceding the development of cancer.
What are the 3 cell types?
Labile e.g. epidermis, GI tract epithelium, stable (G0)e.g. hepatocytes, permanent cell e.g. neurons, cardiac myocytes
What is a hamartoma?
mostly benign, focal malformation that resembles a neoplasm in the tissue of its origin. Tissues are normal for site but excessive e.g. moles, haemangioma - collection of small blood vessels under the skin.
What is hyperplasia?
- increase in cell numbers
- response to stimulus
- regression once stimulus removed
- increased size and function
an example where hyperplasia is physiological?
normal growth and development
puberty and pregnancy
an example where hyperplasia is pathological?
parathyroids and thyroid
Where is hyperplasia common?
bone marrow, lymphoid tissue
• chronic irritation/inflammation
What is hypertrophy?
- increase in cell size
* often occurs with hyperplasia
Give some examples of where pure hypertrophy occurs?
• muscle – mechanical stimulus
skeletal - exercise
smooth - pregnancy
cardiac – LVH in hypertension/MI/endocrine disorder
What is agenesis?
the failure of an organ to develop during embryonic growth and development due to the absence of primordial tissue
What is asplasia?
• fails to develop normal structure
What is hypoplasia?
less tissue formed
Give some examples of hypoplasia
Enamel hypoplasia
Hypoplastic mandible and malocclusion
What is atrophy?
Decrease in size and number of cells
usually by apoptosis, or reduction in structural components of the cell especially proteins
not necrosis (mostly)
Give examples of generalised atrophy?
- nutritional – e.g. in starvation
- senile
- endocrine organs
- bone - osteoporosis
What are the causes of localised atrophy?
- ischaemic
- pressure
- disuse
- neuropathic/denervation
- immune mediated (autoimmune)
- idiopathic
What disease displays hemifacial atrophy? (starts with R)
Romberg’s disease
Why does metaplasia happen?
changes in environmental demands e.g. smoking causes changes in from columnar to metaplastic squamous cell in bronchi
What is ectopia?
a displacement or malposition of an organ or other body part to another part of the body, which is then referred to as ectopic e.g. ectopic pregnancy
normal tissue, abnormal site
What is a neoplasm?
• an abnormal mass of tissue
• growth of which is excessive
• and is unco-ordinated with that of normal
tissues
• and persists after the provoking stimulus is
removed
What is invasion defined as?
unconfined growth into CT –
What is the defining feature of malignant tumours?
Invasion
What does cytology mean?
features of individual cells
What type of tumour is a pleomorphic adenoma in a parotid gland?
Benign
What are the effects of a benign tumour?
- pressure e.g. in the brain
- obstruction
- function – esp hormone secretion
What does anaplasia mean?
the loss of the mature or specialized features of a cell or tissue, as in malignant tumours. They don’t resemble any particular tissue
What does stroma mean?
the supportive tissue of an epithelial organ, tumour, gonad, etc., consisting of connective tissues and blood vessels.
What type of tumour is a SQCC of tongue and larynx?
Malignant
What differences in cytology do cancer cells have to normal cells?
Large number of irregularly shaped dividing cells
large variably shaped nuclei
small, cytoplasmic volume relative to nuclei
variation in cell size and shape
loss of normal specialised cell features
disorganised arrangement of cells poorly defined tumour boundary
odd mitoses
Where do 90% of tumours originate?
Epithelium - benign (in the lining = papilloma, or in glands = adenoma)
mesenchymal/ connective tissue tumours -
What is a teratoma?
a tumour composed of tissues not normally present at the site (the site being typically in the gonads - testes, ovaries).
What are the 4 stages of carcinogenesis? (I, P , T, P)
Initiation - carcinogen causes genetic change - permanent DNA damage
Promotion - cell multiplication
Transformation - genetic changes to malignant cell
Progression - to malignant tumour
Which type of genes are often mutated in cancer?
Tumour suppressor genes
What is the lifetime breast cancer risk if you have the BRCA1 and BRCA2 gene?
BRCA1 - 65%
BRCA2- 45%
onset around age 41-43
What does the histogenetic classification classify tumours into?
On basis of their tissue of origin
epithelial - then benign or malignant
mesenchymal - then benign or malignant
What could be used in young people to create bio-engineered teeth?
Wisdom tooth germs
Further studies need to identify tooth-inducible stem cells in the elderly
What type of stem cells are SHED?
multipotent, capable of differentiating into neural cells, odontoblasts
What are the dental applications of isolating stem cells from teeth?
Growing teeth
repair/regeneration of dental tissue e.g. pulp/PDL
craniomaxillofacial bone repair - DPSC and craniofacil osteoblasts both derived from neural crest cells
What are some cell types that can derived from dental stem cells?
a) Cementoblast
b) Adipocyte
c) Odontoblast
d) Neuronal cells
e) Myoblast
f) Chondrocyte
g) Pulp cells
h) Hepatocyte
i) Endothelial cell
j) Osteoblast
k) Melanocyte
not ameloblast
What extra-oral applications of SHED have been used so far?
SHED improves cognitive function in model of Alzheimer’s
Tissue engineered sheet of DPSC to reconstruct cornea
SHED muscle rengeration in muscular dystrophy
DPSC enhances bone mineral density and enhanced vascular invasion similar intramembranous ossification
What are the problems with stem cells?
Rejection/ Immune reaction
Legal & Ethical & Political, especially embryonic stem cells & human cloning
Adult stem cells difficult to isolate & purify
May be the cells that produce cancer
What 3 things are need to stimulate regeneration of a tissue (C, S, S, )
Cells
Scaffold - ECM
Signals
What is gene therapy?
A technique for correcting defective genes responsible for disease development.
Normal gene inserted into genome to replace defective one.
Vectors deliver gene to patient’s target cells
Vectors commonly viruses (Retro, Adeno or Adeno associated)
Why is the use of salivary glands in gene therapy an advantage?
Encapsulated & accessible. Stable cell population which export large amounts of protein. Can be removed if there is a problem Sjogren’s syndrome / Radiation damage. Could be used for systemic conditions.
What are the problems with gene therapy?
Immune response/ Virus vectors (Jesse Gelsinger 1999)
Gene therapy causes cancer: leukaemia in 2 children treated for X-SCID
Multi-gene disorders e.g. heart disease, most cancers not well suited to gene therapy
Short lived – integration of DNA into genome, rapidly dividing cells
Ethics & Regulation - germ cell therapy
How is the gene actually edited within the cell?
recognise specific DNA sequences - specific genes
cut DNA - restriction enzyme/nuclease
insert new gene via vector
What is CRISPR technology?
Clustered, Regularly Interspaced, Short Palindromic Repeat (CRISPR) technology, an important new approach for generating RNA-guided nucleases, such as Cas9
How is gene editing used in acute lymphoblastic anaemia?
Genetically engineer donor immune cells to attack cancer
TALEN used to add CAR19 gene which will recognise CD19
Also disabled a receptor on donor cells that the body would recognise as ‘foreign
What are the challenges in gene editing?
Technology is in a relatively early stage and needs to be further developed.
Can enough cells be edited to have therapeutic impact?
Will the editing be exquisitely specific, or will other regions of the genome aside from the target be affected?
‘Designer babies’!
How may patients be screened and diagnosed for genetic defects predisposing to a disease?
Microarray analysis –
Gene chips
Expression of 61,000 genes
analysed simultaneously
& rapidly
Could use saliva
Identify patients with: disease (before symptoms) ↑ risk of recurrence responders to therapy customise treatment
Why do benign and malignant tumours arise?
• benign tumours little known, many be inherited factors • malignant tumours inherited factors environmental factors chemical agents physical agents viruses
What is the latent period in cancer?
time from promotion to clinical tumour
What are pro-carcinogens?
a precursor to a carcinogen. One example is nitrites when taken in by the diet. They are not carcinogenic themselves, but turn into nitrosamines in the body, which can be carcinogenic
What are co-carcinogens?
a chemical that promotes the effects of a carcinogen in the production of cancere
What is a direct tumour?
tumour arises at the site of carcinogen application
• e.g. smoking and lung cancer
What is an indirect tumour?
tumour arises at different site from carcinogen application
• e.g. aromatic amines – industrial exposure:
inhaled - lungs
metabolised in liver
excreted in kidney
bladder enzymes release aminophenol which results in bladder carcinoma
Name some chemical carcinogens
Smoking - polycyclic hydrocarbons including tar
diet - burnt hydrocarbons
asbestos - fibrous silicates, when inhaled = fibrosis or mesothelioma ( type of cancer that develops from the thin layer of tissue that covers many of the internal organs (known as the mesothelium). The most common area affected is the lining of the lungs and chest wall.)
Name a physical carcinogen
ionising radiation
damages DNA and causes mutations
source- x rays, radioactive metals and gases
UV light
damages DNA
causes squamous/basal cell carcinoma and malingant melanom
What are the most sensitive tissues to cancer? (most to least sensitive)
those where the
cells are rapidly renewed.
most to least: embryonic tissues haematopoietic organs (spleen, bone marrow) the gonads the epidermis the intestinal mucous membranes (variable) connective tissue muscle tissue and nerve tissue
What is xeroderma pigmentosum?
genetic disorder (autosomal recessive) in which there is a decreased ability to repair DNA damage such as that caused by ultraviolet (UV) light.
Name some viral carcinogens
DNA viruses
• more common
• viral DNA inserted into host DNA
RNA viruses
• reverse transcribed and then inserted
• may contain “oncogenes”
What does Epstein-Barr virus cause?
Epstein-Barr virus - Burkitt’s lymphoma, nasopharyngeal carcinoma
What cancer can hep B/C cause?
hepatocellular carcinoma
What does HPV inactivate to cause cancer?
• Viral protein binds to and
inactivates the tumoursuppressor, p53
What chemicals or processes can act as promotors of carcinogenesis?
• hormones breast cancer hormonal dependence ovary, adrenal - prostate cancer testosterone
- drugs, inc alcohol
- inflammation
What tissue does a leiomyosarcoma affect?
Smooth muscle
What tissue does a chondrosarcoma affect?
Cartilage
What tissue does an adenocarcinoma affect?
Glandular epithelium
What tissue does a carcinoma affect?
Surface epitheliu,
What type are 90% of malignant tumours?
- 90% carcinoma
* 10% lymphoma or sarcoma (more in young)
What types of cancers are increasing in incidence?
Breast, lung, prostate, oral, bowel, malignant melanoma, kidney, liver
What is the link between oral cancer and deprivation?
Higher incidence of oral cancer in more deprived people
How does cancer develop? (3 ways)
de novo - from new
via a benign tumour
via a premalignant lesion - HNSCC some cases
What is premalignancy
some of the changes in cells and tissue architecture are seen before invasion occurs • this disorganisation of the tissue is called DYSPLASIA
forms the basis of cancer screening - detection of premalignancy e.g. cervical smears or oral leukoplakia and dysplasia in the mouth
Where is the maximum rate of growth on a graph?
at the peak height velocity
Where do the genitals experience particularly rapid growth?
During adolescence
What happens to lymphoid growth in childhood and then in adolescence?
The lymphoid tissues grow rapidly in childhood and by twelve years of age represent about twice the size of their relative final size. The tonsils in particular reduce in size during adolescence
Why can standing height be used as a measure of facial growth?
facial growth occurs at more or less the same time as growth in height (with the exception of the orbits and part of the upper face).
Height change over time measured as standing height might therefore be used as a proxy for growth in facial structures.
What is a stadiometer?
a measure device for height
What do velocity charts have on their axis?
Age on the x axis
cm/year on y axis
What is post-natal growth characterised by?
Post-natal growth is characterized by a rapid, then rapidly declining growth, in the early years. This then levels off in the period four to ten years, and increases again during the pubertal growth spurt. Growth then tails off again to zero by the age of sixteen for girls and eighteen for boys.
What did Sullivan show?
it is possible to predict PHV with an error of about six months using standing height.
What is the main limitation of measuring height as a predictor of growth?
Tell us current status and doesn’t predict the future necessarily
Which method remains the mos accurate and least invasive method of assessing growth status in a dental or orthodontic patient?
Standing height measurement
How may use of secondary sexual characteristics be useful in dentistry?
the simple observation that when a young child is entering adulthood these changes occur and generally herald an increase in growth velocity can be valuable when assessing a patient with a dental deformity. Such information can usually be elicited by tactful history taking.
What are the problems with the hand-wrist radiograph measurements?
Houston concluded that information from hand-wrist radiographs is of only limited value in predicting the time of peak height velocity (PHV) and is no more accurate than standing height measurement
Since they use potentially damaging ionising radiation hand-wrist radiographs are now considered an inappropriate tool in orthodontic investigation
Why is a cephalogram a popular method of determining growth?
the analysis can be carried out on a lateral cephalogram which is frequently taken by orthodontists for other clinical reasons.
not using extra radiation
When would peak mandibular growth velocity occur if examining the 3 cervical vertebrae?
They suggested that peak mandibular growth velocity would occur within one year of CVMS II. (second stage out of 5 references stages)
What is the visualised treatment objective (VTO) and what an issue with it?
This uses average growth increments for each chronological age to give expected growth. It produces an output from a computer system.
studies have shown that much of the data produced does not reflect the final outcome as there are great variations in growth and treatment response.
What is the recommended method for making a growth prediction? but what is the problem with this?
use existing data from a patient such as a cephalogram and add average growth increments
Unfortunately the assumption that an individual’s future growth pattern will be the same as average is least appropriate in those patients whose facial growth differs significantly from the average. These are the patients where a good prediction would be most useful.
What did Berhents find about craniofacial changes?
There is an increase in all facial dimensions which continues throughout life. The size and shape of the craniofacial complex changes with time
Vertical changes are most prominent and antero-posterior changes are less prominent. Little change in width occurs
Female growth decelerates in the teens and then resumes in their twenties
The magnitude of these growth changes is small but cumulative over years
Growth rotation continues and on average there is a small decrease in the face height with a reduction in the Frankfurt mandibular plane angle
Compensatory changes occur in the dentition
Greater changes occur in the soft tissues rather than the hard tissues
Lip incompetency decreases with age
Lower lip grows more, and combined lip growth exceeds, lower face height (LFH)
What are three types of bone?
Trabecular/cancellous bone - 20% of skeleton, porous meshwork, mainly in axial skeleton
Cortical/ compact/laminar bone - approx 80% of the sekelton, dense, strong, outer layer
Woven bone - forms quickly during periods of repair or rapid growth and is remodelled into lamellar bone.
What percentage of bone is organic and inorganic?
Bone is 30% organic material (majority is collagen), 45% inorganic [hydroxyapatite (HA)-a hydrated crystalline material of calcium and phosphate].
What is the bone matrix made up of?
Scaffold of interwoven collagen fibres (>95 % type I collagen, <5% type V).
Between fibres are small, uniform, plate-like crystals of carbonated hydroxyapatite
Small amounts of non-collagenous proteins, some which are unique to calcified tissue (eg osteocalcin).
What are the functions of bone?
Support the body and protect internal organs
allows movement - bones provide attachment for muscles so allowing leverage
Haematopoiesis - bone marrow is the major producer of blood cells including cells of the immune system
calcium homeostasis - serum calcium levels maintained by intestinal absorption, renal excretion and skeletal mobilisation or uptake
What is the connective tissue surrounding bone?
Endosteum (inner) and the periosteum (outer)
What are the cell types in bone
Osteoclast (Oc):
Large multinuceated cells. Bone resorbing cells.
Osteoblast (Ob):
Bone forming cells.
Osteocyte:
Originate from osteoblasts which have become embeded in the bone matrix. Involved in sensing mechanical loads and Ca homeostasis.
Bone lining cells.
Originate from osteoblasts. Line quiescent periosteoal and endosteal surfaces of bone .
Osteoprogenitor cells (stromal cells). Precursors of osteoblastic lineage.
What do the cell processes of osteocytes do?
Cell processes lie in cannaliculi and link to each other and blood vessels for passage of nutrients
Why does bone remodelling occur?
release calcium or
alter architecture of cancellous bone to meet new stresses.
What shape cells are osteoblasts?
Cuboidal
Why are osteoblasts arranged in rows on the bone surface?
Because bone can only grow by appositional growth
What is appositional growth?
when the cartilage model also grows in thickness (diameter) due to the addition of more extracellular matrix on the peripheral cartilage surface, which is accompanied by new chondroblasts that develop from the perichondrium.
happens in bone remodelling
What is endochondral ossification?
bone develops by replacing hyaline cartilage. Activity in the epiphyseal plate enables bones to grow in length (this is interstitial growth)
What are the two phases of bone remodelling and
Starts with resorption phase - bone ECM destroyed and removed = 3 weeks
bone formation phase - new ECM formed and mineralised = 3-4 months
What is the mechanism of bone remodelling? (10 steps)
- Bone resorption initiated by recruitment of osteoclast precursors to remodeling site
- Osteoclast precursors mature into osteoclasts.
- Bone lining cells erode a little ECM and leave the remodelling site.
- Osteoclasts bind to the ECM exposed by bone lining cells and digest the bone matrix with enzymes to form a resorption pit.
- Osteoclasts stop digesting matrix and die (apoptosis).
- Osteoblast precursors recruited to the remodeling site.
- Osteoblast precursors develop into mature osteoblasts.
- Osteoblasts make new ECM to fill the resorption pit made by the osteoclasts.
- When the synthesis of matrix is complete, the new bone surface becomes covered in bone lining cells.
- Osteoblasts trapped within the ECM become osteocytes
When is bone formation required to produce new bone?
during formation of the skeleton
during fracture repair
during tooth socket healing after extraction
What is the first type of bone laid down in bone formation?
woven bone - but the trabeculae are disorganised and cannot bear weight until remodelling occurs
What are the two ways that bone can form?
- Bone is formed directly from condensed mesenchyme or ectomesenchyme = intramembranous ossification (IMO) (osteoblasts formed)
- A cartilaginous precursor of the bone is formed and replaced by bone as it grows = endochondral ossification (ECO) (chondrocytes formed)
What are the differences between interstitial and appositional growth?
Interstitial growth occurs in hyaline cartilage of epiphyseal plate, increases length of growing bone. Appositional growth occurs at endosteal and periosteal surfaces, increases width of growing bones. Interstitial growth only occurs as long as hyaline is present, cannot occur after epiphyseal plate closes.
What happens in intramembranous ossification?
mesenchymal stem cells migrate to the site of eventual bone formation condense, align differentiate into osteoblasts and secrete an organic framework of extracellular matrix (osteoid) is laid down in long strands. Others MSCs differentiate to form blood vessels
Osteoblasts line the osteoid and begin to deposit calcium salts, mineralization, forming the bone matrix, forming trabecula - cycles of secretion and mineralisation (appositional growth)
areas that completely fill with mineralised osteoid = compact bone
areas that don’t completely fill in and contain lattice structures = priary cancellous bones
skull, clavicle, part of the mandible, facial bones, basicranium
What happens in endochondral ossification?
the process of converting the cartilage in embryonic skeletons into bone. Cartilage is deposited early in development into shapes resembling the bones-to-be. Cells inside this cartilage grow and begin depositing minerals.
The spongy bone forms, and osteoblasts (build bone, produce proteins, etc.) attach and lay down the mineral portions of spongy bone. Osteoclasts (erode bone to free up calcium) remove material from the center of the bone, forming the central cavity of the long bones. The perichondrium, a connective tissue, forms around the cartilage and begins forming compact bone while the above changes are occurring. Blood vessels form and grow into the perichondrium, transporting stem cells into the interior. Two bands of cartilage remain as the bone develops (epiphyseal plates), one at each end of the bone. During childhood, this cartilage allows for growth and changes in the shape of bones
- all bones except skull, clavicle
- A miniature cartilage replica of a bone is formed by differentiation of mesenchymal or ectomesenchymal cells into chondroblasts which mature into chondrocytes
- Cartilage grows in a specific direction – by interstitial and appositional growth + invasion of blood vessels
- Cartilage is converted into bone
What is a haversian system/ osteon?
the fundamental functional unit of much compact bone
What is creidocranial dysostosis?
a rare genetic disorder that interferes with intramembranous ossification (skeletal dysplasia):
Autosomal dominant-defect in the RUNX2 gene
Neurocranium underdeveloped - delay in closure of sutures
Viscerocranium (facial skeleton) underdeveloped with severe dental malocclusion, delayed formation/ eruption, narrow high arched palate with increased incidence of cleft palette
Large head and frontal bossing
Clavicles reduced or absent-characteristic feature - can touch shoulders together
What are the 3 zones of the epiphyseal growth plate?
Proliferation zone
- parallel columns of dividing cells
- formatin of ECM
hypertrophic zone
- significant increase in cell size
- matrix reduced
- down regulation of ecm
- production of factors to stimulate blood vessel ingrowth
cartilage/ bone interface
- cartilage matrix mineralisation
- chondrocyte apoptosis (cell death)
- blood vessels grow
- production of new bone on mineralised cartilage matrix
after fusion of the plates, EO only happens during fracture repair
What is achondroplasia?
a autosomal dominant genetic condition that affects bone formation via ECO.
= dwarfism
genetic defect in gene for FGFR-3 a membrane receptor is important in response of chondrocytes to growth factor (FGF-18) during development of cartilage template.
all bones formed by ECO reduced in length - trunk and limbs short basicranium short - middle 1/3 of face sunken producing a dish face profile with class III malocclusion
How much calcium is there in the body and where is it primarily?
1kg in bone, 99% in bone
Blood and ECF total 2.2mM = 60% Calcium
Intracellular 100nM basal
What is Trousseau’s sign?
reduced blood flow
Neuromuscular irritability
hypocalcaemia (low calcium) causes sodium influx in nerves - hence triggers uncontrolled contractions
tetanic contraction - muscles twitching
How much calcium does the USA advice in adults?
1300mg adults
How is calcium uptaken from the diet?
In the small intestine
via transcellular (through the cell) - happens in low intake, active process
via paracellular (between cells)- happens in high intake, passive process
How is plasma calcium controlled (gut, kidney, bones, thyroid, parathyroid)?
Gut takes up dietary calcium - plasma absorbs some from the gut
kidney excretes excess calcium - some reabsorption from the kidney with the aid of vitamin D from the gut
Bone resorption and mineralisation balances levels in the plasma
Parathyroid glands - chief cells release PT hormone when calcium levels are low, this causes osteolytic osteolysis (breaks down bone, stimulates osteoclasts - releases calcium ions in the circulation which maintains ION POTENTIAL)
release causes hydroxylation of vitamin D in the kidney - activates vitamin D
calcitonin released from parafollicular cells when calcium is high, inhibits bone resorption, not a significant role as removal of thyroid glands doesn’t affect calcium levels much
What happens when there is too much calcium in the body?
Bone pain, insomnia, high blood pressure, asthma, cramps, anxiety, arrythmias, soft tissue calcification, constipation, increase in urination
What vitamin is crucial to the uptake of calcium and what is its effect?
Vitamin D
Allows SI absorption
upregulates carriers (transcellular) and changes junctions to be more porous to movement- paracellular
What reactions occur to pro-vitamin D by the sun?
pro-vitamin to vitamin D3 and then hydroxylated in the liver and kidney (PT hormone) giving active vit D - 1,25-(OH)2D
not really a vitamin as it can be synthesised in the body
What are the effects of vitamin D deficiency on the developing teeth? 20% incidence
6-24 months of age enamel hypoplasia enlarged pulp horns delayed eruption caries risk prevention : vitamin D and fluoride
What effect does vitamin D have on bone turnover?
Effect on OB
Osteoblasts release RANK ligand
osteoclast differentation
osteoclast activation
What are the non-skeletal roles of vitamin D?
Cancer autoimmune disease hypertension and CVS disease Diabetes muscle strength schizophrenia and depression
What is osteomalacia (adults)?
lack of remineralisation in bones pathological amount of callus matrix causes pseudofractures including mandible bone pain muscle weakness periodontitis
can see areas of radiolucencies and pseudofractures on x rays (not proper fractures, poor mineralisation)
What is osteoporosis?
Bone becomes more porous/meshwork like Bones more likely to break with a fall reduced uptake of dietary calcium imbalance of bone turnover - less oestrogren as you age, so reduces osteoclast inhibition, so more bone is broken down reduced bone mineral density
vitamin D and calcium mixed tablets
Alendronic acid tablets
load bearing exercise in children and not adults
How does cancer affect the patient?
- Invasion (local spread)
- pressure/obstruction
- destruction & loss of function
- metastasis
- non-metastatic effects
- 25% will die from cancer-related cachexia (weakness and wasting of the body due to severe chronic illness)
what are the modes of spread of cancer?
Invasion: local spread
• path of least resistance
• tissue destruction
• perineural spread
Metastasis: lymphatic spread
• invasion of vessels – embolism or permeation
• spread to draining lymph node(s)
Metastasis: haematogenous spread
• invasion of blood vessels– mainly veins
tumour may enter the vascular system from the lymphatics via the thoracic duct
• organs
liver, lung, bone and brain
Metastasis: transcoelomic spread
• spread across serous cavities - pleural, pericardial, peritoneal
• e.g. abdominal cavity
colon cancer, ovarian cancer
How are tumour cells able to spread?
• tumour cells interact with cells and molecules in the local
environment
tumour cells gain new abilities • motility is enhanced • alter adhesion molecules • make poor basement membrane • increase protease production or reduce inhibitors • alter ECM
“metastatic cascade
Where do carcinomas usually spread?
Lymphatic
Blood (often later)
Where do sarcomas usually spread
• blood (lymphatic spread rare)
Where does a lung tumour usually spread to?
local nodes, liver, bone and
brain
When does a tongue tumour usually spread to?
neck nodes, later lung
and spine
What are the effects of tumour spread? (P, D, H, I, P, A, S)
- pressure and obstruction
- destruction
- haemorrhage
- infection
- pain
- anaemia
- starvation & cachexia
What are the non-metastic effects of tumour spread?
often caused by biochemical substances released
by tumour cells, e.g. TNFα
• Fever, anorexia and weight loss/cachexia
• endocrine syndromes
• Cushings syndrome
• metabolic effects e.g. hypocalcaemia
• neurological problems e.g. neuropathy
• haematological syndromes e.g. erythrocytosis
What is paraneoplastic syndrome?
a syndrome (a set of signs and symptoms) that is the consequence of cancer in the body, but unlike mass effect, is not due to the local presence of cancer cells.
What type of assessment is the grading of tumours?
histological assessment • often related to differentiation • linked to prognosis • various methods • numerical grades (1,2,3 etc) • low, intermediate, high
What is the TNM system?
• T = tumour • N =nodes (regional) • M =metastases - distant • specific staging systems for tissue/tumour
How is cancer diagnosed?
- biopsy
- cytology (FNA)
- imaging – CT and MR scanning
- molecular analysis
How is cancer treated?
- Surgery
- Radiotherapy
- Chemotherapy
- Biological (immune) therapy
- Supportive care and palliative cre
What are the side effects of radiotherapy?
- Tiredness
- Feeling sick
- Difficulty eating and drinking
- Skin reaction
- Hair loss
- Haematological changes
- Possible long-term side effects
What is IMRT?
Intensity-modulated radiation therapy (IMRT) is an advanced type of radiation therapy used to treat cancer and noncancerous tumors. IMRT uses advanced technology to manipulate photon and proton beams of radiation to conform to the shape of a tumor - delivers less dose to normal tissue and can save important structures being affected
What types of drugs are used in cancer treatment?
Convention chemotherapy agents - cytotoxic (targeting DNA)
Targeted agents - Targeted therapies act on specific molecular targets that are associated with cancer, whereas most standard chemotherapies act on all rapidly dividing normal and cancerous cells
Hormonal therapies - e.g. blocks oestrogen in breast cancer
Biologic therapies - repair, stimulate, or enhance the immune response.
What does cytostatic mean?
block tumor cell proliferation
What are the side effects of chemotherapy?
Alopecia Pulmonary fibrosis cardiotoxicity local reactions to the injection renal failure neuropathy myalgia sterility cystitis diarrhoea nausea/ vomiting
What are the oral problems in cancer management?
• Oral mucosal disease • Dental disease • Discomfort • Social embarrassment Dry mouth immuno-compromised difficulty in maintain oral hygiene
What questions can be answered by cancer biomarkers?
Is it likely to develop this cancer what type of cancer is it is this the optimal drug for my cancer what's the optimal dose for my body will the cancer return?
What is Cushings’ syndrome?
a collection of signs and symptoms due to prolonged exposure to glucocorticoids such as cortisol. … Cushing’s syndrome is caused by either excessive cortisol-like medication such as prednisone or a tumor that either produces or results in the production of excessive cortisol by the adrenal glands.
causes:
- taking too much steroid
- a growth (tumour) in the pituitary gland in the brain
- a tumour in one of the adrenal glands above the kidneys
What are the main endocrine glands/organs in the body?
Pituitary gland Thyroid gland Thymus gland Adrenal glands Pancreas Ovary glands Testis
What does the hypothalamus releasing hormoning stimulate the pituitary to do and where does the hormone get secreted from?
Stimulates the pituitary to release hormones which leave from the anterior pituitary
What is acromegaly?
a hormonal disorder that develops when your pituitary gland produces too much growth hormone during adulthood. When this happens, your bones increase in size, including those of your hands, feet and face. Acromegaly usually affects middle-aged adults
- not increasing in height in middle age
What is gigantism?
As its name implies, gigantism causes the individual to grow taller than average. This condition, which most often affects children, occurs due to a noncancerous tumor on the pituitary gland that creates too much growth hormone.
What is the homeostatic system linking the hypothalamus, pituitary and liver?
Hypothalamus releases growth hormone releasing hormone which stimulates pituitary to release growth hormone which stimulates the liver to release insulin-like growth factor 1 which has a negative feedback effect on the pituitary and hypothalamus
What effect does IGF-1 have on chondrocytes?
Increases their recruitment, proliferation and matrix - hence bones get fatter and longer in acromegaly/gigantism
What effect does oestrogen have on growth hormone?
Increases GH secretion
Induces epiphyseal plate closure - so becomes insensitive to GH, won’t grow any taller
What is the affect of androgens?
testosterone and other androgens can be converted to oestrogen via enzymatic pathways
hence why males grow bigger - extra oestrogen pathway
androgen receptor in bone too
oestrogen acting on growth plate whereas androgen acting on radial bone?
How does growth hormone affect muscles?
GH affects via IGF1 for myofibril prolliferation
usually proportionate to body size but little evidence that GH promotes hypertrophy
Pararcrine IGF1 has a rolr ein load-induced hypertrophy
How does oestrogen affect condylar growth?
Oestrogen inhibits condylar growth and testosterone increases
how do glucocorticoids modulate growth hormone?
Increases GH secretion
Affects sst and GHRH release
chronic exposure reduces GH release
treatment of children with corticosteroids likely to reduce growth
in adults risk of osteoporosis, protein loss and raised serum lipids
chronic glucocorticoid use mitigated by rGH
leads to glucose intolerance
What does growth hormone promote?
Promotes gluconeogenesis, glucogenolysis, lipolysis - increases blood glucose levels (diabetogenic)
insulin is then released to compensate
long term this can lead to insulin resistance
How does thyroid hormone affect growth?
T3 affects chrondrocytes and osteoblasts in growth plate
drives IGF1 synthesis prepubertal
Stimulated GH synthesis
Hypothydroidism reduces adult height
At what stage is thyroid hormone and growth hormone more important?
TH dependent - prepuberty
GH dependent - puberty
both drop off after puberty
What are the 4 models of disability? (SIMB)
Social model Individual model (includes the medical model) medical model biopsychosocial model
What is the medical model of disability?
Views disability as functional limitation which
is biologically or physiologically determined
Medical-biological diagnosis which emphasises: Individual pathology, Individual (personal) deficit, Individual medical treatment
What is the individual model of disability?
Disability is viewed as a tragic problem
for isolated, unfortunate individuals.
The focus is on what the individual can’t
do, or what’s wrong with them
The individual model incorporates the
medical model
What is the UPIAS definition of disability?
it was not our impairments that were the main cause of our problems as disabled people, but that it was the way society responded to us as an oppressed minority
What is impairment?
the permanent loss or limitation of physical, cognitive or sensory functioning
What is disability?
the loss or limitation of
opportunities to take part in the everyday life of any given community on an equal basis with others, resulting from structural and social barriers which take little or no account of people with disabilities, and excludes them from the mainstream of social activities.
What is the UK social model of disability?
Disability is seen as oppression either institutional or societal or both We live in a disabling society Society disables (through barriers; attitudinal or structural) those who have impairments
How may be medicine be part of the problem in addressing disability?
For some disabled people health care workers (doctors, dentists, nurses etc.)
are ‘part of the problem’.
Health assessments often emphasise individual deficit in an attempt to ensure that disabled people receive the resources and services they need
What is the biopsychosocial model of disability?
Views disability as arising from a combination
of factors at the physical, emotional and
environmental levels
Consistent with the WHO’s revised definitions of disability
Recognizes that impairments are often due to illness or injury and does not dismiss the importance of the impact of biological,
emotional and environmental issues on health, well-being, and function in society
What legal acts are relevant to disability?
Mental Capacity Act (fully enacted November
2007) - Any preconceptions and prejudicial assumptions held by a person making the assessment of capacity must therefore have no input into the assessment of capacity
Human Rights Act 1998 (in force 2004)
Equality Act Oct 2010 (supersedes DDA)
What 4 reasons are there for why a person may not be able to make a decision?
the person cannot comprehend the information relevant to the decision
the person can’t retain the information for long enough to make the decision
the person cannot use the information to weight it up and arrive at a decision
the person cannot communication the decision in any way e.g. not even by blinking to say yes or no
What is fluctuating capacity?
Capacity in the past does not mean the person has capacity now however take into consideration past as well as present wishes
consider written statements whilst capacity was present
consider values and beliefs of the person
seen in progressive or acquired impairments
Talk to the person Include them in choices and decisions about their care Find out how each individual communicates Use non-medical language to explain Do not assume they cannot understand
How are craniofacial anomalies classified?
Embryological defects
- evident at birth
- more severe anomlies may be incompatible with life
Developmental defects
- may not be immediately apparant
- presentation often worsens with growth
Give some examples of embryological defects
Facial clefts - cleft lip and/or palate, mid face clefts
first arch anomalies - hemi facial microsomia, treacher collins syndrome
What is the mildest presentation of incomplete cleft lip?
Forme frustre - almsot there
failure of fusion of the last little section
causes gap in the vermillion border and a minor degree of asymmetry
affects later incisor/canine - canine guidance
What are the clinical issues with cleft lip or palate?
Facial appearance Hearing difficulties speech difficulties dental anomalies, crowding oronasal fistula growth and scarring from surgery skeletal III pattern
Why can cleft palate cause hearing loss?
Abnormal palatal function affects drainage of the inner ear
build up of fluid in the middle ear which can be intermittent or cause a long term hearing deficit
Why do half of all children with cleft palate have speech difficulties?
Backing issue - can’t say d sounds - G instead because hard to place tongue against upper front teeth normally
Nasality - palate doesn’t seal off the back of the mouth well - surgery can make the palate longer
Which tooth is missing in 30-50% of cleft case?
Upper permanent lateral incisor
What percentage of cleft cases have anomalies?
54%
What can surgical repair of a cleft palate lead to?
Restriction of maxillary development
adverse effects of facial growth
Why do cleft children suffer with more dental disease than their peers?
Because of the connection to the nose (oronasal fistula), strong tastes aren’t preferred so toothpaste is too strong for them and toothbrush bristles are hard and dont want it to go near the sensitive area.
Prefer soft food that can just be swallowed which are usually heavily sugar laden
quality of their enamel - pitted hypoplastic enamel makes it hard to maintain poor oral hygiene
What is holoprosencephaly?
Failure of the brain to dividie into left and right hemispheres
causes median facial clefting
all midline features affected to variable extent
range of presentations
pituitary gland develops in the midline
What is hemifacial microsomia?
Embryological defect at 4 weeks - interrupted blood supply to branchial arch causing restricted facial development
range of presentations
one side of the face doesn’t grow as well as the other - affects the development of the lower half of the face, most commonly the ears, the mouth and the mandible.
What is treacher collins syndrome?
Autosomal dominant mutation of gene controlling TREACLE protein which affects amount and low of mesenchyme in first and second pharyngeal arches
What are the main signs of treacher collins syndrome?
Hypoplastic maxilla (espec zygomatic arches) and mandible Ear anomalies often with atresia of auditory canals Ocular anomalies - coloboma Cleft palate/high arched palate Airway problems affects zygomatic bone- very little support for the cheekbones usually have a bone achored hearing aid
What craniofacial abnormalities may be developmental?
Craniosynostoses e.g
Crouzon’s syndrome
Apert’s syndrome
Achondroplasia
What is craniosynostosis?
Premature fusion of 1 or more fibrous
sutures resulting in distortion/abnormal
cranial development and facial features.
20% are linked to a specific syndrome
Aetiology- autosomal dominant/spontaneous
mutation
What is Crouzon’s synrome?
Type of craniosynostosis
•Autosomal dominant/spontaneous mutation •Variable expression •Premature fusion of sutures results in abnormal skull development and raised intra cranial pressure (often needs early surgical release).
What are the clinical issues with craniosynostoses? (8)
•Facial appearance •Increased intra cranial pressure – often require early and subsequent surgery. •Hydro cephalus. •Restricted mid face development: Choanal atresia (blocking of nasal air passages),Obstructive Sleep Apnoea •High arched palate •Speech difficulties •Hearing difficulties •Class III skeletal pattern
What is Apert’s syndrome?
incidence 1 in 50,000
Similar facial presentation to Crouzon but also has associated syndactyly
Aperts is also associated with learning difficulties whereas crouzon’s is not
What is achondropalsia?
Dwarfism
autosomal dominant
a disorder of bone growth that prevents the changing of cartilage (particularly in the long bones of the arms and legs) to bone.
It is characterized by dwarfism, limited range of motion at the elbows, large head size (macrocephaly), small fingers, and normal intelligence.
What is the dental importance of craniofacial abnormalities?
•Understand the multidisciplinary nature of
care for these individuals
•Prevention as a high priority.
•Ensure routine care is accessable and a
crucial part of a complex overall treatment
strategy
Which arches fuse to form a single arch?
4, 5, 6,
What are the arches separated by externally?
Clefts
What are the arches separated by internally?
Pouches that correspond to clefts
What is the structure of the pharyngeal arches?
Outer surface covered by ectoderm
Inner surface covered by endoderm
mesoderm between the endoderm and ectoderm
Packed with ectomesenchyme
Each arch has an arch artery, vein and cranial nerve, skeletal element and muscle block (from mesoderm so migrated into the arch).
What cranial nerves are associated with each of the 4 arches?
• 1st arch, trigeminal • 2nd arch, facial • 3rd arch, glossopharyngeal • 4th arch, vagus
What genes set up identity?
• Patterns of Hox gene expression within the midbrain and hindbrain set up identity • As cells migrate from the neural tube they keep this pattern • Regulates movement and differentiation of the cells
What muscles develop from arch 1?
muscles of mastication
• some suprahyoids
• tensor veli palatini
• Supplied by third division of CNV
What muscles develop from arch 2?
muscles of facial expression
• some suprahyoids
• stapedius
• All supplied by CNVII
What muscles develop from arch 3?
- one trivial muscle (stylopharyngeus)
* Supplied by CNIX
What muscles develop from arch 4?
- pharyngeal constrictors
- muscles of soft palate and larynx
- All supplied by CNX
What muscles develop from arch 1?
muscles of mastication • some suprahyoids • tensor veli palatini digastric anterior belly tensor tympani • Supplied by third division of CNV
What muscles develop from arch 2?
muscles of facial expression • some suprahyoids • stapedius posterior belly of digastric • All supplied by CNVII
What skeletal derivatives develop from arch 1?
meckel's cartilage - malleus and incus of ear maxilla and mandible spine of sphenoid bone sphenomandibular ligament palatine bone squamous part of temporal bone anterior ligament of malleus
What skeletal derivatives develop from arch 2?
Stapes,
styloid process,
Stylohyoid ligament, and
Lesser cornu of the hyoid bone.
What skeletal derivatives develop from arch 3?
Large proportion of the hyoid bone (neural crest)
What skeletal derivatives develop from arch 4?
laryngeal cartilages and epiglottis
Which pharyngeal cleft gives rise to the external auditory meatus?
1st cleft
all others only form temporary cervical sinuses – which are then obliterated by the rapidly proliferating 2nd pharyngeal arch.
What do the pharyngeal pouches give rise to?
1st Eustachian tube and middle ear cavity
2nd Lining of the palatine tonsils
3rd
Dorsal – Inferior parathyroid glands
Ventral – Thymus
4th
Dorsal – Superior parathyroid glands
Ventral – Ultimobranchial body (C cells)
What does the fifth pharyngeal pouch develop into?
cells that migrate into the
thyroid gland and secrete
thyrocalcitonin
Describe the development of the tongue
1st arch - Lateral lingual swellings and tuberculum impar from 1st arch which produces the anterior portion of tongue (body) – innervated by lingual nerve (from trigeminal nerve)
Arch 3 swellings overgrows arch 2 so doesn’t contribute to development of tongue really
Arch 3 – posterior 1/3 of tongue receives innervation from glossopharyngeal nerve
4th arch - epiglottis - vagus
Why are muscles of the tongue innervated by the hypoglossal nerve?
Muscles of tongue are innervated by hypoglossal nerve
Muscle migrates from paraxial mesoderm and drag their nervous supply with them – hypoglossal nerve
Which arch do the majority of arch malformations affect?
1st
Clearest impact on skeletal structures • Hypotrophic mandible • Conductive hearing loss (incus and malleus) • Malformed external ear • Can be part of a syndrome arch
