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List causes of breathlessness in children

• Asthma: This is one of the most common causes of breathlessness in children.

• Pneumonia:

• Bronchiolitis:

• Croup:

  Other Causes

  • Foreign object inhalation:

  • Anxiety

  • Heart conditions:

• Allergic Reactions

  • Anaphylaxis

  • Hay fever:

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Describe the basic structure of DNA

DNA is composed of two strands coiled around each other in a double helix shape. The key components of DNA structure include:

Nucleotides: The basic building blocks of DNA, consisting of:

• A sugar group (deoxyribose)

• A phosphate group

• A nitrogenous base

Backbone: The sugar and phosphate groups form the "backbone" of each DNA strand.

List the nitrogenous bases in DNA

Nitrogenous Bases: There are four types:

• Adenine (A)

• Thymine (T)

• Guanine (G)

• Cytosine (C)

Describe base pairing and directionality in DNA

Base Pairing: The two DNA strands are held together by hydrogen bonds between complementary base pairs:

• Adenine (A) pairs with Thymine (T)

• Guanine (G) pairs with Cytosine (C)

Directionality: The two DNA strands run in opposite directions (antiparallel) to each other.

What is a gene

A gene is a section of DNA that contains the instructions for making a specific protein.

Describe the structure of genes

• Coding Regions (Exons): These contain the actual instructions for building proteins.

• Non-coding Regions (Introns): These are sections within genes that are removed before protein synthesis.

• Regulatory Regions: These control when and how much of a gene is expressed, including:

  • Promoter: A sequence that initiates gene transcription

  • Enhancers: Sequences that can increase gene expression

What is a genetic mutation

Mutations are changes in the DNA sequence that can lead to genetic variation. 

List the types of genetic mutations

• Point Mutations: Changes in a single nucleotide base

  • Substitution: One base is replaced by another

  • Insertion: An extra base is added

  • Deletion: A base is removed

• Chromosomal Mutations: Large-scale changes affecting chromosome structure or number

What are the effects of mutations

• Silent mutations: No change in amino acid sequence

• Missense mutations: Change in amino acid sequence

• Nonsense mutations: Premature stop codon, truncating the protein

• Frameshift mutations: Alter the reading frame of the genetic code

What is a silent mutation

No change in amino acid sequence

what is a missense mutation

A single nucleotide change results in the substitution of one amino acid for another in the protein produced.

This can affect the protein's function, potentially leading to various effects on the organism, depending on the role of the altered amino acid.

What is a nonsense mutation

A single nucleotide change results in a premature stop codon in the coding sequence of a gene.

This leads to the production of a truncated protein, which is usually nonfunctional, potentially causing various genetic disorders or diseases.

What is a frameshift mutation

A genetic mutation caused by the insertion or deletion of nucleotides in a DNA sequence that shifts the reading frame of the genetic code.

This alteration can lead to changes in the amino acid sequence of a protein, potentially resulting in a nonfunctional protein or a completely different protein.

Frameshift mutations can have significant effects on an organism's phenotype.

What is transciption of DNA

Transcription is the process of copying DNA into RNA. The main steps are:

1. Initiation

2. Elongation

3. Termination

4. Processing

Describe in detail the process of transciption

1. Initiation:

   • RNA polymerase binds to the promoter region of a gene

   • The DNA double helix unwinds at the transcription start site

2. Elongation:

   • RNA polymerase moves along the template DNA strand in the 3' to 5' direction

   • Complementary RNA nucleotides are added to the growing RNA chain in the 5' to 3' direction

   • The RNA transcript is synthesized using base pairing rules (A pairs with U, C with G)

3. Termination:

   • RNA polymerase reaches a termination sequence

   • The newly synthesized RNA transcript is released

   • The DNA double helix reforms

4. Processing (in eukaryotes):

   • Addition of 5' cap and 3' poly-A tail

   • Splicing to remove introns and join exons

The result is a mature messenger RNA (mRNA) molecule.

What occurs as part of initiation in DNA transcription

• RNA polymerase binds to the promoter region of a gene

• The DNA double helix unwinds at the transcription start site

What occurs as part of elongation in DNA transcription

• RNA polymerase moves along the template DNA strand in the 3' to 5' direction

• Complementary RNA nucleotides are added to the growing RNA chain in the 5' to 3' direction

• The RNA transcript is synthesized using base pairing rules (A pairs with U, C with G)

What occurs as part of termination in DNA transcription

• RNA polymerase reaches a termination sequence

• The newly synthesized RNA transcript is released

• The DNA double helix reforms

What occurs as part of processing in DNA transcription

1. Addition of 5' cap and 3' poly-A tail

2. Splicing to remove introns and join exons

The result is a mature messenger RNA (mRNA) molecule.

Describe processing as a part of DNA transcription

During DNA transcription, processing refers to the modifications that pre-mRNA undergoes before becoming mature mRNA. This includes:

1. Capping: Addition of a 5' cap to the beginning of the mRNA for stability and recognition.

2. Polyadenylation: Addition of a poly-A tail at the 3' end, enhancing stability and export from the nucleus.

3. Splicing: Removal of introns (non-coding regions) and joining of exons (coding regions) to form a continuous coding sequence.

What is DNA Translation

Translation is the process of synthesizing a protein using the mRNA as a template. The main steps are:

1. Initiation:

2. Elongation:

3. Termination:

4. Post-translational modifications:

Describe in detail the process of DNA translation

1. Initiation:

   • The small ribosomal subunit binds to the mRNA at the start codon (AUG)

   • The large ribosomal subunit joins to form the complete ribosome

2. Elongation:

   • tRNA molecules bring amino acids to the ribosome

   • The ribosome reads the mRNA codons in sets of three nucleotides

   • Amino acids are joined together by peptide bonds to form the growing polypeptide chain

3. Termination:

   • The ribosome reaches a stop codon (UAA, UAG, or UGA)

   • The completed polypeptide is released

   • The ribosome dissociates from the mRNA

4. Post-translational modifications:

   • The polypeptide may undergo further modifications (e.g. folding, glycosylation)

What occurs as part of initiation in DNA translation

• The small ribosomal subunit binds to the mRNA at the start codon (AUG)

• The large ribosomal subunit joins to form the complete ribosome

What occurs as part of elongation in DNA translation

• tRNA molecules bring amino acids to the ribosome

• The ribosome reads the mRNA codons in sets of three nucleotides

• Amino acids are joined together by peptide bonds to form the growing polypeptide chain

What occurs as part of termination in DNA translation

• The ribosome reaches a stop codon (UAA, UAG, or UGA)

• The completed polypeptide is released

• The ribosome dissociates from the mRNA

What occurs as part of Post-translational modifications in DNA translation

• The polypeptide may undergo further modifications (e.g. folding, glycosylation)

What are the common symptoms of anaemia

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• F - Fatigue

• P - Paleness

• S - Shortness of breath

• D - Dizziness or lightheadedness

• R - Rapid heartbeat (palpitations)

• H - Headaches

• C - Cold hands and feet

• B - Brittle nails

• G - Growth problems (in children)

List the causes of microcytic anaemia MCV<80

• Iron deficiency anaemia: This is the most common cause of microcytic anaemia.

• Thalassemia: An inherited blood disorder affecting haemoglobin production.

• Anaemia of chronic disease: e.g. kidney disease, certain cancers, and inflammatory diseases

List the causes of normocytic anaemia MCV 80-100

• Acute blood loss

• Hemolytic disorders:

  • Inherited conditions like sickle cell disease, thalassemias

  • Acquired conditions like autoimmune hemolytic anemia

• Bone marrow disorders:

  • Aplastic anemia

  • Myelodysplastic syndromes

  • Pure red cell aplasia

• Chronic kidney disease

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List the causes of macrocytic anaemia

• Vitamin B12 deficiency: This is one of the most common causes.

• Folate (vitamin B9) deficiency: Another very common cause, especially during pregnancy.

• Alcoholism: Chronic alcohol use can lead to macrocytic anemia.

• Liver disease: Various liver conditions can contribute to this type of anemia.

• Hypothyroidism: An underactive thyroid can cause macrocytic anemia.

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Where do erythrocytes originate

• Produced in bone marrow through erythropoiesis

• Develop from hematopoietic stem cells

Describe the structure of erythrocytes

• Biconcave disk shape, 7-8 μm in diameter

• No nucleus or organelles

• Flexible membrane composed of proteins and lipids

• Cytoplasm filled with hemoglobin

What is the function of erythrocytes

• Transport oxygen from lungs to tissues

• Transport carbon dioxide from tissues to lungs

• Regulate blood pH

Where are WBCs produced

• Produced in bone marrow

• Develop from hematopoietic stem cells

Describe the structure of WBCs

• Vary in size and shape depending on type

• Contain nucleus and organelles

What are the types of WBCs

• Neutrophils:

• Lymphocytes:

• Monocytes:

• Eosinophils:

• Basophils:

What is the function of neutrophils

• Phagocytosis of bacteria and fungi

What is the function of lymphocytes

• Produce antibodies and regulate immune response

What is the function of monocytes

• Phagocytosis and antigen presentation

What is the function of eosinophils

• Defense against parasites and allergic reactions

What is the function of basophils

• Release histamine in allergic reactions

What is the origin of platelets

• Produced in bone marrow

• Fragment from megakaryocyte

Describe the structure of platlets

• Small, irregularly shaped cell fragments

• No nucleus

• Contain granules with clotting factors

Describe the function of platelets

• Blood clotting and hemostasis

• Release growth factors for wound healing

Describe the structure of primary proteins

• Linear sequence of amino acids

• Held together by covalent peptide bonds between amino acids

Describe the structure of secondary proteins

• Regular folding patterns within sections of the polypeptide chain

• Main types: alpha-helices and beta-pleated sheets

• Stabilized primarily by hydrogen bonds between the main-chain peptide groups

• Alpha-helix: coiled structure with hydrogen bonds between every fourth amino acid

• Beta-pleated sheet: extended zig-zag structure with hydrogen bonds between adjacent strands

Describe the structure of tertiary proteins

• Overall three-dimensional shape of a single polypeptide chain

• Stabilized by various interactions between amino acid side chains:

  • Hydrophobic interactions: major driving force for folding, involving non-polar side chains

  • Hydrogen bonds: between polar side chains

  • Ionic bonds: between oppositely charged side chains

  • Disulfide bridges: covalent bonds between cysteine residues

  • Van der Waals forces: weak interactions between nearby atoms

Describe the structure of quaternary proteins

• Arrangement of multiple polypeptide chains (subunits) in a single functional protein

• Stabilized by the same types of interactions as tertiary structure:

  • Non-covalent interactions (hydrophobic, hydrogen bonds, ionic bonds)

  • Sometimes disulfide bridges between subunits

Describe the structure of haemoglobin

Quaternary structure:

• Tetramer composed of four subunits: two α and two β chains

• Each subunit contains a heme group

Haeme group:

• Iron-containing molecule of protoporphyrin-IX

• Allows binding of oxygen and other gases

Conformational states:

• T state (tense): low oxygen affinity, deoxygenated form

• R state (relaxed): high oxygen affinity, oxygenated form

Describe the function of haemoglobin

Primary function: Oxygen transport

• Binds oxygen in lungs and releases it in tissues

• Increases oxygen-carrying capacity of blood by ~50-100 times

Secondary functions:

• CO2 transport (10-20% of total CO2)

• pH regulation

• Nitric oxide metabolism

Cooperative binding:

• Sigmoid oxygen dissociation curve

• Allows efficient loading and unloading of oxygen

What are the adaptions of RBCs for oxygen delivery

• High surface area to volume ratio for gas exchange

• Flexibility to pass through small capillaries

• Ability to deform without rupturing

• Contain enzymes to maintain hemoglobin in reduced state

List the clinical features of Sickle cell anamia

1. Anaemia: Fatigue, shortness of breath, delayed growth and development in children

2. Painful episodes (vaso-occlusive crises): Acute pain in various parts of the body

3. Increased risk of infections

4. Jaundice and yellowing of the eyes

5. Hand-foot syndrome in infants (painful swelling of hands and feet)

6. Stroke risk, especially in children

7. Acute chest syndrome: Chest pain, fever, difficulty breathing

8. Pulmonary hypertension

9. Organ damage (kidneys, liver, spleen, brain)

10. Priapism in males

11. Leg ulcers

12. Vision problems, including potential blindness

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List the pathological features of sickle cell anaemia

1. Abnormal hemoglobin S production

2. Sickle-shaped red blood cells

3. Hemolytic anemia due to premature destruction of sickled cells

4. Vaso-occlusion due to sickled cells blocking small blood vessels

5. Chronic organ damage from repeated vaso-occlusion and ischemia

6. Splenic sequestration and potential functional asplenia

7. Increased risk of gallstone formation

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What are the clinical features of thalassaemia?

1. Severe anemia: Profound fatigue, weakness, pale skin

2. Failure to thrive and growth retardation in children

3. Enlarged liver and spleen (hepatosplenomegaly)

4. Jaundice

5. Bone deformities, especially in the face (frontal bossing, prominent cheekbones)

6. Increased susceptibility to infections

7. Iron overload complications (without proper management):

   • Heart problems (heart failure, arrhythmias)

   • Liver cirrhosis

   • Endocrine disorders (diabetes, thyroid problems, growth hormone deficiency)

8. Osteoporosis

9. Delayed puberty

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What are the pathological features of thalassaemia?

1. Defective production of beta-globin chains

2. Ineffective erythropoiesis (red blood cell production)

3. Extramedullary hematopoiesis leading to hepatosplenomegaly

4. Hemolytic anemia

5. Iron overload in various organs due to repeated blood transfusions

6. Expansion of bone marrow cavities, leading to skeletal deformities

7. Increased gastrointestinal iron absorption

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What is the difference between sickle cell and thalassaemia

Sickle cell anemia is characterized by abnormal hemoglobin that causes red blood cells to sickle, while thalassemia major involves insufficient production of normal hemoglobin components

Define anaemia

A condition characterized by a deficiency of red blood cells or hemoglobin in the blood, leading to reduced oxygen transport to the body's tissues.

What mutation occurs in sickle cell disease

• Sickle cell disease is caused by a single point mutation in the HBB gene, which codes for the β-globin subunit of hemoglobin.

• The mutation changes the 6th codon of the β-globin gene from GAG to GTG.

• This results in the substitution of glutamic acid (a hydrophilic amino acid) with valine (a hydrophobic amino acid) at the 6th position of the β-globin chain.

What effects does the sickle cell mutation have on protein structure

• The mutated hemoglobin is called hemoglobin S (HbS).

• The substitution of a hydrophilic amino acid with a hydrophobic one creates a sticky patch on the surface of the hemoglobin molecule.

• Under low oxygen conditions, this sticky patch allows hemoglobin molecules to aggregate and form long, rigid polymers.

What affect does the sickle cell mutation have on RBC shape

• The polymerization of hemoglobin S distorts the shape of red blood cells.

• Instead of the normal biconcave disc shape, affected red blood cells become crescent or sickle-shaped.

What is the functional consequences of sickle cell mutation

• Sickle-shaped cells are less flexible and can obstruct small blood vessels, leading to vaso-occlusion.

• These cells are also more fragile, resulting in premature destruction (haemolysis).

• The abnormal hemoglobin has a reduced ability to carry oxygen effectively.

What are the effects of oxygen deprivation

1. Tissue ischemia: When sickled red blood cells occlude blood vessels, the tissues supplied by those vessels become deprived of oxygen (ischemia).

2. Cell death: Prolonged oxygen deprivation leads to cell death in the affected tissues.

3. Inflammation: The ischemia-reperfusion injury that occurs when blood flow is restored triggers an inflammatory response.

4. Chronic organ damage: Repeated episodes of vaso-occlusion and ischemia lead to progressive organ dysfunction and damage.

What are the problems occur to the brain in sickle cell anaemia caused by vasocclusion.

• Stroke

• Silent cerebral infarcts

• Cognitive impairment

What are the problems occur to the lungs in sickle cell anaemia caused by vasocclusion.

• Acute chest syndrome

• Pulmonary hypertension

• Chronic lung disease

What are the problems occur to the heart in sickle cell anaemia caused by vasocclusion.

• Cardiomegaly

• Myocardial infarction

• Heart failure

What problems can occur in the kidneys in sickle cell anaemia caused by vasocclusion.

• Renal infarction

• Chronic kidney disease

• Proteinuria

What problems can occur in the liver in sickle cell anaemia caused by vasocclusion.

• Hepatic infarction

• Hepatomegaly

• Liver fibrosis

What problems can occur in the Spleen in sickle cell anaemia caused by vasocclusion.

• Splenic infarction

• Functional asplenia

• Increased susceptibility to infections

What problems can occur in the Bone in sickle cell anaemia caused by vasocclusion.

• Avascular necrosis (especially of the hip)

• Osteomyelitis

• Chronic bone pain

What problems can occur in the eyes in sickle cell anaemia caused by vasocclusion.

• Retinopathy

• Retinal detachment

• Vision loss

What problems can occur in the skin in sickle cell anaemia caused by vasocclusion.

• Leg ulcers

• Poor wound healing

What problems can occur in the genitourinary system in sickle cell anaemia caused by vasocclusion.

• Priapism

• Renal papillary necrosis

what is Priapism

Priapism is a medical condition characterized by a prolonged and often painful erection that lasts for more than four hours and occurs without sexual stimulation.

List the functions of the spleen

• Blood Filtration

• Immune function

• Blood cell storage and release

• Iron recycling

• Haematopoiesis

• Blood volume regulation

• Removal of abnormal cells

• Production of Opsonins

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Describe the role of the spleen in blood filtration

• Removes old, damaged, and abnormal red blood cells from circulation

• Filters out pathogens and foreign particles from the blood

Describe the role of the spleen in immune function

• Houses antibody-producing lymphocytes in the white pulp

• Produces antibodies and components of the immune system

• Contains macrophages that remove antibody-coated bacteria and blood cells

• Facilitates interactions between antigen-presenting cells and lymphocytes

Describe the role of the spleen in blood cell storage and release

• Stores up to 1/3 of the body's platelets

• Stores a reserve of red blood cells

• Can release stored blood cells into circulation when needed (e.g. during hemorrhage)

Describe transient skin flora

• Colonizes the superficial layers of the skin

• More easily removed by routine hand hygiene

• Often acquired through contact with patients or contaminated surfaces

• Does not usually multiply on the skin but can survive temporarily

• More frequently associated with healthcare-associated infections

• Examples include various bacteria picked up from the environment

Describe resident skin flora

• Resides under the superficial cells of the stratum corneum and on the skin surface

• More difficult to remove through hand hygiene

• Includes species like Staphylococcus epidermidis, other coagulase-negative staphylococci, and corynebacteria

• Has protective functions like microbial antagonism and competition for nutrients

• Generally less likely to cause infections

How can normal skin flora become pathogenic

1. Damage to the skin barrier can allow normally harmless bacteria to enter deeper tissues and cause infection

2. Immunosuppression of the host can allow normally benign bacteria to proliferate and cause disease

3. Changes in skin conditions (e.g. increased moisture) can promote overgrowth of certain species

4. Some resident flora can cause infections if introduced to sterile body sites or non-intact skin (Entry into sterile sites)

5. Certain strains of normally commensal bacteria may have increased virulence factors

6. Changes in the balance of the skin microbiome can allow potential pathogens to dominate

In summary, while the normal skin flora is generally harmless or even beneficial, changes in the host or microbial community can lead to pathogenic behaviour from these typically commensal organisms.

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Describe the morphology of Staphylococcus

• Staphylococci appear as spherical (cocci) bacteria

• They typically occur in grape-like clusters

• They may also be seen in pairs or short chains

Describe the staining characteristics of Staphylococcus

• Staphylococci are Gram-positive, meaning they retain crystal violet stain and appear purple/blue when Gram stained

• They stain uniformly (no internal structures visible)

Describe some common features of staphylococcus under the microscope

Size:

• Individual cocci are approximately 0.5-1.5 μm in diameter

 Arrangement:

• The characteristic grape-like clusters are due to cell division occurring in multiple planes

• Clusters typically contain 5-30 individual cocci

 Other features:

• Non-motile (do not move)

• Non-spore forming

List the common infections associated with sickle cell

1. Pneumococcal infections: Streptococcus pneumoniae is one of the most common and serious pathogens in sickle cell disease patients, especially children.

2. Salmonella infections: Salmonella species are frequently associated with osteomyelitis in sickle cell patients.

3. Staphylococcal infections: Staphylococcus aureus is another common cause of infections, particularly osteomyelitis.

4. Urinary tract infections: These were found in about 3.9% of sickle cell patients in one study.

5. Bloodstream infections (bacteremia): More common in sickle cell patients, especially children.

6. Respiratory infections: Including pneumonia caused by various pathogens.

7. Meningitis: Particularly pneumococcal meningitis in children.

8. Osteomyelitis: Bone infections, often caused by Salmonella or Staphylococcus.

9. Sepsis: Severe systemic infections are more common in sickle cell patients.

10. Parvovirus B19 infection: Can cause aplastic crisis in sickle cell patients.

11. Malaria: In regions where malaria is endemic, it can be a significant problem for sickle cell patients.

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Explain the mechanism of damage to the spleen seen in sickle cell disease

1. Vaso-occlusion: Sickled red blood cells can block small blood vessels in the spleen, leading to repeated episodes of ischemia and infarction.

2. Congestion: Sickled cells can get trapped in the spleen's filtration beds, causing congestion and enlargement (splenomegaly).

3. Sequestration: Acute splenic sequestration crises can occur when large amounts of blood become trapped in the spleen, causing rapid enlargement and a drop in circulating blood volume.

4. Progressive damage: Over time, repeated episodes of vaso-occlusion and infarction lead to scarring and gradual loss of splenic function (functional asplenia).

5. Autosplenectomy: In many SCD patients, especially those with HbSS genotype, the spleen gradually shrinks and becomes non-functional by early childhood due to repeated damage.

Why does spleen damage from sickle cell disease predisposes to infections with encapsulated bacteria:

1. Loss of filtration function: The spleen normally filters blood to remove pathogens, especially encapsulated bacteria. Loss of this function increases susceptibility to these infections.

2. Impaired immune response: The spleen plays a crucial role in producing IgM antibodies, which are important for opsonizing encapsulated bacteria. Decreased splenic function leads to reduced IgM levels.

3. Reduced memory B-cells: The spleen is important for maintaining a population of memory B-cells that respond quickly to encapsulated bacteria. Loss of splenic function reduces this population.

4. Impaired phagocytosis: Splenic macrophages are important for phagocytosing opsonized bacteria. Their loss reduces the body's ability to clear these pathogens.

5. Specific vulnerability: Encapsulated bacteria like Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis are particularly challenging for the immune system without splenic function, as the capsule provides protection against other immune mechanisms.

Name 4 types of encapsulated bacteria capable of causing severe infection.

1. Streptococcus pneumoniae (pneumococcus)

2. Neisseria meningitidis (meningococcus)

3. Haemophilus influenzae

4. Streptococcus agalactiae (Group B Streptococcus)