Clinical Sciences Flashcards
What is Niacin ?
Vitamin B3 -
It is a precursor to NAD+ and NADP+ and hence plays an essential metabolic role in cells.
what does B3 deficiency lead to?
pellagra: dermatitis, diarrhoea, dementia
what are the different types of molecular biology techniques?
Southern blotting Detects DNA
Northern blotting Detects RNA
Western blotting Detects proteins
Uses gel electrophoresis to separate native proteins by 3-D structure
Examples include the confirmatory HIV test
SNOW (South - NOrth - West)
DROP (DNA - RNA - Protein)
what are interferons?
Interferons (IFN) are cytokines released by the body in response to viral infections and neoplasia. They are classified according to cellular origin and the type of receptor they bind to. IFN-alpha and IFN-beta bind to type 1 receptors whilst IFN-gamma binds only to type 2 receptors.
what produces interferon alpha?
what is its action and what are the adverse effects?
produced by leucocytes
antiviral action
useful in hepatitis B & C, Kaposi’s sarcoma, metastatic renal cell cancer, hairy cell leukaemia
adverse effects include flu-like symptoms and depression
what produces interferon beta ?
what is it action and what is it useful in?
produced by fibroblasts
antiviral action
reduces the frequency of exacerbations in patients with relapsing-remitting MS
what is interferon gamma?
what produces it, what is its action and what is it useful in ?
predominately natural killer cells. Also by T helper cells
weaker antiviral action, more of a role in immunomodulation particularly macrophage activation
may be useful in chronic granulomatous disease and osteopetrosis
What HLA antigen is haemochromatosis associated with?
HLA-A3
What HLA antigen is Behçet’s disease associated with?
HLA-B51
What conditions are associated with HLA B27?
ankylosing spondylitis
reactive arthritis
acute anterior uveitis
psoriatic arthritis
What HLA antigen is Coeliac associated with?
HLA-DQ2/DQ8
What conditions are associated with HLA-DR2?
narcolepsy
Goodpasture’s
What conditions are associated with HLA-DR3?
dermatitis herpetiformis
Sjogren’s syndrome
primary biliary cirrhosis
what conditions are associated with HLA-DR4?
type 1 diabetes mellitus
rheumatoid arthritis - in particular the DRB1 gene (DRB104:01 and DRB104:04 hence the association with DR4)
What is the chloride shift?
CO2 diffuses into RBCs
CO2 + H20 —- carbonic anhydrase -→ HCO3- + H+
H+ combines with Hb
HCO3- diffuses out of cell,- Cl- replaces it
what is the Bohr effect?
increasing acidity (or pCO2) means O2 binds less well to Hb
what is the Haldane effect?
increase pO2 means CO2 binds less well to Hb
what is IL-1?
What secretes IL-1?
Interleukin 1 (IL-1) is a key mediator of the immune response. It is secreted mainly by macrophages and monocytes and acts as a costimulator of T cell and B cell proliferation.
what are the effects of IL-1?
increasing the expression of adhesion molecules on the endothelium. By stimulating the release by the endothelium of vasoactive factors such as PAF, nitric oxide and prostacyclin it also causes vasodilation and increases vascular permeability. It is therefore one of the mediators of shock in sepsis. Along with IL-6 and TNF, it acts on the hypothalamus causing pyrexia.
What are examples of IL-1 inhibitors and what’re they used for?
anakinra
IL-1 receptor antagonist
used in the management of rheumatoid arthritis
canakinumab
monoclonal antibody targeted at IL-1 beta
used systemic juvenile idiopathic arthritis and adult-onset Still’s disease
What is Phenylketonuria?
Phenylketonuria (PKU) is an autosomal recessive condition caused by a disorder of phenylalanine metabolism. This is usually due to defect in phenylalanine hydroxylase, an enzyme which converts phenylalanine to tyrosine. In a small number of cases the underlying defect is a deficiency of the tetrahydrobiopterin-deficient cofactor, e.g. secondary to defective dihydrobiopterin reductase. High levels of phenylalanine lead to problems such as learning difficulties and seizures.
where is the gene for phenylalanine hydroxylate located?
he gene for phenylalanine hydroxylase is located on chromosome 12.
What are the features of Phenylketonuria?
usually presents by 6 months e.g. with developmental delay
child classically has fair hair and blue eyes
learning difficulties
seizures, typically infantile spasms
eczema
‘musty’ odour to urine and sweat*
How is Phenylketonuria diagnosed?
Guthrie test: the ‘heel-prick’ test done at 5-9 days of life - also looks for other biochemical disorders such as hypothyroidism
hyperphenylalaninaemia
phenylpyruvic acid in urine
X-llinked recessive inheritance?
In X-linked recessive inheritance only males are affected. An exception to this seen in examinations are patients with Turner’s syndrome, who are affected due to only having one X chromosome. X-linked recessive disorders are transmitted by heterozygote females (carriers) and male-to-male transmission is not seen. Affected males can only have unaffected sons and carrier daughters.
Each male child of a heterozygous female carrier has a 50% chance of being affected whilst each female child of a heterozygous female carrier has a 50% chance of being a carrier.
The possibility of an affected father having children with a heterozygous female carrier is generally speaking extremely rare. However, in certain Afro-Caribbean communities G6PD deficiency is relatively common and homozygous females with clinical manifestations of the enzyme defect are seen.
How is Vitamin D Resistant rickets inherited?
What causes it?
Vitamin D-resistant rickets is a X-linked dominant condition which usually presents in infancy with failure to thrive. It is caused by impaired phosphate reabsorption in the renal tubules
Features of Vitamin D-resistant rickets?
failure to thrive
normal serum calcium, low phosphate, elevated alkaline phosphotase
x-ray changes: cupped metaphyses with widening of the epiphyses
Diagnosis and management of Vitamin D resistant rickets?
Diagnosis is made by demonstrating increased urinary phosphate
Management
high-dose vitamin D supplements
oral phosphate supplements
what cancers does EBV increase risk of?
Burkitt’s lymphoma
Hodgkin’s lymphoma
Post transplant lymphoma
Nasopharyngeal carcinoma
What cancers does HPV 16/18 increase risk of ?
Cervical cancer
Anal cancer
Penile cancer
Vulval cancer
Oropharyngeal cancer
What virus increases risk of Kaposi’s sarcoma?
HPV 8
What is Penetrance and Expressivity?
Penetrance describes the proportion of a population of individuals who carry a disease-causing allele who express the related disease phenotype. Expressivity describes the extent to which a genotype shows its phenotypic expression in an individual.
Penetrance
describes ‘how likely’ it is that a condition will develop
examples of conditions with incomplete penetrance include retinoblastoma and Huntington’s disease
in contrast, achondroplasia shows 100%, or complete, penetrance
Expressivity
describes the ‘severity’ of the phenotype
a condition with a high level of expressivity is neurofibromatosis
what causes varying gene penetrance and expressivity?
These phenomena are thought to be due to a number of factors, including:
Modifier genes
Environmental factors
Allelic variation
what is Riboflavin?
What does deficiency in Riboflavin lead to?
Riboflavin is a cofactor of flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) and is important in energy metabolism.
Consequences of riboflavin deficiency:
angular cheilitis
how is iron absorbed?
upper small intestine especially the duodenum
about 10% of dietary iron absorbed
Fe2+ (ferrous iron) much better absorbed than Fe3+ (ferric iron)
absorption is regulated according to body’s need
increased by vitamin C, gastric acid
decreased by proton pump inhibitors, tetracycline, gastric achlorhydria, tannin (found in tea)
Distribution of iron in the body?
total body iron = 4g
haemoglobin = 70%
ferritin and haemosiderin = 25%
myoglobin = 4%
plasma iron = 0.1%
what is iron carried by in the plasma?
carried in plasma as Fe3+ bound to transferrin
What is iron stored as?
stored as ferritin in tissues
what is the role of IgD in the initiation of immune response?
This role in B cell activation makes IgD crucial for the initiation of immune responses. When an antigen binds to the IgD molecule on a B cell, it triggers the cell to proliferate and differentiate into an antibody-secreting plasma cell.
what kind of disease is Weber’s optic atrophy?
Mitochondrial disease
symptoms typically develop at around the age of 30 years
central scotoma → loss of colour vision → rapid onset of significant visual impairment
what are examples of mitochndrial disease??
Leber’s optic atrophy
symptoms typically develop at around the age of 30 years
central scotoma → loss of colour vision → rapid onset of significant visual impairment
MELAS syndrome: mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes
MERRF syndrome: myoclonus epilepsy with ragged-red fibres
Kearns-Sayre syndrome: onset in patients < 20 years old, external ophthalmoplegia, retinitis pigmentosa. Ptosis may be seen
sensorineural hearing loss
characteristics of mitochondrial disease?
inheritance is only via the maternal line as the sperm contributes no cytoplasm to the zygote
none of the children of an affected male will inherit the disease
all of the children of an affected female will inherit the disease
generally, encode rare neurological diseases
poor genotype:phenotype correlation - within a tissue or cell there can be different mitochondrial populations - this is known as heteroplasmy
e
function of the rough endoplasmic reticulum?
translation and folding of new proteins
manufacture of lysosomal enzymes
site of N-linked glycosylation
examples of cells with extensive RER include pancreatic cells, goblet cells, plasma cells
functions of the smooth endoplasmic reticulum?
steroid, lipid synthesis
examples of cells with extensive SER include those of the adrenal cortex, hepatocytes, testes, ovaries
functions of the Golgi apparatus?
Modifies, sorts, and packages these molecules that are destined for cell secretion
The addition of mannose-6-phosphate to proteins designates transport to lysosome
functions of the mitochondrion?
Aerobic respiration. Contains mitochondrial genome as circular DNA
Functions of the nucleus?
DNA maintenance
RNA transcription
RNA splicing
the process that removes the intervening, non-coding sequences of genes (introns) from pre-mRNA and joins the protein-coding sequences (exons)
function of the lysosome?
Breakdown of large molecules such as proteins and polysaccharides
Functions of the nucleolus?
ribosome production
Function of ribosome?
Translation of RNA into proteins
Function of peroxisome?
Catabolism of very long chain fatty acids and amino acids
Results in the formation of hydrogen peroxide
Function of Proteasome?
Along with the lysosome pathway involved in degradation of protein molecules that have been tagged with ubiquitin
T-helper 1 ?
what is it involved in
what does it secrete?
involved in the cell-mediated response and delayed (type IV) hypersensitivity
secrete IFN-gamma, IL-2, IL-3
T-helper cell 2
what is it involved in
what does it secrete?
involved in mediating humoral (antibody) immunity
e.g. stimulating production of IgE in asthma
secrete IL-4, IL-5, IL-6, IL-10, IL-13
Characteristic features of toxoplasmosis?
Cerebral calcification
Chorioretinitis
Hydrocephalus
other features:
anaemia
hepatosplenomegaly
cerebral palsy
Up to 70% of infected and untreated children will remain clinically well at birth and will exhibit signs of the infection later in life. Chorioretinitis remains the most common presentation of congenital toxoplasmosis. It is seen as a white focal lesion with surrounding exudate located adjacent to an old scar. Small pigmented/atrophic scars can also be seen.
Characteristic features of Congenital Cytomegalovirus?
Low birth weight
Purpuric skin lesions
Sensorineural deafness
Microcephaly
Other features:
Visual impairment
Learning disability
Encephalitis/seizures
Pneumonitis
Hepatosplenomegaly
Anaemia
Jaundice
Cerebral palsy
Characteristic features of congenital Rubella?
Sensorineural deafness
Congenital cataracts
Congenital heart disease (e.g. patent ductus arteriosus)
Glaucoma
Other features:
Growth retardation
Hepatosplenomegaly
Purpuric skin lesions
‘Salt and pepper’ chorioretinitis
Microphthalmia
Cerebral palsy
What is the role of vitamin D?
Vitamin D is a fat-soluble vitamin that plays a key role in calcium and phosphate metabolism. It is converted into the prohormone calcifediol in the liver. Circulating calcifediol is then converted into calcitriol (the biologically active form of vitamin D) in the kidneys.
what are the functions of Vitamin D?
increases plasma calcium and plasma phosphate
increases renal tubular reabsorption and gut absorption of calcium
increases osteoclastic activity
increases renal phosphate reabsorption
Vitamin D increases serum calcium primarily through raising its absorption via the small intestine
what does vitamin D deficiency lead to?
Osteomalacia
what are the three types of troponin and what do they bind to?
Subunits of troponin
troponin C: binds to calcium ions
troponin T: binds to tropomyosin, forming a troponin-tropomyosin complex
troponin I: binds to actin to hold the troponin-tropomyosin complex in place
what is meant by the poor genotype:phenotype correlation in mitochondrial disease?
the same genetic defect can result in a wide range of clinical manifestations. This variability is due to factors such as heteroplasmy - the presence of both normal and mutated mitochondrial DNA (mtDNA) within a cell - and other genetic or environmental influences.
Cardiac complications of Down syndrome?
multiple cardiac problems may be present
endocardial cushion defect (most common, 40%, also known as atrioventricular septal canal defects)
ventricular septal defect (c. 30%)
secundum atrial septal defect (c. 10%)
tetralogy of Fallot (c. 5%)
isolated patent ductus arteriosus (c. 5%)
clinical features of Down;s syndrome?
face: upslanting palpebral fissures, epicanthic folds, Brushfield spots in iris, protruding tongue, small low-set ears, round/flat face
flat occiput
single palmar crease, pronounced ‘sandal gap’ between big and first toe
hypotonia
congenital heart defects (40-50%, see below)
duodenal atresia
Hirschsprung’s disease
Later complications of Down’s syndrome?
Subfertility
learning difficulties
short stature
repeated respiratory infections
acute lymphoblastic leukaemia
hypothyroidism
Alzheimers disease
atlantoaxial instability
what are the different forms of trials when testing a new drug?
superiority: whilst this may seem the natural aim of a trial one problem is the large sample size needed to show a significant benefit over an existing treatment
equivalence: an equivalence margin is defined (-delta to +delta) on a specified outcome. If the confidence interval of the difference between the two drugs lies within the equivalence margin then the drugs may be assumed to have a similar effect
non-inferiority: similar to equivalence trials, but only the lower confidence interval needs to lie within the equivalence margin (i.e. -delta). Small sample sizes are needed for these trials. Once a drug has been shown to be non-inferior large studies may be performed to show superiority
What is the function o interferon-gamma?
activates macrophages
What is Kearns-Sayre syndrome?
a rare mitochondrial disorder characterized by the triad of onset before 20 years of age, progressive external ophthalmoplegia (PEO), and pigmentary retinopathy (retinitis pigmentosa).
What is Lawrence Moon Biedl syndrome?
a rare genetic disorder characterized by obesity, intellectual disability, retinitis pigmentosa, polydactyly (extra fingers or toes), and hypogonadism.
what are the features of Usher syndrome?
Genetic disorder characterized by sensorineural hearing loss at birth and progressive vision loss due to retinitis pigmentosa
What is Refuse disease?
a rare metabolic disorder caused by a deficiency of phytanic acid alpha-hydroxylase enzyme resulting in an accumulation of phytanic acid in tissues. The clinical features include retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia, anosmia (loss of smell), and ichthyosis (dry scaly skin).
Refsum disease
Usher syndrome
Lawrence-Moon-Biedl
Kearns-Sayre syndrome
Alport’s syndrome
Refsum disease: AR -cerebellar ataxia, peripheral neuropathy, deafness, ichthyosis, anosmia,
Usher syndrome- AR, deafness - most common form of deaf blind
abetalipoproteinemia
Lawrence-Moon-Biedl syndrome is a rare AR It is characterized predominantly by hypogonadism, polydactyly, retinitis pigmentosa, obesity, and mental retardation.
Kearns-Sayre syndrome- mitochondria deletion, <20 year old, prog external ophthalmoplegia, assoc with heart block, cerebellar ataxia, ragged red fibre on muscle biopsy
Alport’s syndrome- x linked- renal (GBM t4 collagen), deafness, protrusion of lens, ret pigment
what is MELAS ?
mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS)
what are the 4 phases of clinical trials?
0 - Exploratory studies
I - safety assessment
II - Assess efficacy
III - assess effectiveness
IV - postmarketing surveillance
what is phase 0 clinical trial?
Exploratory studies
Involves a very small number of participants and aim to assess how a drug behaves in the human body. Used to assess pharmacokinetics and pharmacodynamics. Phase 0 trials help in determining whether it is feasible to move on to further phases.
What is phase I clinical trial?
Safety assessment
Determines side-effects prior to larger studies. Conducted on healthy volunteers
What is phase II clinical trial?
assess efficacy
Involves small number of patients affected by particular disease
May be subdivided into
IIa - assesses optimal dosing
IIb - assesses efficacy
What is phase III clinical trial?
Assess effectiveness
Typically involves 100-1000’s of people, often as part of a randomised controlled trial, comparing new treatment with established treatments
What is phase IV clinical trial?
Post marketing surveillance?
Monitors for long-term effectiveness and side-effects
what are trinucleotide repeat disorders?
Fragile X (CGG)
Huntington’s (CAG)
myotonic dystrophy (CTG)
Friedreich’s ataxia* (GAA)
spinocerebellar ataxia
spinobulbar muscular atrophy
dentatorubral pallidoluysian atrophy
What is Homocystinuria?
Homocystinuria is a rare autosomal recessive disease caused by a deficiency of cystathionine beta synthase. This results in severe elevations in plasma and urine homocysteine concentrations.
what are the features of homocystinuria?
often patients have fine, fair hair
musculoskeletal
> Marfanoid body habitus: arachnodactyly etc
>osteoporosis
> kyphosis
neurological: may have learning difficulties, seizures
ocular
>downwards (inferonasal) dislocation of lens
> severe myopia
increased risk of arterial and venous thromboembolism
also malar flush, livedo reticularis
What is Fabry Disease?
Fabry disease is an X-linked recessive disorder characterised by a deficiency of alpha-galactosidase A.
clinical features of Fabry disease?
Severe neuropathic/limb pain brought on by stress, heat, or cold
Angiokeratomas
Renal features: proteinuria, polyuria, polydipsia
Cardiac: left ventricular hypertrophy, coronary artery disease, valvular abnormalities and heart failure
Cerebrovascular: TIAs/strokes
management of Fabry disease?
Enzyme replacement therapy with agalsidase alfa
what drugs interfere with folic acid metabolism?
Drugs which interfere with metabolism
trimethoprim
methotrexate
pyrimethamine
Drugs which can reduce absorption
phenytoin
What types of tumour will metastases to the brain?
lung (most common)
breast
bowel
skin (namely melanoma)
kidney
What is a Glioblastoma multiforme?
On imaging
Histology
Treatment
Glioblastoma is the most common primary tumour in adults and is associated with a poor prognosis (~ 1yr).
On imaging: Solid tumour with central necrosis and a rim that enhances with contrast.
Histology: Pleomorphic tumour cells border necrotic areas
Treatment is surgical with postoperative chemotherapy and/or radiotherapy. Dexamethasone is used to treat the oedema.
What is a meningioma?
Where are they located?
Histology?
Investigations?
Meningiomas are typically benign, extrinsic tumours of the central nervous system. They arise from the arachnoid cap cells of the meninges and are typically located next to the dura and cause symptoms by compression rather than invasion.
- They typically are located at the falx cerebri, superior sagittal sinus, convexity or skull base.
- Histology: Spindle cells in concentric whorls and calcified psammoma bodies
- Investigation is with CT (will show contrast enhancement) and MRI, and treatment will involve either observation, radiotherapy or surgical resection.
Vestibular Schwannoma?
Histology
Treatment?
A vestibular schwannoma (previously termed acoustic neuroma) is a benign tumour arising from the eighth cranial nerve (vestibulocochlear nerve). Often seen in the cerebellopontine angle. It presents with hearing loss, facial nerve palsy (due to compression of the nearby facial nerve) and tinnitus.
- Neurofibromatosis type 2 is associated with bilateral vestibular schwannomas.
- Histology: Antoni A or B patterns are seen. Verocay bodies (acellular areas surrounded by nuclear palisades)
- Treatment may involve observation, radiotherapy or surgery.
what is the most common primary Brian tumour in children?
The most common primary brain tumour in children
Histology: Rosenthal fibres (corkscrew eosinophilic bundle)
what is a medulloblastoma?
Histology
A medulloblastoma is an aggressive paediatric brain tumour that arises within the infratentorial compartment. It spreads through the CSF system. Treatment is surgical resection and chemotherapy.
- Histology: Small, blue cells. Rosette pattern of cells with many mitotic figures
where are Ependyomas seen ? what would histology show?
- Commonly seen in the 4th ventricle
- May cause hydrocephalus
- Histology: perivascular pseudorosettes
What is Oligodendroma?
Histology?
- Benign, slow-growing tumour common in the frontal lobes
- Histology: Calcifications with ‘fried-egg’ appearance
What Is a haemangioblastoma?
What is seen on histology?
Vascular tumour of the cerebellum
* Associated with von Hippel-Lindau syndrome
* Histology: foam cells and high vascularity
