GEP (Life Protection) Week 2 Flashcards
How many vertebrates does the human body have, seperrate them into their sections and what is the strucutre inbetween the discs.
- 33 vertebrae
-7 cervical
-12 thoracic
-5 lumbar
-5 sacral
-4 coccygeal
-Intervertebral discs between vertebrae
What are the 4 natural curvature of the spine
Cervical lordosis
Thoracic kyphosis
Lumbar lordosis
Sacral kyphosis
-Kyphosis = concave anteriorly and convex posteriorly
-Lordosis = opposite
Name these anatomical areas on the vertebral
How many segments is the spinal cord broken down into and what is its function
Divided into 31 segments
-Each has a dorsal and ventral roots
-These combine to form mixed spinal nerves
Runs from Brain stem and ends at lower boarder of L1
Functions
Transmits nerve impulses to and from the brain
Mediates important reflexes
Coordinates complex motor sequences
What are spinal cord enlargements and how many are there
Cervical
Motor and sensory upper limb supply
Lumbar
Motor and sensory lower limb supply
Enlargement due to the vast bundle of motor and sensory supply in that region.
What are efferents and afferents
General Memory Aid: Afferent pathways Arrive, Efferent pathways Eff off
What does dorsal and ventral roots do
Dorsal Root
Sensory pathway through the somatic afferent
Autonomic sensory through visceral afferent
Ventral Root
Motor pathways through somatic efferent
Autonomic motor and secretory pathways through visceral efferent
Somatic = Skin, Muscles, Bones and Joints
Visceral = Organs
What is the lymphatic system
The lymphatic system is the body’s drainage system
It removes excess fluid from the body
Cleans fluid and returns it to the blood
What is the 3 main functions of the lymphatic system
3 main functions:
Tissue drainage
Fat transport
Immune responses
What are the primary and secondary lymphoid organs
Primary lymphoid organs = where lymphocytes are made
Thymus: T cells
Red Bone marrow: B cells
Secondary lymphoid organs:
Spleen
Lymph nodes
What is Lymph
Lymph = clear fluid that is transported through lymph vessels. In the capillary beds, 20L of fluid per day leak out of the capillaries, 17L are reabsorbed, leaving 3L lost in the interstitium
How does tissue drainage occur in the lymph
When there is high pressure in the interstitium in the lymphatic capillary endothelial 1 way mini-valves open absorbing the fluid. When the pressure in the interstitium is less than the pressure in the capillary the endothelial valves are pushed shut.
Lymphatic capillaries merge to form lymphatic vessels, which drain lymph through lymph nodes until lymphatic trunks are formed, and as the lymph vessels get bigger their walls get thicker.
Finally lymphatic trunks converge to form lymphatic ducts: specifically; right lymphatic duct and the thoracic duct
There are no pumps in the lymph system instead SM in walls of lymph vessels squeeze, and skeletal muscle exerts external pressure to keep lymph flowing. Lymph vessels have valves like veins.
What are the 2 main lymph drainage system
Right lymphatic duct drains:
R side of head and neck
R side of chest
R upper limb
Drains into the right venous angle: meeting point of the right IJV and R subclavian vein
Thoracic duct drains:
L side of head and neck
L side of chest
L upper limb
Abdomen
Both lower limbs
The thoracic duct begins as the cisterna chyli: dilated sac where lymphatic trunks from lower limbs, abdominal viscera and pelvis converge
The thoracic duct travels through the thoracic cavity and drains into the left venous angle: meeting point of left IJV and subclavian.
Once drained into the right and left venus angles, the lymph from the thoracic duct and the right lymphatic duct mixed with the blood drain into the SVC > right atrium of the heart
How is fat absorbed
The lymphatics absorb fats and fat soluble vitamins from the digestive system
The mucosa that lines the small intestine is covered in villi
In each villi there are blood vessels and lymph vessels - lacteals.
The blood capillaries absorb most nutrients but fatty acids (which are packaged into balls of fat: chylomicrons by the small intestine) are too big to move across into capillaries so they go into the lacteals.
The chylomicrons make their way into the thoracic duct and subsequently travel into the venous blood
How does the lymph aid in immune response
1) Lymph enters the lymph nodes via the afferent lymphatic vessels
2) Valves stop lymph from flowing in the wrong direction
3) Medullary sinus = densely packed with B-cells, T-cells, macrophages and plasma cells, which will sample and present any antigens and decide what to do
4) Lymph then drain out by the efferent vessel
What is the functions of an antibody
Functions:
Opsonize pathogens
Neutralize toxins
Activate complement
Key concept- each B cell produces antibodies with specificity for a single antigen
What does antibody affinity and avidity mean
Affinity - the strength of binding at one single sight
Avidity: the total binding strength of an antibody
What is the structure of an antibody
Each antibody has 2 identical light chains & two identical heavy chains
Antigen binding Region: Fab
Heavy chains : V, D and J segments
Light chains: V & J
Heavy chains are connected by a double disulphide bond.
Heavy and light chains are connected by a single disulphide bond
Constant region: Fc
Interacts with cell surface receptors
Determined by the heavy and light chain constant genes
C =Constant and Cell surface
What is lymphopoiesis
Refers to the production of new lymphocytes, including B lymphocytes, T lymphocytes, and natural killer (NK) cells.
How does the B-cell develop
Developing B cells interact with the stromal cells of the bone marrow: mesenchymal stem cells (which are multipotent differentiating into endothelial cells and macrophages.
Mesenchymal cells supply B cells with adhesion molecules and growth factors: IL-7, which they need to grow and proliferate.
How does the B-cell develop step by step
Step 1: Starts with a common lymphoid progenitor cell: RAG-1 and RAG-2 are expressed signifying its now an early Pro-B cell
Step 2: D and J segments are spliced together, when D and J segments are successfully spliced then creates a late Pro-B cell
Step 3: The late Pro-B cell has to attach its DJ segment to a V segment which requires VDJ recombinase, once these heavy chains combine the VDJ antigen binding portion of the heavy chain is complete. It then needs to attach to the mu gene. The Mu gene codes for the IgM constant region of the antibody = now a large Pre-B cell.
Step 4: It now tests out if the heavy chain is functional and binds to a surrogate light chain (made of VpreB and lambda 5). The surrogate light chain and complete heavy chain are transported to the cell membrane in a vesicle if they dock correctly to make a functional heavy chain a signal is sent to the nucleus - triggering rapid proliferation = small Pre-B cell
Step 5: The Small Pre-B cells start rearranging its light chains, they all have the same heavy chain, but their own distinct light chain.
There are two types of light chain Kappa and Lambda, Kappa starts first.
If the light chain doesn’t work, the small Pre-B cell either iterates or is killed off = Prevents self-reactive B cells
How is B-cell development regulated
To prevent self-reactive B cells, there is the AIRE (AutoImmune REgulator) gene
AIRE is expressed in primary lymphoid organs and enables them to express antigens that are normally found all around the body.
It allows primary lymphoid organs to serve as a microcosm of the rest of the body, the primary lymphoid organs test the newly formed B cell in a controlled environment. If it attaches strongly to a self-antigen it is apoptosed. Whereas if it only attaches with intermediate force it rearranges its light chain to reduce affinity to the self antigen. The Pre-B cell creates new VJ rearrangements on their light chain: kappa chromosome 1, then 2, lambda chromosome 1, then 2.
Step 6: Only small Pre-B cells who don’t reactive to self-antigens at all become immature B cells.
Step 7: To get into the blood, the B cell undergoes alternative splicing: some use the mu gene - IgM constant region, whereas some use the delta gene - IgD constant region, but both IgM and IgD have the same antigen binding specificity. When an immature B cell displays both IgM and IgD it can then leave the bone marrow.
What are the key checkpoints of B-Cell Development
Production:
Pro-B cells undergo heavy chain rearrangement = checkpoint 1 (bone marrow)
Pre-B cells: kappa or lambda light chain rearrangement = checkpoint 2 (bone marrow)
Small pre-B cells are tested for self-reactivity if IgM binds to self ‘antigens’ = apoptosis checkpoint 3
Immature B cells have to express both IgM and IgD before they are deemed mature and can move to secondary lymphoid tissue where they can respond to foreign antigens they encounter (proliferation and development
Antibodies are secreted B-cell receptors, once a B cell has bound to its specific antigen - the B cell will differentiate into a plasma cell - which secretes antibody specific antigens.
How does plasma and Memory B-cell production happen
B-cells express IgM on surface (BCR)
BCR recognises antigen = engulfs
Presents antigen on MHCII
CD40 expression on cell surface
Meanwhile, macrophage presents the same antigen to naïve CD4+ T-cell
Activates CD4+ into Th2 cells
Th2 cells recognise the antigen
Interaction between B-cell and Th2 via antigen presenting MHCII and TCR
CD40L expression on Th2 interacts with CD40
Cytokine production – IL-4 and IL-21, causing proliferation and differentiation of B-cells into antibody producing plasma cells & memory B-cells
What are the 5 main types of Immunoglobins
IgG, IgA, IgM, IgD, IgE
What is an amyloid and why is it dangerous for the body
Amyloid = any protein which has assembled abnormally into beta-pleated sheets
This renders the protein insoluble
The body cannot break down these proteins and there is no inflammatory response to it
Slowly it builds up in extracellular spaces leading to cell strangulation and death
Gradual organ failure
Often undiagnosed until patients are gravely ill due to organ failure
Most common affected organs = kidneys, heart, GI tract
What is amyloidosis
A group of conditions in which there is an excess deposition of amyloid in tissues
Amyloid proteins are designated A followed by an abbreviation to designate the protein of origin
AA and AL = most common
What are the risk factors of Multiple Myeloma
Strong
Age
>65 years
Male
2x higher risk
Afro-Caribbean
2x higher risk
Obesity
Weak
Family Hx
Radiation exposure
Epstein-Barr Virus (EBV)
What the differential diagnosis of Multiple Myeloma
Skeletal metastases
Amyloidosis
Osteoporosis
Connective tissue disorders
Chronic infection
Other rarer plasma cell disorders
Any other condition that causes lower back pain
What is the epidemiology of Multiple Myeloma
1% of all cancers
19th most common cancer
Incidence = 10/100,000
Prevalence = 18,000
Mortality = 3100 deaths per year
What is the aetiology for Multiple Myeloma
MGUS - Monoclonal Gammopathy of Unknown Significance
Non-cancerous production of paraprotein (M protein - light chain fragment)
Higher risk of developing myeloma
Smouldering Myeloma
Classic M protein and bone marrow myeloma findings but with NO symptoms
50% go on to develop myeloma
Multiple Myeloma
A form of active, malignant leukaemia
Extensive and diffuse plasma cell involvement (<60%)
Symptomatic - CRAB symptoms
What are the clinical features of Multiple myeloma
There are a specific set of symptoms and clinical features that present with Multiple Myeloma, termed CRAB symptoms
- hyperCalcaemia
Cellular signalling from Il3 + 6 causes increased breakdown and decreased building of bone - Renal dysfunction
Buildup of paraproteins in fine capillaries in the nephron
Leads to renal dysfunction - Anaemia
Bone marrow colonisation of hyperproliferative B cells
Less production of erythrocytes - Bone pain
Generalised thinning of the bone and local bone damage
Collapsing of bones leading to compression fracture
General cancer red flags:
Fatigue
Weight loss
Loss of appetite
Night sweats
Specific myeloma red flag:
Pain that wakes the patient up
Pain does not improve with pain relief
What are the clinical features of Hypercalcaemia
4 key features
- Bones
Bony pain - Stones
Renal stones - Abdominal groans
Nausea
Vomiting
Constipation
Indigestion - Psychological moans
Lethargy
Depression
Memory loss
Psychosis
What is CRAB, regarding the clinical features of Multiple Myeloma
What is the pathophysiology of Multiple Myeloma
M Cells crowd out the production of blood cells, causing pancytopenia
Causes anaemia
Immunsuppression
Thrombocytopenia
MM cells overproduce abnormal Igs
Accumulates in kidney
Precipitate in tissues
Precipitate in blood
MM cells release cytokines →IL-6,IL-3 and DKK1 (there are others too)
Increase osteoclast activity, decrease osteoblast activity
Osteolytic lesions
Bony pain
Hypercalcaemia
Why does Multiple Myeloma cause Hypercalcemia
Bones are comprised of:
Calcium - Ca2+
Phosphate - PO43-
2 key cells
Osteoblasts - build bone (B for Build)
Osteoclasts - break down bone (C for Crumble)
Why do you get renal impairment with Multiple Myeloma and how.
3 causes of renal impairment in MM:
Light chain paraprotein deposition
Forms casts in the convoluted tubules
Forms amyloid which deposits in the glomeruli
Hypercalcaemia
Renal calculi → insoluble deposits
NSAIDs
Used to treat bony pain
Cause kidney damage
Prostaglandin inhibition → revise mechanism
What are the investigations for multiple myeloma
Bloods
FBC
Anaemia or leukopenia
Calcium
Raised in myeloma
ESR
Increased in myeloma
Plasma Viscosity
Increased in myeloma
U&E
For renal impairment
Gene Profiling
Some genes will give a better or worse prognosis
**Bone Marrow Biopsy - this is DIAGNOSTIC **
Confirms diagnosis and perform cytogenetic testing
Imaging
Whole-body MRI
Whole-body low dose CT
Skeletal survey - X-Ray images of the entire skeleton
Typically will show well-defined lytic lesions, diffuse osteopenia and abnormal (pathological) fractures
Raindrop/pepper pot skull refers to the lytic lesions seen in the skull upon x-ray
What are the specialsit investigations for Multiple Myeloma
Specialist Analysis
- Serum protein electrophoresis (SPEP)
Detection of paraproteinaemia
Intact paraproteins give a spike in the gamma region of the graph - Serum-free light-chain assay
Detection of abnormally abundant light chains
Used when SPEP does not detect paraprotein
Kappa or lambda - normal is 2:1, abnormal can be >100:1 - Urine protein electrophoresis
Detection of Bence Jones Protein - precipitation of light chains
Presentation in 75% of cases (heavy and light chain myeloma)
What is the management for Multiple Myeloma
Initial
Oncology and Haematology MDT
Coordinate treatment to control the disease
**Chemotherapy - VTD Therapy is 1st line in otherwise healthy patients **
Bortezomib (Velcade)
Thalidomide
Dexamethasone
Stem Cell Transplant
Autologous
Using the person’s own stem cells
Allogenic
Using stem cells from a healthy donor
What are the management fro symptoms
Symptom Management
- Bisphosphonates
Osteoclast apoptosis
Adverse effect = osteonecrosis of the jaw - Denosumab
Decreased osteoclast activity through RANKL inhibition - EPO injections + transfusions
Anaemia treatment - Renal
Dialysis
Avoidance of nephrotoxic drugs (like NSAIDs) - Radiotherapy
Bone lesions can improve bone pain - Orthopaedic Surgery
Stabilise bones - inserting prophylactic intramedullary rod
Treat fractures - Cement augmentation
Injecting cement into vertebral fractures or lesions to improve spine stability and pain
MICRA VTD (Bortezomib (Velcade),
Thalidomide,
Dexamethasone)
What is the prognonsis of Multiple myeloma
Prognosis
Survival rate in 15-49 year olds → 74%
Survival rate in 80-99 year olds → 25%
Complications
Infection
Bone pain
Fractures
Renal failure
Anaemia
Hypercalcaemia
Peripheral neuropathy
Spinal cord compression
Hyperviscosity syndrome
VTE
