Alveolar-arterial gradient (A-a gradient)

Calculated A-a gradient = 150mmHg - PaCO2/0.8 - PaO2
Expected A-a gradient = Age/4 + 4


Normal A-a gradient suggest hypoventilation (hypoxia proportional to low ventilatory effort)
Increased A-a gradient suggest defect in diffusion, V/Q mismatch or right-left shunt

T-score interpretation

Chromosome and genetic disease

Mnemonics
Marfan's syndrome : chromosome 15 (15 alphabates)
APKD 1 (Polycystic kidney) : chromosome 16 (16 alphabates)
Neurofibromatosis 1 / Von Recklinghausen : chromosome 17 (17 alphabates)

Note: The above are all autosomal dominant

PKD 2 : chromosome 4
NF type 2 : chromosome 22
Cystic fibrosis : chromosome 7
Haemochromatosis : chromosome 6
Huntington's disease : chromosome 4
Wilson's disease : chromosome 13

Human leukocyte antigen (HLA)

- found on chromosome 6
- HLA corresponds to MHC class I (A,B and C)
- HLA corresponds to MHC class II (D)

HLA associations
- HLA DR2 : SLE
- HLA DR3 : autoimmune hepatitis, Sjogren syndrome
- HLA DR4 : Felty syndrome
- HLA DQ2 / DQ8 : coeliac disease
- HLA B27 : AS, Reiter's syndrome
- HLA Cw6 : psoriasis
- HLA B8 : myasthenia gravis
- HLA B5 / B51 : Behcet's disease

Incretin

- 2 main incretins, GLP-1 (glucagon-like peptide-1) and GIP (glucose dependent insulinotropic peptide)
- secreted by L cells of ileum and colon
- incretin effect: insulin response to oral glucose is better than intravenous glucose
- promotes glucose induced insulin release from pancreatic beta cells, delays rate of gastric emptying, promotes satiety, reduce appetite in brain
- suppress postprandial glucose secretion
- GLP-1 analogue (exenatide) is given by twice daily subcutaneous injection
- dipeptidyl peptidase 4 (DPP4) rapidly inactivates GLP-1. DPP4 inhibitor (sitagliptin or vildagliptin)

Basic respiratory physiology

Nerve conduction studies

Polymyositis - reduced amplitude and duration of motor units
Motor neurone disease - fibrillation due to denervation
Myasthenia gravis - diminished response to repetitive stimulation
Lambert Eaton syndrome - enhanced response to repeated stimulation
Myotonia dystrophia - high frequency action potentials (Kamikazee discharge)
Demyelinating neuropathy - slow nerve conduction velocity
Axonal neuropathy - diminished action potential

DNA-containing viruses

- Herpesvirus
- Hepadnavirus
- Adenovirus
- Papovavirus
- Pox virus
- Parvovirus

All DNA viruses are double stranded except Parvovirus

Oncogenesis

- Proto-oncogenes found in normal human genomes, have a central role in signal transduction pathway that control cell growth and differentiation
- Mutated proto-oncogenes are called oncogenes (gain of function mutation)
- Examples:
  - Ras oncogenes - rhabdomyosarcoma, sporadic tumor (colon and lungs)
  - c-myc - Burkitt lymphoma
  - N-myc - neuroblastoma
  - SRC - sarcoma

- Tumor suppressor gene requires both copies mutation before tumorigenesis occurs. Mutation results in loss of function
- Examples;
  - NF-1 - neurofibroma
  - BRCA-1 - breast and ovarian cancer
  - Rb - retinoblastoma
  - VHL - von Hippel Lindau
  - p53 - Li Fraumeni syndrome

Pellagra

- triad of Dermatitis, Dementia and Diarrhea
- caused by niacin deficiency
- redness, cracks, chronic thickening, dryness and pigmentation (Casal's necklace or collar)
- painful, red, raw tongue, glossitis and angular stomatitis can occur
- encephalopathy characterised by confusion, disorientation, hallucination and memory loss occur
- neurological manifestation involves CNS and spinal cord where posterior and lateral tracts may be affected
- pellagra may occur in isoniazid therapy, alcohol dependent patients, carcinoid syndrome, Hartnup disease

Glucose transporter

GLUT-1 : basal non-insulin-stimulated glucose uptake into many cells
GLUT-2 : glucose sensing (glucose transport into beta cells)
GLUT-3 : non-insulin-mediated glucose uptake into brain neurones and placenta
GLUT-4 : channel through which glucose is taken up into muscle and adipose tissue cells following stimulation of insulin receptor (peripheral action of insulin)

Apoptosis

- programmed cell death
- features: cell shrinkage, compaction of chromatin, nuclear blebbing, cell fragmentation, energy dependent process, phagocytosis
- functions: elimination of cells in embryological development, induction of tolerance to self antigen, removal of virally infected cells and cells with damaged DNA
- 2 pathways
i) Extrinsic: Fas-Fas ligand interaction leads to release of caspase 8 and then caspase 3 (executioner caspase) activating DNA cleavage by CAD (caspase-activatable DNAase)
ii)Intrinsic: cellular stress (eg:growth factor withdrawal or p53 cycle arrest) induces pro-apoptotic proteins (bax,bak). Cytochrome C binds Apaf1 (forming apoptosome) activates caspase 9
- Bax, Bad and Bak are members of oncogenes which promote cell death
- Bcl-2 inhibits apoptosis
- disease of excess and insufficient apoptosis
excess: neurodegeneration, HIV disease
insufficient: cancer, autoimmunity

Chronic granulomatous disease

- rare immunodeficiency due to a defect in neutrophil killing and characterised by deep seated infection
- defect in production of NADPH-oxidase found in phagocytes
- patients with CGD have defective phagocytes that are able to engulf bacteria, but once engulf unable to kill them, leads to granuloma and microabscesses in skin, liver and bone
- nitroblue tetrazolium test is a simple screening test of reducing power of phagocytes

Minerals deficiency

Zinc deficiency
- acrodermatitis enteropathica is an inherited disorder caused by malabsorption of zinc
- causes dermatitis, growth retardation, severe diarrhea, alopecia, poor wound healing and impaired taste and smell

Selenium deficiency
- rare, except in Keshan (Chine) where soil has low selenium conteny
- causes cardiomyopathy

Copper deficiency
- Menkes' kinky hair syndrome is caused by malabsorption of copper
- causes anemia, growth failure, mental retardation, brittle hair

Hyper IgM syndrome

- X-linked defect in CD40 ligand
- B cells are trapped at immature level producing only IgM
- Levels of other types of immunoglobulin are low/absent
- Opportunistic infections (PCP, cryptosporidium, candida) occurs.

Blotting methods

Southern blot : DNA analysis (detection of specific DNA sequence)
Northern blot : RNA analysis
Western blot :  Protein analysis
Eastern blot : Protein post translational modification analysis (eg: lipids and glycoconjugate)
Southwestern blot : DNA binding protein analysis

G protein

- located in cytoplasm
- coupled to transmembrane receptor (G protein coupled receptor) - seven helical membrane receptors
- ligand binding site is exposed outside surface of cell. Many ligands binds to GPCR, such as TSH, ACTH, serotonin and GABA
- Ligand binding initiates secondary messenger - cAMP or IP3
- best described human disease caused by mutation of G protein is pseudohypoparathyroidism (Albright's hereditary osteodystrophy)

Wiskott Aldrich syndrome

- X linked recessive
- mutation in WASP gene
- triad of pyogenic infection, eczema and thrombocytopenia
- due to lack of sialophorin, produces low IgM levels and impaired cell mediated immunity

Live vaccine

Live vaccines (to be avoided in immunocompromised patient)

" MMR BOY"

MMR : measles, mumps, rubella
B : BCG
O : oral polio (Sabin), oral typhoid
Y: yellow fever

Selective IgA deficiency

- most common primary immunodeficiency
- typically present at any age with recurrent infections caused by pyogenic organisms and affecting mucosal sites
- can coexist with IgG2 deficiency
- deficient response to polysaccharide based vaccination
- predispose to pernicious anemia and thus gastric carcinoma
- increased risk of coeliac disease
- no specific treatment. Replacement is not practical as IgA has short half life
- Infusion of exogenous IgA (eg: blood transfusion) could result in anaphylaxis (10-44% of patients may have anti-IgA antibodies)