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Define and compare disorder and disease

A disorder is the general term for any derangement of abnormality of function that is typically used for a problem or condition
A disease is a change in structure or function that is considered to be abnormal within the body


What is a syndrome?

A group of symptoms that might be caused by a specific disease or by several interrelated problems


Define pathogensis

The description of how a particular disease progresses (acute or chronic)


What is the étiologie of a disease?

The cause
Can be idiopathic (unknown), nosocomic (acquired), or iatrogenic (caused by treatment)


Compare morbidity and mortality

Morbidity refers the the state of being diseased or unhealthy within a population
Mortality is the term used for the number of people who died within a population


What are the top 5 causes of death in children under 5?



What are some typical paediatric problems?

Acute illness (respiratory infections)
Chronic illness (asthma, diabetes)
Injury (accidental or not)
Disability (physical, intellectual)
Eating disorders
Mental health disorders


What are some causes of disease?

Inflammation and infection
Nutritional imbalance
Impaired immunity
Hyperplasies and neoplasms


What is hyperplasia?

An increase in the number of cells in an organ or tissue
Appear normal under a microscope
Not cancer but may become cancer


What is désolasia?

Cells that look abnormal under a microscope but are not cancer


What are neoplasm?

Abnormal mass of tissue (tumor) arising from new cell growth (uncontrolled) and/or inability of cells to die when they should
Can be benign (limited growth, encapsulated, easily removed, non fatal) or malignant (uncontrolled growth, invade surround tissue, metastasize, deadly)


What are the two types of leukaemia?

Acute lymphoblastic leukaemia (ALL) -75%
Acute myeloid leukaemia (AML) -20%


Describe ALL

B cell: 85-90%
T cell: 10-15%
Can be infant (<12 months), childhood (1-9 years), or adolescent (>/=10)


What are some symptoms of leukemia?

Bone pain
Bleeding or bruising


How do you diagnose leukemia?

Bone marrow aspiration


What is the most common genetic abnormality in leukemia?



What are the sanctuary sites of cancer?



What is the treatment for leukemia?

Involves risk stratification to low, standard, high, or very high.
Treatment is then based in age, presence after induction, presence of disease at sanctuary sites and cytogenetics and molecular genetics results
Treatment may involve chemo, stem cell for very high, and immunotherapy for relapsed


What are the two types of SCT?

Allogeneic: stem cells from donor, complications include graft versus host, failure to take, spurious infection due to immunocompromise, used for patients with leukemia
Autologous: receive your own stem cells that were previously harvested, no graft vs host, fewer complications, used to allow higher doses of chemo


What are the different types of solid Timor?

Bone sarcoma
Soft tissue sarcomas
Rénal tumours
Liver tumours
Germ cell tumours


What are the two types of bone sarcomas?

Ewing’s or osteosarcoma


What are the two types of soft tissue sarcomas?

Rhabdomyosarcoma (40%): occurs mainly in young kids (<10), two subtypes (alveolar t1:13, and t2:13, and envryonal), prognosis depends on site, pathology, stage, and resection, treated with anything
Non-rhabdomyosarcoma (60%): heterogenous group of diseases, mainly treated with surgery (infant fibrosarcoma can use chemo)


What are the different types of renal tumours?

Wilms tumour
Clear cell sarcoma of the kidney
Rhabdoid tumour
Rénal cell carcinoma


What are the different types of liver tumours?

Hepatocellular carcinomas


Describe CNS tumours

Can occur in supratentorium (gluons and ependydmoma) or infratentorium (posterior fossa and brain stem)
Account for 20% of all childhood cancers
Second most common group
Frequently occur in young children <3 years with worse prognosis but can occur with all kids


What are some hallmarks of cancer?

Sustaining proliferation signalling
Resisting cell death
Inducing angiogenesis
Enabling replicative immortality
Activating invasion and metastasis
Evading growth suppressors


What is apoptosis?

Programmed cell death
The death of cells that occurs as a normal and controlled part of an organisms growth or development
Cell suicide
Hallmarks: morphological (cell shrinkage, chromatic condensation, cell budding) and biochemical (DNA fragmentation, activation of caspases, protéolytic cleavage of key proteins)


What is the purpose of apoptosis?

Needed for proper development in tissue remodeling, organ formation, formation of synopses
Needed to destroy cells that represent a threat to the integrity of the organism


What are the three pathways to apoptosis?

ER mediated
Death-receptor mediated
Mitochondria mediated
All lead to formation of caspases by cleavage of subunits and combination of large and small


Describe the activation of caspases

Extrinsic: death receptors indice signalling complex with activates initiator caspase 8 and pro-apoptopic BID protein (which goes to mitochondria). 8 activiste executioner caspases
Intrinsic: mitochondria releases cytochrome c which causes conformation change in caspases leading to activation of initiator caspase 9


How are caspases inhibited?

Indirect: regulation of mitochondria and ER permeability
Direct: caspase inhibitors


How is permeability regulates?

Closing and opening of channels
Opening: proapoptotic bid binds to pro-survival Bcl-2, removing it from the opening and allowing the releases of pro-spoptotic factors leading to apoptosis


What possible treatment Does the permeabilkty pathway of apoptosis inhibition lead to?

Targeting the Bcl-2 family to allow apoptosis in cancer cells to occur using agents such as ABT-737


What is p35?

Baculorviral protein that blocks defensive apoptosis (direct inhibition)
Contains a broad range of inhibitors, inhibiting caspase-1,3,6,7,8,10
Also inhibits C. Elegans
Once bound, p35 undergoes conformational change and is therefore irreversible


What are IAPs?

Inhibitors of apoptosis protein
Are often implicated in neurofegenerative diseases and cancer
Inhibit cell death induced by various triggers


How to IAPs supress apoptosis?

1. BIR domains: are involved in the direct binding and inhibition of cell-death professes, specifically caspases 3,7,9
2. RING domains: function as E3 ligase that médiate the ubiquitination of binding proteins to target them either for proteasomal degradation or for signaling complex formation


What are SMAC mimetics?

Promising new anti-cancer drugs
Stable and bio available small molecule compounds
Designed against the AVPI tetrapeptide sequence of SMAC that antagonizes IAP function
Potency has been shown t greatly increase dimerization
Pan-IAP antagonists that mainly target cIAP1 and cIAP2 and to a lesser extent XIAP
Kills through multiple mechanisms


What are the four major factors known to cause congenital malformations?

1. Chromosomal abnormalities
2. Gêne abnormalities
3. Intra-utérine injury
4. Environmental factors


What are the different types of congenital malformations?

Structural: clubfoot, congenital dislocated hip, gear defects, spina bifida, cleft palate
Metabolic: phenylketonuria, yay-Sachs disease, galactosemia, maple syrup urine disease


Describe congenital dislocated hip

Abnormality of the hip joint where the femoral bead slips out of the normal position that becomes noticed in the first months
Symptoms: asymmetrical folds of the affected thigh, difference in leg length, positive Ortolanis (clicking)
Étiology: unknown ex improper position prior to or during birth or relaxation of joint due to maternal hormones
Diagnosis: x Ray
Treatment: cast/splint for 3 months (maybe surgery)
Prevention: prenatal care


Describe clubfoot

Frequent deformity of foot or ankle
Symptoms: fixation of the foot
Etiology: unknown ex. Fetal positioning, genetics
Diagnosis: physical exam and X-ray to assess severity
Treatment: successful if caught early by using splint or cast depending on severity
Prevention: none


Describe spina bifida

Neurological tube effect where the vertebrae fail to close over the spinal cord, generally in the low back
Symptoms: skeletal malformation, deformed joints, paralysis of legs, bowel incomtinence
Etiology: unknown risk factors are maternal radiation, obesity, diabetes, lack of folate, genetic factors
Diagnosis: x Ray and prenatal screening, look for skin defect over spinal area and muscle abnormalities
Treatment: surgery in first 24 hours w/ addition support depending on severity
Prevention: folic acid level maintenance


What are the three types of spina bifida?

Occulta: most coming, a symptomatic, dumpling of skin, dark hairy patch
Mengingocele: meninges of spinal cord peptide though the opening in vertebrae, fluid filled sack, nerve tissues not involved therefore no neurological issues
Myelomengocele: most severe form, spinal cord protrudes, neurological problem


What are some chomoskm abnormalities that can leads to genetic defects?

Failure of segregation: aneuploidy (one less) or polyploidy (one more), can occur in first of second division
Breaks and rearrangement: deletions, translocations (balanced or unbalanced), inversions (paracentric:long part, or pericentric:middle part), or duplication


What are some examples of chromosomal disorders?

Trisomy 13, 18, or 22
Turners syndrome
47 XYY syndrome


Describe tricking 13

Patau syndrome
Typically not compatible with life, most dying in first days or weeks
Only 10% live past first year
Symptoms: severe intellectual disability and physical abnormalities (also see heart defects, brain and spinal cord abnormalities, very small or poorly developed eyes, extra digits, cleft lil, and hypotonia


Describe trisomy 18

Edwards syndrome
1/5000 births but frequently fatal before and after birth (6-10% past first year)
Symptoms: severe intellectual disability (other system abnormalities, growth delay, low birth weight, small abnormally shaped head, small jaw and mouth, clenched fist, club feet


Describe trisomy 21

Down syndrome
1 in 800 but goes up with age
Symptoms: mild to moderate intellectual disability (facial appearance, hypotonia, heart defects, GI tract abnormalities)
Increased risk of reflux, celiac disease, hearing an vision problems, leukemia and hypothyroidism
Can be very productive members of society


Describe turners syndrome

Missing or partially X chromosome
1 in 25000 newborn girls
Symptoms: impaired devlopment (short stature, loss of ovary function, don’t undergo puberty without hormone therapy, may also see webbed neck, low hairline on back, swelling in lower extremities, and heart defects)


Describe klinefelter’s

Extra copy of X chromosome in males
1/500-1000 but usually not diagnosed until puberty
Symptoms: failure of normal male sexual development (sterility, small penis and tests, large breasts, minimal or absent body hair, decreased muscle development)


Décrive 47 XYY syndrome

Extra Y chromosome on males
Symptoms: not physically obvious, may be taller, normal sexual development, can have kids (complications: risk of learning disabilities, delayed language development and skills and motor skills, hypotonia, motor ticks, behavioural and emotional difficulties, autism)


What was Garrod’s hypothesis?

In an organism, one metabolic step is catalyzed by one enzyme
One gene = one enzyme
Genetic input in each metabolic step in an organism


Describe the first real example of inherited metabolic diseases

PKU in 1934 by folling
He found 2 children with severe mental retardation and noticed that the urine had an unusual odor. He found it had an unusual chemical reaction with FeCl and discovered it was phenylpyruvic acid.
Found that 8 of 430 children shared the same reaction. He found it was chased by a blocking of tyrosine formation from phenylalanine, resulting in a build-up of phenylalanine and resulting in the formation of phenylketones


What are the different things doctors look at to diagnose a metabolic disease?

Substrates: acylcarnitines (MCAD)
Products: glucose (GSD I-glycogen storage disease)
Byproducts: succinylacetone (type I tyrosinemia)
Enzyme: hexosaminidase (Tay-Sachs disease)
Gene: aldolase B (HFI)


What was the PKU treatment discovered in 1953?

Bickel found that restriction of dietary phenylalanine intake prevents mental retardation. He found the diet must be instituted before any significant symptoms are evident.


What are some treatments of PKU aside from diet?

Biopterin: allows more tolerance of Phe in diet as a chaperone therapy but very expensive
Large natural amino acid supplements: Phe enters the brain via LNAA transporters so LNAA act as competitive inhibitors
Enzyme replacement therapy: give enzyme that breaks down Phe either orally in intestines of parenterally in blood
Gene therapy


What are the different types of prevention?

Tertiary; treatment of affected individuals to prevent séquelae (presenting clinically)
Secondary: early diagnosis and treatment prevent morbidity, trying to find the disease before an individuals expresses it
Primary: intervention to prevent disease, stop smoking


What is the current test for PKU?

Guthrie test
Put a drop of blood on agar that contains a bacteria that is Phe dépendant in growth. Blood diffusés out radial, the concentration dropping as it goes. The larger the bacterial circle the higher the Phe and the higher the chance they have PKU
Also used tandem mass spectronomy


Describe the Wilson and jungner criteria

Disease characteristics: serious, natural history understood, preclinical stage (high prevalence, period before overt disease)
Screening test: sensitive and specific, simple and cheap, safe and acceptable, reliable
Diagnosis and treatment: facilities are adaquste, effective acceptable and safe treatment available


What are lysosome storage disorders?

Results from the disruption in the sequential degradation of by-products or cellular turnover
Most are autosomal recessive disorders excepts for Danon, fabry, and hunter syndrome
Results in storage of hndegraded substrate


How are mitochondrial disorders classified?

Small molecule disease: carbs, amino acids, organic acids, purines/pyrimidines
Organelle disease: lysosomal, peroxisomal, mitochondrial, golgi/ER


What is MCAD deficiency?

As fatty acids are shortened via fatty acid oxidation, enzymes don’t work as well with smaller chains resulting multiple enzymes overlapping in the cycle in normal bêta oxidation
Occurs when one enzyme defect blocks remaining chain
Risk factor: infancy (30% risk of death due to severe fasting hypoglycaemia, 30% risk of beurocognitive disability)
Treatment is highly effective/simple using intravenous glucose and avoiding fasting