Basic sciences Flashcards
HLA-B27
Ankylosing spondylitis
Postgonococcal arthritis
Acute anterior uveitis
Reiter’s syndrome (reactive arthritis)
HLA-DR2
Narcolepsy
Goodpasture’s
HLA-DR3
Autoimmune hepatitis
Primary biliary cirrhosis
Diabetes mellitus type 1
Dermatitis herpetiformis
Coeliac disease (95% associated with HLA-DQ2)
Primary Sjögren syndrome
HLA-DR4
Rheumatoid arthritis
Diabetes mellitus type 1 (> DR3)
HLA-A3
Hemochromatosis
the major clusters of differentiation
(CD) molecules
CD1 HLA molecule that presents lipid molecules
CD2 Found on thymocytes, T cells, and some natural killer cells that acts as a ligand for CD58 and
CD59 and is involved in signal transduction and cell adhesion
CD3 The signalling component of the T cell receptor (TCR) complex
CD4 Co-receptor for HLA class II; also a receptor used by HIV to enter T cells
CD8 Co-receptor for HLA class I; also found on a subset of myeloid dendritic cells
Hypersensitivity Type I - Anaphylactic
Antigen reacts with IgE bound to mast cells
* Anaphylaxis, atopy
Hypersensitivity Type II
Cell bound
* IgG or IgM binds to antigen on cell surface
* Autoimmune hemolytic anemia, ITP, Goodpasture’s
Hypersensitivity Type III - Immune complex
Free antigen and antibody (IgG, IgA) combine
* Serum sickness, SLE, post-streptococcal glomerulonephritis, extrinsic allergic alveolitis
(especially acute phase)
Hypersensitivity Type IV
Delayed hypersensitivity
* T cell mediated
* Tuberculosis, Tuberculin skin reaction, grafT versus hosT disease, allergic conTacT
dermaTiTis, scabies, exTrinsic allergic alveoliTis (especially chronic phase)
Hypersensitivity Type V
Stimulated hypersensitivity
* IgG antibodies stimulate cells they are directed against
* Graves’, myasthenia Gravis
Immunoglobulins IgG
75% Monomer Enhance phaGocytosis of bacteria and viruses.
Immunoglobulin IgA
15% Mono+Dimer Found in secretions, provide localized protection on mucous membranes
Immunoglobulin IgM
10% Pentamer first to be secreted, anti-A, B blood antibodies → Blood Transfusion
Immunoglobulin IgD
1% Monomer Involved in activation of B cells
- IgG Facts
IgG makes up approximately 75% of the serum antibodies.
* IgG has a half-life of 7-23 days depending on the subclass.
* IgG is a monomer and has 2 epitope-binding sites
* The Fc portion of IgG can activate the classical complement pathway.
* The Fc portion of IgG can bind to macrophage and neutrophils for enhanced phaGocytosis.
* The Fc portion of IgG can bind to NK cells for antibody-dependent cytotoxicity (ADCC).
* The Fc portion of IgG enables it to cross the placenta. (IgG is the only class of antibody that
can cross the placenta and enter the fetal circulation).
- IgA facts
IgA makes up approximately 15% of the serum antibodies, it has a half-life of ≈ 5 days.
* IgA is found mainly in body secretions (saliva, mucous, tears, colostrum and milk) as
secretory IgA (sIgA) where it protects internal body surfaces exposed to the environment
by blocking the attachment of bacteria and viruses to mucous membranes.
* Secretory IgA is the most immunoglobulin produced.
* IgA is made primarily in the mucosal-associated lymphoid tissues (MALT).
* IgA appears as a dimer of 2 “Y”-shaped molecules and has 4 epitope-binding sites and a
secretory component to protect it from digestive enzymes in the secretions
* The Fc portion of secretory IgA binds to components of mucous and contributes to the
ability of mucous to trap microbes.
* IgA can activate the alternative complement pathway. (IgA ≈ Alternate)
- IgM Facts
- IgM
* IgM makes up approximately 10% of the serum antibodies and is the first antibody produced
during an immune response.
* IgM has a half-life of about 5 days.
* IgM is a pentamer and has 10 epitope-binding sites
* The Fc portions of IgM are able to activate the classical complement pathway (most efficient)
* Monomeric forms of IgM are found on the surface of B-lymphocytes as B-cell receptors or sIg.
IgD facts
IgD makes up approximately 1% of the serum antibodies.
* IgD is a monomer and has 2 epitope-binding sites.
* IgD is found on the surface of B-lymphocytes (along with monomeric IgM) as a B-cell
receptor or sIg where it may control of B-lymphocyte activation and suppression.
* IgD may play a role in eliminating B-lymphocytes generating self-reactive autoantibodies.
Primary Immunodeficiency
Neutrophil disorders
* Chronic granulomatous disease
* Chediak-higashi syndrome
* Leukocyte adhesion deficiency
B-cell disorders
* IgA deficiency
* Bruton’s congenital agammaglobulinemia
* Common variable immunodeficiency
T-cell disorders = DiGeorge
* DiGeorge syndrome is an example of a microdeletion syndrome. Patients are consequently at ↑
risk of viral and fungal infections.
Combined B- and T-cell disorders
* Severe combined immunodeficiency
* Ataxic telangiectasia (Autosomal recessive - 10% risk of developing malignancy, lymphoma or
leukaemia, but also non-lymphoid tumours - recurrent chest infections)
* Wiskott-Aldrich syndrome inherited in an X-linked recessive fashion and is thought to be
caused by mutation in the WASP gene. Features include recurrent bacterial infections (e.g.
chest), eczema and thrombocytopenia with low IgG.
cANCA
cANCA
* Most common target serine proteinase 3 (PR3)
* Some correlation between cANCA levels and disease activity
* Wegener’s granulomatosis, positive in > 90%
* Microscopic polyangiitis, positive in 40%
pANCA
Most common target is myeloperoxidase (MPO)
* Cannot use level of pANCA to monitor disease activity
* Associated with immune crescentic glomerulonephritis (positive in c. 80% of patients)
* Microscopic polyangiitis, positive in 50-75%
* Churg-Strauss syndrome, positive in 60%
* Wegener’s granulomatosis, positive in 25%
C3 def vs C5 def
Whilst C3 deficiency is associated with recurrent bacterial infections, C5 deficiency is more
characteristically associated with disseminated meningococcal infection
Complement Deficiencies
Complement is a series of proteins that circulate in plasma and are involved in the inflammatory and
immune reaction of the body. Complement proteins are involved in chemotaxis, cell lysis and
opsonisation
C1 inhibitor (C1-INH) protein deficiency
Causes hereditary angiedema
* C1-INH is a multifunctional serine protease inhibitor
* Probable mechanism is uncontrolled release of bradykinin resulting in edema of tissues
C1q, C1rs, C2, C4 deficiency (classical pathway components)
Predisposes to immune complex disease
* E.g. SLE, Henoch-Schonlein Purpura
C3 deficiency
Causes recurrent bacterial infections
C5 deficiency
Predisposes to Leiner disease
* Recurrent diarrhea, wasting and seborrhoeic dermatitis
* Disseminated meningococcal infection.
C5-9 deficiency
Encodes the membrane attack complex (MAC)
* Particularly prone to Neisseria meningitidis infection
Normal anion gap (hyperchloraemic metabolic acidosis)
Gastrointestinal bicarbonate loss: diarrhea, ureterosigmoidostomy, fistula
* Renal tubular acidosis
* Drugs: e.g. Acetazolamide
* Ammonium chloride injection
* Addison’s disease
Raised anion gap acidosis
Lactate: shock, hypoxia
* Ketones: DKA, alcohol
* Urate: renal failure
* Acid poisoning: salicylates, methanol
Metabolic Alkalosis
Causes
* Vomiting / aspiration (e.g. Peptic ulcer leading to pyloric stenosis, nasogastric suction)
* Diuretics
* Liquorice, carbenoxolone
* Hypokalemia
* Primary hyperaldosteronism
* Congenital adrenal hyperplasia
* Cushing’s syndrome
* Bartter’s syndrome
Mechanism of metabolic alkalosis
Activation of renin-angiotensin II-aldosterone (RAA) system is a key factor
* Aldosterone causes reabsorption of Na+
in exchange for H+ in the distal convoluted tubule
- ECF depletion (vomiting, diuretics) → Na+
and Cl-
loss → activation of RAA system → raised
aldosterone levels
* In Hypokalemia, K+
shift from cells → ECF. Alkalosis is caused by shift of H+
into cells to
maintain neutrality
Hyperkalemia causes
Acute renal failure
* Drugs*: potassium sparing diuretics, ACE
inhibitors, Cyclosporin
* Metabolic acidosis
* Addison’s
* Rhabdomyolysis
* Massive blood transfusion
K ++++ treatment
Stabilisation of the cardiac membrane
* intravenous calcium gluconate
Short-term shift in potassium from extracellular
to intracellular fluid compartment
* combined insulin/dextrose infusion
* nebulised salbutamol
Removal of potassium from the body
* calcium resonium (orally or enema)
* loop diuretics
* dialysis
Hypokalemia
Potassium and hydrogen can be thought of as competitors. Hyperkalemia tends to be associated with
acidosis because as potassium levels rise fewer hydrogen ions can enter the cells
Hypokalemia with alkalosis
Vomiting
* Diuretics
* Cushing’s syndrome
* Conn’s syndrome (primary hyperaldosteronism)
Hypokalemia with acidosis:
Diarrhea
* Renal tubular acidosis
* Acetazolamide
* Partially treated DKA
ECG features of hypokalemia:
U waves
* Small or absent T waves (occasionally inversion)
* Prolong PR interval
* ST depression
* Long QT
Hypomagnesemia:
- Diuretics
- Total Parenteral Nutrition (TPN)
- Diarrhea
- Alcohol
- Hypokalemia, hypocalcemia
Features - Paraesthesia
- Tetany
- Seizures
- Arrhythmias
- ↓ PTH secretion → hypocalcemia
- ECG features similar to those of Hypokalemia
- Exacerbates digoxin toxicity
The two hormones which primarily control calcium metabolism are:
- parathyroid hormone (PTH)
- vitamin D
Actions of parathyroid hormone
(↑ plasma Ca from bones and kidneys and activation of Vit-D)
* ↑ plasma calcium, ↓ plasma phosphate
* ↑ renal tubular reabsorption of calcium
* ↑ osteoclastic activity
* ↑ renal conversion of 25-hydroxy vitamin D to 1,25 dihydroxy vitamin D
* ↓ renal phosphate reabsorption
Actions of vitamin D
(↑ plasma Ca from bones and kidneys and GIT)
* ↑ plasma calcium and ↑ plasma phosphate
* ↑ renal tubular reabsorption and gut absorption of calcium
* ↑ osteoclastic activity
* ↑ renal phosphate reabsorption
Hypocalcemia
Causes
* Vitamin D deficiency (osteomalacia)
* Chronic renal failure
* Hypoparathyroidism (e.g. Post thyroid/parathyroid surgery)
* Pseudohypoparathyroidism (target cells insensitive to PTH)
* Rhabdomyolysis (initial stages)
* Magnesium deficiency (due to end organ PTH resistance)
Trousseau’s sign
Carpal spasm if the brachial artery occluded by inflating the blood pressure cuff and
maintaining pressure above systolic
* Wrist flexion and fingers drawn together
* Seen in around 95% of patients with hypocalcemia and around 1% of normocalcaemic people
Hyperuricemia
↑ levels of uric acid may be seen secondary to either ↑ cell turnover or ↓ renal
excretion of uric acid. Hyperuricemia may be found in asymptomatic patients who have not
experienced attacks of gout
↑ Synthesis:
* Lesch-Nyhan disease
* Myeloproliferative disorders
* Diet rich in purines
* Exercise
* Psoriasis
* Cytotoxics
↓ Excretion:
* Drugs: low-dose aspirin, diuretics, pyrazinamide
* Pre-eclampsia
* Alcohol
* Renal failure
Acute Phase Proteins:
CRP
* ferritin
* fibrinogen
* α-1 antitrypsin
* caeruloplasmin
* serum amyloid A
* serum amyloid P component
* haptoglobin
* complement
During the acute phase response the liver ↓ the production of other proteins (sometimes referred to as
negative acute phase proteins).
The following proteins ↓:
* albumin
* transthyretin (formerly known as prealbumin)
* transferrin
* retinol binding protein
* cortisol binding protein
Rheumatoid Factor (RF)
is a circulatinjg antibody (usually IgM) which reacts with antigenic
sites on the Fc portion of the patients own IgG
Rheumatoid factor is an IgM antibody against IgG
RF is positive in 70-80% of patients with rheumatoid arthritis; high titre levels are associated with
severe progressive disease (prognosis but NOT a marker of disease activity)
Other conditions associated with a positive RF include:
- Sjogren’s syndrome (around 100%)
- Felty’s syndrome (around 100%)
- Infective endocarditis (= 50%)
- SLE (= 20-30%)
- Systemic sclerosis (= 30%)
- General population (= 5%)
- Rarely: TB, HBV, EBV, leprosy
Nitric Oxide Effects
It is formed
from L-arginine and oxygen by nitric oxide synthetase (NOS). An inducible form of NOS has been
shown to be present in macrophages. Nitric oxide has a very short half-life (seconds), being inactivated
by oxygen free radicals
Effects
* Acts on guanylate cyclase leading to raised intracellular cGMP levels and therefore decreasing
Ca++ levels
* Vasodilation, mainly venodilation
* Inhibits platelet aggregation
Niitric oxide clinical importance
Clinical relevance
Underproduction of NO is implicated in hypertrophic pyloric stenosis
* Lack of NO is thought to promote atherosclerosis
* In sepsis ↑ levels of NO contribute to septic shock
* Organic nitrates (metabolism produces NO) is widely used to treat cardiovascular disease (e.g.
Angina, heart failure)
* Sildenafil is thought to potentiate the action of NO on penile smooth muscle and is used in the
treatment of erectile dysfunctions
Atrial Natriuretic Peptide (ANP)
(ANP) is a powerful vasodilator, and a protein (polypeptide)
hormone secreted by heart muscle cells. It is involved in the homeostatic control of body water,
sodium, potassium and fat (adipose tissue). ANP acts to ↓ the water, sodium and adipose loads on the
circulatory system, thereby reducing blood pressure
Basics
* Secreted mainly from myocytes of right atrium and ventricle in response to ↑ blood volume
* Secreted by both the right and left atria (right»_space; left)
* 28 amino acid peptide hormone, which acts via cGMP
* Degraded by endopeptidases
Actions
* Natriuretic, i.e. Promotes excretion of sodium
* Lowers BP
* Antagonises actions of angiotensin II, aldosterone
B-type Natriuretic Peptide (BNP)
hormone produced mainly by the left ventricular
myocardium in response to strain
Vasodilator
* Diuretic and natriuretic
* Suppresses both sympathetic tone and the renin-angiotensin-aldosterone system
- Initial evidence suggests BNP is an extremely useful marker of prognosis
Tumour Necrosis Factor (TNF)
is a pro-inflammatory cytokine with multiple roles in
the immune system
TNF is secreted mainly by macrophages and has a number of effects on the immune system, acting
mainly in a paracrine fashion:
* Activates macrophages and neutrophils
* Acts as costimulator for T cell activation
* Key mediator of bodies response to gram NEGATIVE septicemia
* Similar properties to IL-1
* Anti-tumour effect (e.g. Phospholipase activation)
Tumour Necrosis Factor (TNF) bind to?
TNF-α binds to p55 and p75 receptors, these receptors can induce apoptosis. It also cause activation of
NFkB
TNF Endothelial effects
↑ expression of selectins and ↑ production of platelet activating factor, IL-1
and prostaglandins. TNF promotes the proliferation of fibroblasts and their production of protease and
collagenase. It is thought fragments of receptors act as binding points in serum. Systemic effects
include pyrexia, ↑ acute phase proteins and disordered metabolism leading to cachexia. TNF is
important in the pathogenesis of rheumatoid arthritis - TNF blockers (e.g. infliximab, etanercept) are
now licensed for treatment of severe rheumatoid.
TNF blockers
- Infliximab: monoclonal antibody, IV administration
- Etanercept: fusion protein that reversibly binds soluble TNF receptors, subcutaneous
administration - Adalimumab: monoclonal antibody, subcutaneous administration
- Adverse effects of TNF blockers include reactivation of latent tuberculosis and demyelination
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-α
and IFN-β bind to type-1 receptors, whilst IFN-gamma binds only to type-2 receptors.
IFN-α (aLpha)
Produced by Leucocytes
* Antiviral action
* Useful in hepatitis B & C, kaposi’s sarcoma, metastatic renal cell cancer, hairy cell leukemia
* Adverse effects include fLu-Like symptoms and depression
IFN-β
- Produced by fibroBlasts
- Antiviral action
- ↓ the frequency of exacerbations in patients with relapsing-remitting MS
IFN-gamma
Produced by T lymphocytes & NK cells
* weaker antiviral action (inhibit viral duplication), more of a role in immunomodulation
particularly macrophage activation
* May be useful in chronic granulomatous disease and osteopetrosis
Interleukin 1 (IL-1)
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. While TNF
is secreted mainly by macrophages, it is a key mediator of body response to gram NEGATIVE
septicemia and it is a costimulator of T cell.
Other effects include 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 ↑ 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.
Leukotrienes
Function
* Mediators of inflammation and allergic reactions
* Cause bronchoconstriction, mucous production
* ↑ vascular permeability, attract leukocytes
* Leukotriene D4 has been identified as the SRS-A (slow reacting substance of anaphylaxis)
Production
* secreted by leukocytes
* formed from arachidonic acid by action of lipoxygenase
* it is thought that the NSAID induced bronchospasm in asthmatics is secondary to the express
production of leukotrienes due to the inhibition of prostaglandin synthetase
T-Helper Cells Th1
Involved in the cell mediated response and delayed (type IV) hypersensitivity
* Secrete IFN-gamma, IL-2, IL-3
T-Helper Cells Th2
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
Cardiac and Protien Markers:
- Myoglobin is the first to rise
- CK-MB is useful to look for reinfarction as it returns to normal after 2-3 days (troponin T
remains elevated for up to 10 days)
Raised ALP and raised calcium
Paget’s
* Bone metastases
* Hyperparathyroidism
Raised ALP and low calcium
- Osteomalacia
- Renal failure
Leukocyte alkaline phosphatase:Raised in
Myelofibrosis
* Leukemoid reactions
* Polycythemia rubra vera
* Infections
* Steroids, Cushing’s syndrome
* Pregnancy, oral contraceptive pill
Leukocyte alkaline phosphatase:Low in
Chronic myeloid leukemia
* Pernicious anemia
* Paroxysmal nocturnal hemoglobinuria
* Infectious mononucleosis
Autosomal Recessive Conditions
NB autosomal recessive conditions are often thought to be ‘metabolic’ as opposed to autosomal
dominant conditions being ‘structural’, notable exceptions:
* Mucopolysaccharidoses: Hunter’s (X-linked recessive)
* G6PD (X-linked recessive)
Only homozygotes are affected
* ♂s and ♀s are equally likely to be affected
* Does not manifest in every generation - may ‘skip a generation’
Autosomal Dominant Conditions:
Achondroplasia
* Acute intermittent porphyria (all hepatic porphyrias except congenital erythropoietic porphyria)
* Adult polycystic disease
* Antithrombin III deficiency
* Ehlers-Danlos syndrome
* Familial adenomatous polyposis (including Gardner syndrome)
* Familial hypercholesterolemia
* Hereditary hemorrhagic telangiectasia
* Hereditary motor and sensory neuropathy (HMSN) including Charcot–Marie–Tooth
* Hereditary spherocytosis
* Hereditary non-polyposis colorectal carcinoma
* Huntington’s disease
* Hyperlipidemia type II
* Hypokalaemic periodic paralysis
* Malignant hyperthermia
* Marfan’s syndromes
* Myopathies (most of them including HOCM, Ocular Myopathy)
* Myotonic dystrophy
* Neurofibromatosis
* Noonan syndrome
* Osteogenesis imperfecta
* Peutz-Jeghers syndrome
* Retinoblastoma
* Romano-Ward syndrome
* Tuberose sclerosis
* Von Hippel-Lindau syndrome
* Von Willebrand’s disease*
In autosomal dominant diseases:
Both homozygotes and heterozygotes manifest disease (THERE IS NO CARRIER STATE)
* Both ♂s and ♀s affected
* Only affected individuals can pass on disease
* Disease is passed on to 50% of children
* Normally appears in every generation (although see below)
* Risk remains same for each successive pregnancy
X-linked Recessive inheritance
only ♂s are affected.
♂-to-♂transmission not seen
X-linked Dominant:
A woman with an X-linked dominant disorder has a 50% chance of having an
affected daughter or son with each pregnancy.
Sons of affect dads will not get condition - ALL daughters will
Trinucleotide Repeat Disorders
are genetic conditions caused by an abnormal number of
repeats (expansions) of a repetitive sequence of three nucleotides. These expansions are unstable and
ay lead to an earlier age of onset in successive generations
known as anticipation*. In most cases, an ↑ in the severity of symptoms is also noted
Mitochondrial Diseases:
Inheritance is only via the maternal line as the sperm contributes no cytoplasm to the zygote
* All children of affected ♂s will not inherit the disease
* All children of affected ♀s will inherit it
* Generally encode rare neurological diseases
* Poor genotype:phenotype correlation
* Heteroplasmy: within a tissue or cell there can be different mitochondrial populations
Tumour Suppressor Genes
Basics
* Genes which normally control the cell cycle
* Exhibit a recessive effect - both copies must be mutated before cancer occurs
Examples
* P53
* APC: colorectal cancer
* NF-1: neurofibromatosis
* RB: retinoblastoma
P53 Gene
is a tumour suppressor gene located on chromosome 17p. It is the most commonly
mutated gene in breast, colon and lung cancer
P53 is thought to play a crucial role in the cell cycle, preventing entry into the S phase until DNA has
been checked and repaired. It may also be a key regulator of apoptosis
Cardiac complications of T21
Multiple cardiac problems may be present
* Endocardial cushion defect (40%, also known as atrioventricular septal canal defects)
* Ventricular septal defect (30%)
* Secundum atrial septal defect (10%)
* Tetralogy of fallot (5%)
* Isolated patent ductus arteriosus (5%)
Turner Syndrome
is a chromosomal disorder affecting around 1 in 2,500 ♀s. It is caused by
either the presence of only one sex chromosome (X) or a deletion of the short arm of one of the X
chromosomes. Turner’s syndrome is denoted as 45, XO or 45 X
Turner features
Features
* Short stature
* Shield chest, widely spaced nipples
* Webbed neck
* Bicuspid aortic valve (15%), coarctation of the aorta (5-10%)
* Primary amenorrhoea
* High-arched palate
* Short fourth metacarpal
* Multiple pigmented naevi
* Lymphedema in neonates (especially feet)
Klinefelter Syndrome
(Hypogonadotropic hypogonadism) is associated with karyotype 47,
XXY
Features
* Often taller than average
* Lack of secondary sexual characteristics
* Small, firm testes (hypogonadism)
* Infertile
* Gynaecomastia - ↑ incidence of breast cancer
* Elevated gonadotrophin levels
Marfan Syndrome
Features
* Tall stature with arm span > height ratio > 1.05
* High-arched palate
* Arachnodactyly (spider fingers; fingers are abnormally long, in some cases all or few fingers
can be bent backwards of 180 degrees)
* Pectus excavatum
* Pes planus
* Scoliosis of > 20 degrees
* Heart: dilation of the aortic sinuses (seen in 90%) which may lead to aortic regurgitation,
mitral valve prolapse (75%), aortic dissection
* Lungs: repeated pneumothoraces
* Eyes: upwards lens dislocation (superotemporal ectopia lentis), blue sclera
Noonan Syndrome:
Often thought of as the ‘♂ Turner’s’, Noonan’s syndrome is an autosomal dominant condition associated with a normal karyotype. It is thought to be caused by a defect in a gene on chromosome 12. As well as features similar to Turner’s syndrome (webbed neck, widely-spaced nipples, short stature, pectus carinatum and excavatum), a number of characteristic clinical signs may also be seen:
* Cardiac: pulmonary valve stenosis
* Ptosis
* Triangular-shaped face
* Low-set ears
* Coagulation problems: factor XI deficiency
Fragile X
trinucleotide repeat disorder, complex X-linked inheritance.
Features in ♂s
* Learning difficulties
* Large low set ears, Long thin face, High arched palate
* Macroorchidism (Large testes)
* Hypotonia
* Autism is more common
* Mitral valve prolapse
Patau Syndrome features
Trisomy 13
additional chromosome 13 due to a non-disjunction of chromosomes during meiosis.
Mental & motor challenge
* Polydactyly (extra digits)
* Microcephaly
* Low-set ears
* Holoprosencephaly (failure of the forebrain to divide properly).
* Heart defects
* Structural eye defects, including microphthalmia, peters anomaly, cataract, iris and/or fundus
(coloboma), retinal dysplasia or retinal detachment, sensory nystagmus, cortical visual loss, and
optic nerve hypoplasia
* Cleft palate
* Meningomyelocele (a spinal defect)
* Omphalocele (abdominal defect)
* Abnormal genitalia
* Abnormal palm pattern
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* Overlapping of fingers over thumb.
* Cutis aplasia (missing portion of the skin/hair)
* Prominent heel
* Kidney defects
* Deformed feet known as “rocker-bottom feet”
Prader-Willi Syndrome
Prader-Willi syndrome if gene deleted from father
hromosome 15 (same as Marfan’s chromosome). This may be due to:
* Microdeletion of paternal 15q11-13 (70% of cases)
* Maternal uniparental disomy of chromosome 15
Features
* Hypotonia during infancy
* Dysmorphic features
* Short stature
* Hypogonadism and infertility
* Learning difficulties
* Childhood obesity
* Behavioural problems in adolescence
* Acanthosis nigricans
Edwards Syndrome
Trisomy 18
Infants born with Edward’s syndrome may have some or all of the following characteristics:
* Kidney malformations
* Structural heart defects at birth
* Intestines protruding outside the body (omphalocele)
* Esophageal atresia
* Mental retardation
* Developmental delays
* Growth deficiency
* Feeding difficulties
* Breathing difficulties
* Arthrogryposis (a muscle disorder that causes multiple joint contractures at birth)
* Microcephaly accompanied by a prominent occiput
Low-set, malformed ears
* Abnormally small jaw (micrognathia)
* Cleft lip/cleft palate
* Upturned nose
* Narrow eyelid folds (palpebral fissures)
* Widely-spaced eyes (ocular hypertelorism)
* Ptosis
* A short sternum
* Clenched hands
* Underdeveloped thumbs and or nails
* Absent radius
* Webbing of the second and third toes
* Clubfoot or rocker bottom feet,
* Undescended testicles
Def in A1 - Retinoids
Night-blindness (nyctalopia)
Def in Thiamine B1
Beriberi
* Polyneuropathy, Wernicke-Korsakoff syndrome
* Heart failure
Def in Niacin (Nicotinic Acid) B3
Pellagra
* Dermatitis
* Diarrhea
* Dementia
Def in Pyridoxine B6
Anemia, irritability, seizures
Def in Biotin B7
Dermatitis, seborrhoea
Def in Folic acid B9
Megaloblastic anemia, deficiency during pregnancy - neural tube defects
Def in B12 Cyanocobalamin
Megaloblastic anemia
Def in Ascorbic acid - Vit C
Scurvy
* Gingivitis
* Bleeding
Def in Ergocalciferol, cholecalciferol Vit d
Rickets, osteomalacia (good source is cod liver oil)
Def in Tocopherol, tocotrienol Vit E
Mild hemolytic anemia in newborn infants, ataxia, peripheral neuropathy
Def in Naphthoquinone Vit K
Hemorrhagic disease of the newborn, bleeding diathesis
Pellagra
caused by nicotinic acid (niacin) Vitamin B3 deficiency. The classical features are the 3 D’s - dermatitis, diarrhea and dementia
Pellagra may occur as a consequence of isoniazid therapy (isoniazid inhibits the conversion of tryptophan to niacin)
Vitamin B12 where absorbed
Vitamin B12 is actively absorbed in the Terminal Ileum
Causes of vitamin B12 deficiency
Pernicious anemia
* Post gastrectomy
* Poor diet
* Disorders of terminal ileum (site of absorption): crohn’s, blind-loop etc
* Metformin
Vitamin D-Resistant Rickets PP
-linked dominant (along with Rett and Alport syndrome) condition which usually presents in infancy with failure to thrive. It is caused by impaired phosphate reabsorption in the renal tubules
Features of vitamin B12 deficiency
- Macrocytic anemia
- Sore tongue and mouth
- Neurological symptoms: e.g. Ataxia
- Neuropsychiatric symptoms: e.g. Mood disturbances
Vitamin D-Resistant Rickets features
Features
* Failure to thrive
* Normal serum calcium, low phosphate, elevated alkaline phosphotase
* X-ray changes: cupped metaphyses with widening of the epiphyses
Diagnosis is made by demonstrating ↑ urinary phosphate
Vitamin D-Resistant Rickets diagnosis
Diagnosis is made by demonstrating ↑ urinary phosphate
Folate Metabolism
Drugs which interfere with metabolism
- Trimethoprim * Methotrexate
- Pyrimethamine
Iron Metabolism
Upper small intestine
* About 10% of dietary iron absorbed
* Fe++ (ferrous iron) much better absorbed than Fe+++ (ferric iron)
* Absorption is regulated according to bodies need
* ↑ by vitamin C, gastric acid
* ↓ by proton pump inhibitors, tetracycline, gastric achlorhydria, tannin (found in tea)
Distribution in body
Iron distribution
Total body iron = 4g
* Hemoglobin = 70%
* Ferritin and hemosiderin = 25%
* Myoglobin = 4%
* Plasma iron = 0.1%
Iron transport -
Transport
Carried in plasma as Fe+++ bound to transferrin
Iron Storage
Stored as ferritin in tissues
Iron Lost
Lost via intestinal tract following desquamination
Zinc Deficiency:
Features
* Perioral dermatitis: red, crusted lesions
* Acrodermatitis
* Alopecia
* Short stature
* Hypogonadism
* Hepatosplenomegaly
* Geophagia (ingesting clay/soil)
* Cognitive impairment
Endoplasmic reticulum feature
Translation and folding of new proteins (rough endoplasmic reticulum), expression of lipids (smooth endoplasmic reticulum)
Golgi apparatus feature
Sorting and modification of proteins
Mitochondrion
Energy production. Contains mitochondrial genome as circular double stranded DNA
Nucleus
DNA maintenance and RNA transcriptio
Ligand-gated ion channel
Generally mediate fast responses
* E.g. nicotinic acetylcholine, GABA-A & GABA-C, glutamate receptors
Tyrosine kinase receptors
Contain intrinsic enzyme activity
* E.g. Insulin, growth factors, interferon
Guanylate cyclase receptors
Contain intrinsic enzyme activity
* E.g. Atrial natriuretic factor (ANP), nitric oxide receptors
G protein-coupled receptors
Generally mediate slow transmission and affect metabolic processes
* Activated by a wide variety of extracellular signals e.g. Peptide hormones, biogenic amines,
lipophilic hormones and light.
* Consist of 3 main subunits: α, β and gamma
* Ligand binding → conformational changes to receptor, this induces exchange of GDP for GTP
* E.g. Muscarinic acetylcholine, adrenergic receptors, GABA-B
α-1
(Agonist → phenylephrine)
* V asoconstriction
* Relaxation of GI smooth muscle
* Salivary secretion
* Hepatic glycogenolysis
α-2
(Agonist → clonidine)
* Mainly presynaptic: inhibition of transmitter release (inc NA, Ach from autonomic nerves)
* Inhibits insulin
* Platelet aggregation
β-1
(Agonist → dobutamine)
* Mainly located in the heart
* ↑ heart rate + force
β-2
(Agonist → salbutamol)
* V asodilation
* Bronchodilation
* Relaxation of GI smooth muscle
β-3
(Agonist → being developed, may have a role in preventing obesity) * Lipolysis
Adrenoreceptors pathways
α-1:activate phospholipase C → IP3 → DAG
* α-2: inhibit adenylate cyclase
* β-1: stimulate adenylate cyclase
* β-2: stimulate adenylate cyclase
* β-3: stimulate adenylate cyclase
Cyclic AMP
E.g. Adrenaline, noradrenaline, glucagon, LH, FSH, TSH, calcitonin, parathyroid hormone
Protein kinase activity
E.g. Insulin, growth hormone and factor, prolactin, oxytocin, erythropoietin.
Calcium and/or phosphoinositides
E.g. ADH, GnRH, TRH
Cyclic GMP
E.g. ANP, nitric oxide
Foramina of the skull
Optic canal
Optic canal
Sphenoid
Ophthalmic A.
Optic nerve (II)
Foramina of the skull
Superior orbital fissure
Sphenoid
Superior ophthalmic V.
Inferior ophthalmic V
Oculomotor nerve (III)
Trochlear nerve (IV)
lacrimal, frontal and nasociliary branches of ophthalmic nerve (V1)
Abducent nerve (VI)
Foramina of the skull
Inferior orbital fissure
Sphenoid and maxilla
Inferior ophthalmic V. Infraorbital artery Infraorbital vein
Zygomatic nerve and infraorbital nerve of maxillary nerve (V2)
Orbital branches of pterygopalatine ganglion
Foramina of the skull
Foramen Rotundum
Maxillary nerve (V2)
Jugular Foramen
Occipital and temporal
Posterior meningeal A. Ascending pharyngeal A. Inferior petrosal sinus Sigmoid sinus Internal jugular V.
Glossopharyngeal nerve (IX) Vagus nerve (X)
Accessory nerve (XI)
anatomical relations of Right kidney
Directly - Right suprarenal gland Duodenum
Colon
Layer of peritoneum in-between - Liver
Distal part of small intestine
anatomical relations Left kidney
Directly - Left suprarenal gland Pancreas
Colon
Ilayer of peritoneum - Stomach
Spleen
Distal part of small intestine
Myocardial Action Potential
0 Rapid depolarisation - Rapid sodium influx
1 Early repolarisation - Efflux of potassium
2 Plateau - Slow influx of calcium
3 Final repolarisation - Efflux of potassium
4 Restoration of ionic concentrations
Resting potential is restored by Na+/K+ ATPase
There is slow entry of Na+ into the cell decreasing the potential difference until the threshold potential is reached, triggering a new action potential
Antidiuretic hormone (ADH)
secreted from the posterior pituitary gland. It promotes water
reabsorption in the collecting ducts of the kidneys by the insertion of aquaporin-2 channels
