Module 9 Integrative Flashcards

Question

Cerebral toxoplasmosis

Answer 1

Toxoplasma gondii - cat poo parasite Most common cause mass lesion CD4 <200- reactivation Confusion/headache/hemiparesis/fits/fever Ring enhancing lesions- cortex/grey matter Sulphadiazine, pyrimethamine, folic acid Clindamycin 2nd line Septrin prophylaxis

Answer 2

Cryptococcus neoformans- encapsulated yeast CD4<100 Sub acute meningitis, headache, fever Raised CSF pressure, positive serum CRAG Scan normal or Cryptococcomas - basal ganglia Daily LP- to reduce pressure, IV amphotericin B, flucytosine Can also cause lung infection

Answer 3

Demyelinating disease JC Virus Advanced HIV Sub acute/chronic Personality change/aphasia/hemiparesis/ White matter changes- parieto- occipital, no mass effect

Answer 4

Seroprevalence of 50-70% Human herpes virus CD4 <100 Retinitis Colitis Pneumonitis Encephalitis Ganciclovir +/- Foscarnet HAART

Answer 5

X-linked (inherited) agammaglobulinemia also called Bruton’s disease/Bruton’s agammaglobulinemia, related to a dysfunctional tyrosine kinase, rare, 1:200,000 people, caused by an inability to produce antibodies due to lack of maturation between pre-B-cell and formation of a B-cell. All classes of immunoglobulins depleted. Recurrent infections that may be evidenced in neonate.

Answer 6

Lack of T-helper cell mediated isotype class switching, hence predominantly produce IgM. Often X-linked, autosomal recessive. Characterized by normal or elevated serum IgM levels and decreased levels or absence of other serum immunoglobulins, resulting in susceptibility to bacterial infections.

Answer 7

Characterized by a low level of antibody production, hence susceptibility to bacterial infections. Low circulatory IgG and IgA, diagnosed as hypogammaglobulineamia, arises from a number of genetic causes. Relatively rare, affecting ≈1:25,000.

Answer 8

Developmental, arising from a microdeletion on the long arm of chromosome 22. Affects facial regions and the thymus, can result in a thymic hypoplasia. Deficiency in T-cell production and maturation, vulnerable to viral and fungal infections.

Answer 9

Caused by human immunodeficiency virus (HIV), HIV-1 and HIV-2. HIV-1 is more virulent and the cause of most AIDS. Spread by exchange of bodily fluids, via sexual intercourse and blood products such as infected needles or blood (transfusions), and vertical transmission (mother to offspring). HIV displays cellular tropism via binding of HIV gp120 to CD4 receptors (present on T-cells, DC, Mθ). Of these, CD4+ T cells are the major source of HIV throughout infection and can lead to their depletion.

Answer 10

Inherited stem cell defect that results in loss of B-cells or T-cells or both. Typically presents in first year of life with persistent infections of all types (bacterial, viral, fungal, protozoan eg pneumocystis) and diarrhoea and faltering growth. Generally fatal if untreated without a bone marrow transplant – ‘life in a bubble’.

Answer 11

(severe congenital neutropenia (SCN)), lack of production of mature neutrophil within bone marrow, results in life-threatening bacterial infections in infancy. Treatment with G-CSF.

Answer 12

(cyclical reductions in neutrophil count), rare (~1:1x10^6), such as germline mutation in neutrophil elastase, patients vulnerable to recurrent infections.

Answer 13

lack of neutrophil phagocytotic activity, patients with persistent bacterial and fungal infections.

Answer 14

Regulatory components eg. C1q inhibitor deficiency results in acquired angioedema. Complement proteins: eg. immune complex disease (unable to remove used up immune complexes) which can cause vascular damage; MAC complex loss results in bacterial infection.

Answer 15

Erythematous papules and plaques Prominent on trunk and extremities Perivascular inflammatory infiltrates involving neutrophils, lymphocytes and eosinophils Can result from an exposure to food, drugs, temperature, pressure and pollens Microscopic features include: Superficial dermal oedema Dilated blood vessels with perivascular inflammatory cells Normal epidermis (no spongiosis or hyperplasia)

Answer 16

Self-limited hypersensitivity to infections, drugs like penicillin, malignancy Clinical features: formation of bull’s eyes (hallmark) Rash tends to be symmetrical Types: erythema multiform minor (less severe) and erythema multiform major (severe) Leads to intense itching or burning sensation

Answer 17

Group of diseases: red, itchy (pruritic) skin with tiny blisters (vesicles). Scaly, cracking, bleeding. It could be acute or chronic Failure of the skin barrier: water lost (dry), influx of allergens: hypersensitivity and inflammation (lymphocytic) Different distribution suggests causes Swelling or cracking in the epidermis: spongiosis Persistent scratching of blisters can lead to skin thickening Redness – dilated blood vessels Thickened skin from prolonged rubbing/itching: (hyperkeratosis and acanthosis) Chronic inflammation in the dermis: oedema and fibrosis Long rete ridges

Answer 18

Chronic dermatitis Excessive growth of skin cells Neutrophilic Red raised plaques covered by thick white scale which bleeds on removal Epidermis: Rapid rate of epidermal cell renewal. Thin with parakeratosis Dermis: oedema and numerous dilated capillaries Long rete ridges Pink plaques, itching and intense burning, silvery scales and sometimes arthritis “Oil slick” nail discolouration with nail pitting Histologically: diminished granular layer, elongation of the Rete ridges

Answer 19

Chronic condition Mainly affect mucus membrane and extremities Purple, polygonal, planar, pruritic papules and plaques Abnormal T cell mediated immune reaction against body’s own tissue Skin lesions are small, flat topped and itching (common) Can involve the skin, genitals and oral cavity Patients may experience nail pitting Severe cases can lead to scarring

Answer 20

Bacterial: superficial (epidermal), deep (epidermis, dermis and hypodermis) Viral: Direct: Pox virus (molluscum), Herpes simplex (oral herpes), varicella-zoster (chicken pox and shingles). Human papilloma virus (HPV): warts and verrucae (papillary epidermal growth) Indirect: measles, rubella Fungal: Superficial (athlete’s foot, ringworm), deep (rare) or systemic (immunocompromised: aspergillus) Mycobacteria: TB, Leprosy Protozoa: Leishmania Parasites: scabies, schistosomiasis

Answer 21

Staph/strep Sub corneal bullae +/- neutrophils Burst and spread: yellow crusting Scratching encourages spreading Highly contagious, children

Answer 22

Strep pyogenes/staph Superficial dermis, spreading factor Risk factors: weak immune system, lymph edema, eczema, previous episode Can lead to necrotising fasciitis (mixed bacteria)

Answer 23

over production of sebum. infected follicle blocked with keratin plug. Can be triggered/worsened by hormonal changes

Answer 24

infection in a hair follicle

Answer 25

Premalignant dysplastic lesion in upper epidermis

Answer 26

Premalignant dysplastic lesion in full thickness epidermis

Answer 27

Most common: 75-80% of skin cancer Less common in dark skinned people Linked to total cumulative sun exposure Common on head and neck, chest and back, forearms and hands Diagnosed by biopsy, removed and monitored for recurrence. Curable Nodular - Smooth translucent nodule with telangiectatic vessels under surface / Pigmented with pearly appearance Can also be flat, scaly erythematous plaque with vessels and nodular borders mimicking other dermatological conditions Extends wide and deep, central depression and ulceration

Answer 28

10-20% of skin cancer Linked to total sun exposure and occupational exposure (arsenic/coal) Men x2 prevalence than women Malignancy of upper epidermal layers Intraepidermal (years) or Invasive (breach of BM and metastases to regional LNs) Metastases 0.5-16% Invasion can be from intraepidermal or other pre-malignant lesion e.g actinic keratosis Curable. Diagnose by biopsy, remove and monitor recurrence 5yr survival with metastases: 25% Red, scaly, slightly elevated with irregular border Ulcerates with raised red border and crusts (chronic) (no BVs or rolled border) Common on nose, forehead, ear, lip and hand (exposed areas, lighter skin), unexposed areas (darker skin)

Answer 29

Hyperpigmentation: excess melanin. Causes include melasma, post-inflammatory, sun damage, medications like antibiotics Hypopigmentation: loss of melanin activity. Causes include vitiligo (auto-immune disorder against melanocytes), albinism (genetic condition), tinea versicolor (fungal)

Answer 30

Proliferation of melanocytes in the epidermis and dermis Tan-deep brown, Uniformally pigmented papules with well defined borders

Answer 31

Nests of rounded melanocytes at E:D junction. Flat or slightly raised.

Answer 32

Grow into dermis as nests/cords More elevated. Can have different shapes

Answer 33

Situated primarily within the dermis. Disappearance of nests in epidermis More elevated, pinkish brown growth. Can vary in shape with well defined borders

Answer 34

Atypical groups of melanocytes at epidermal-dermal junction: pleiomorphism, mitoses

Answer 35

Affects people of middle age (>40 years) Round, flat, velvety plaques or patches Growth are waxy and attempt to pick the off can cause bleeding. Number of growth increases with age Could be hereditary Exposure to direct sunlight may influence development of seborrheic keratosis

Answer 36

Originate in the melanocyte Aggressive, rapidly progressive, metastatic Arise from pre-existing or new nevi Uneven surface, irregular borders, slightly raised, black/brown colour Most common on areas exposed intermittently (back, legs) and in indoor workers Superficial spreading (most common) Nodular: aggressive - vertical dermal invasion Lentigo malignant melanoma: more prevalent in older individuals - atypical basal melanocytes Thin malignant melanoma - clumps of atypical melanocytes and microinvasion of dermis

Answer 37

Kaposi sarcoma - endothelial cells of dermal blood vessels. Several places at once

Answer 38

Langerhans cell histiocytosis

Answer 39

Merkel cell carcinoma-neuroendocrine

Answer 40

Yolk sac, then liver, then In adults, haemopoiesis, the production of blood cells, takes place in the red marrow of long bones such as vertebrae, ribs, sternum, proximal ends of femur as well as tibia

Answer 41

Various BM residential cell types such as macrophages, fibroblasts, fat cells interact with stem cells either via growth factor release or direct contact. Extracellular matrix also plays an important role in supporting BM stem cells Major growth factors and cytokines involved in haemopoiesis: Stem cell factor, interleukin-3, Granulocyte Monocyte-colony stimulating factor (GM-CSF), Thrombopoietin, Erythropoietin

Answer 42

Myeloid (aka GEMM) progenitors: Myeloblast – Granulocytic (Neutrophilic, eosinophilic and basophilic) lineage Erythroblast – Erythroid lineage Monoblast – Monocytic lineage Megakaryblast - Megakaryocytic lineage Lymphoid progenitor: B / T lymphocytes Natural Killers

Answer 43

Haemopoietic stem cells and lineage committed progenitors actively proliferate to maintain the pool. Proliferation of early stage immature blood cells continues till cells have nearly completed their maturation pathway

Answer 44

EPO is one of the major erythropoiesis stimulation growth factors. When there are insufficient circulating RBC hypoxia occurs in local tissue microenvironment HIF produced by interstitial fibroblasts in kidneys is sensitive to oxygen and undergoes continuous degradation. In hypoxia, HIF degradation is suppressed. HIF acts as a transcription factor for EPO production EPO stimulates erythropoiesis in BM. Increase in RBCs will restore oxygen tension, HIF degradation resumes. This acts as a negative feedback loop for haemopoiesis

Answer 45

RBC size variation

Answer 46

Macrocytic, megaloblastic anaemia Not only RBCs affected, WBCs also show hypersegmentation

Answer 47

Erythroblast maturation affected Many megaloblasts undergo apoptosis Red blood cell synthesis decreases due to apoptosis of defective megaloblasts Decrease in number of RBC in peripheral blood Red cell derived from surviving megaloblast mature with larger nuclei affecting cell sizes - macrocytosis Often presents with oval macrocytes Non-oval macrocytes found in liver diseases Hyper-segmented neutrophils also found but not exclusively in megaloblastic anaemia

Answer 48

Gradual progression of symptoms Mild jaundice due to increased apoptosis of RBC precursors in bone marrow Pallor, glossitis (Beefy tongue) Peripheral neuropathy (Affecting mainly lower than upper limbs) – Ataxia, paraesthesia, muscle weakness Laboratory findings FBC marked macrocytosis, mild anaemia Blood smear – oval macrocytes, neutrophil hyper-segmentation Bone marrow (if performed in some cases) – megaloblastic changes Diagnostic testing – serum B12 folate levels

Answer 49

Folate absorbed as Methyl TetraHydroFolate (THF) in duodenum and jejunum B12 forms a complex with intrinsic factor (IF) produced by gastric parietal cells IFB12 complex binds to IF receptors in ileum B12 transported by Transcobalamin (TC) out from gut lumen Both MetTHF and B12 carried away by portal vein

Answer 50

Autoantibodies against intrinsic factor (IF) Neutralising IF or compete with B12 for binding sites Autoantibodies against gastric parietal cells Decrease in IF level due to less parietal cells producing IF Both affects B12 absorption leading to megaloblastic anaemia

Answer 51

Genes encoded by loci on Chromosome 11 and 16

Answer 52

4 copies of 'a' gene Lose one - carrier, asymptomatic Lose two - a Thal minor - asymptomatic, mild microcytic Lose three - Hb H Disease/intermediate - symptomatic, haemolytic and microcytic anaemia, splenomegaly Lose 4 - fatal in utero - foetus depends on 2a2y Hb; Foetal development impossible without alpha chain

Answer 53

More than 200 variants / mutations (as opposed to locus deletion in a-thalassaemia) Beta thalassaemia trait (minor) Asymptomatic or mild microcytic hypochromic anaemia Beta thalassaemia intermediate Variable severity, mild to moderate anaemia, possibility of extramedullary haemopoiesis Beta thalassaemia major (Cooley’s anaemia) Severe anaemia, transfusion dependent (leading to iron overload), extramedullary haemopoiesis

Answer 54

Bone marrow compensation – extramedullary erythropoiesis Maxilla, bossed skull with prominent frontal and parietal bones bone marrow expansion into cortical bone ‘hair on end’ X ray

Answer 55

Crescent shaped red blood cells lose flexibility when passing through narrow channels such as the branches of small blood vessels These shapes cause red blood cells to interlock each other occluding the micro-circulation Leading to clinical symptoms: crisis pain hands or feet (particularly in young children) ribs and sternum, spine pelvis tummy legs and arms vision loss Infections Transient ischaemic attack

Answer 56

Red blood cell synthesis defects Bone marrow failure Myelodysplastic syndrome Myelofibrosis (may also see pear-shaped RBCs / poikilocytes when cells squeeze through fibrotic marrow space when released from bone marrow) Chemo- / radio-therapy Chronic blood loss – internal bleeding. Plasma volume restored by anti-diuretic feedback. Continuous loss of normal RBCs

Answer 57

Intrinsic RBC defects Unstable Hb HbC, HbE Hereditary membrane structural defects Hereditary elliptocytosis,spherocytosis Enzymes deficiency Some enzymes responsible for membrane integrity and redox balance e.g. Glucose-6-phosphate dehydrogenase Antibody (Ab) binding to RBC Ab against own antigens (auto-antibodies) Warm or cold reacting autoantibodies e.g. cold agglutinins – autoimmune haemolytic anaemia Ab against RBC membrane modified by drugs

Answer 58

Mechanical / Physical insults March haemoglobinuria - Continuous excessive impacts on soles. Used to be military-associated but now also sports Thermal – burns Artificial heart valves, arterial grafts Coagulation defects thrombosis, Disseminated Intravascular coagulation Infections Malarial parasite (red cell lysis when parasites erupt from RBCs) Toxin from bacteria

Answer 59

Leukaemia is a malignant disease of blood forming organs Malignancies of immature haematopoietic cells that are present in the blood and bone marrow - increased number of circulating leucocytes is usually seen

Answer 60

bone marrow aspirate Immunophenotyping Fluorescent-labelled antibodies identify the proteins expressed by the leukaemic cells Identifies the lineage (myeloid or lymphoid) Demonstrates that the leukemic cells are abnormal and clonal Cytogenetics Missing or extra chromosomes Structural abnormalities Abnormal karyotype (number/appearance of chromosomes) Molecular tests Screen the leukaemic cells for specific abnormalities using PCR

Answer 61

Acute Myeloid Leukaemia (AML) Acute Lymphoblastic Leukaemia (ALL) Characterised by increased immature cells (blasts) in marrow short survival (weeks to months) if untreated A myeloid or lymphoid precursor becomes malignant, resulting in uncontrolled proliferation limited potential for progeny to differentiate resistance to programmed cell death (apoptosis) Leukaemic cells proliferate so much that production of healthy blood cells is compromised resulting in bone marrow failure Anaemia – tiredness, fatigue, pallor Thrombocytopenia – bleeding, bruising Neutropenia - infections

Answer 62

A malignancy of an early myeloid cell 80% acute leukaemias in adults are AML Risk Factors Age, Male Pre-existing haematological disorders (myelodysplasia, myeloproliferative disorders) Occupational exposure to benzene, smoking tobacco Down’s Syndrome Previous chemo/radio Environmental factors e.g. exposure to formaldehyde, herbicides First degree relative with AML Symptoms for weeks to few months only Reduced production of red cells leads to anaemia - Breathlessness, dizzy, fatigued - Pale skin Low platelet count - Bleeding (skin, gums, nose, gut) Reduced production of mature myeloid cells / weakened immune system - susceptible to bacterial or fungal infection, Bone pain especially in arms and legs Splenomegaly, hepatomegaly, weight loss due to decreased appetite Diagnosis may be made from blood count and film Blast cells seen, Auer rods (pathognomy of AML) Definitive diagnosis made through bone marrow aspiration. Cytogenic analysis to examine chromosomes of AML cells Potentially curable if can withstand intensive chemotherapy; Allo-SCT if donor available Relapse is common 15% in some ‘good risk’ patients, >90% in ‘poor risk’ patients

Answer 63

A malignancy of B or T cell lymphoid precursor Commonest malignancy of children (80% acute leukaemias in children are ALL) peak age at diagnosis is 4-5 years old rare in adults Risk Factors: Down’s Syndrome Reduced production of red cells leads to anaemia - Breathlessness, dizzy, fatigued - Pale skin Low platelet count - Bleeding (skin, gums, nose, gut) Reduced production of mature myeloid cells / weakened immune system - susceptible to bacterial or fungal infection, Bone pain especially in arms and legs Splenomegaly, hepatomegaly, weight loss due to decreased appetite Bone pain is very common in children with ALL limping, refusing to walk sclerotic or lytic bony lesions on X Ray Hepatosplenomegaly or lymphadenopathy is common

Answer 64

ALL can also occur in testes, CNS or ovary These are also ‘sanctuary sites’ where relapse may occur conventional chemotherapy is not good at eradicating ALL from these sites

Answer 65

Chronic Myeloid Leukaemia (CML) Chronic Lymphocytic Leukaemia (CLL) Characterised by increased numbers of mature cells in the blood but not usually bone marrow failure potential for prolonged survival (years) even if untreated

Answer 66

malignant proliferation of myeloid cells A mutation is acquired in a haematopoietic stem cell which results in uncontrolled proliferation of the progeny Differentiation still occurs i.e. marked increase in mature myeloid cells in blood and BM Diagnosis Cytogenetics 95% will be ‘Philadelphia positive’ Molecular testing BCR-ABL translocation The Philadelphia chromosome/ BCR-ABL translocation; Fusion of chromosome 9 and 22 leads to formation of the BCR-ABL genes which have a constitutively active tyrosine kinase domain Development of targeted therapies that specifically inhibit the activity of the abnormal protein produced by the BCR-ABL1 fusion gene Primary goal of treatment is to reduce the number of leukemic cells in the blood and bone marrow, achieve complete cytogenetic response (CCyR), and prevent disease progression Tyrosine kinase inhibitors (TKIs) – inhibit the activity of the abnormal protein. Stem cell transplant (also known as bone marrow transplant) Staging: Chronic phase: characterized by the presence of a relatively small number of immature white blood cells (blasts) in the blood and bone marrow. Mild or no symptoms. Prescence of Philadelphia chromosomes is a defining characteristics. Accelerated phase: intermediate phase between chronic and blast phases. characterized by a higher risk of disease progression and a decreased response to TKIs. Stem cell transplant may be considered. Blast phase: most advanced/ most aggressive phase. a large number of immature blast cells are present in the blood and bone marrow. Patient experience severe symptoms. Survival rate is significantly reduced. Treatment options are limited as patients may not respond well to TKIs

Answer 67

Philadelphia chromosome identified in the 1960’s by Peter and David results from reciprocal translocation between chromosome 9 and chromosome 22. In a normal cell, these chromosomes are separate entities. They become fused in chronic myeloid leukaemia. Fusion of chromosome 9 and 22 leads to formation of the BCR-ABL genes which have a constitutively active tyrosine kinase domain

Answer 68

A malignancy of mature B cells Relatively common ( 3000 cases/year in UK ) Increases with age Majority of patients die of unrelated conditions Treatment is only required for troublesome symptoms, bulk disease or marrow failure Reproductive rate of most CLL is less than ordinary blood cells, but defective apoptosis means they don’t die normally 70% are diagnosed as an incidental finding - high lymphocyte count on routine FBC Lymphadenopathy Hepatosplenomegaly Infections shingles recurrent bacterial infections Bone marrow failure if advanced disease

Answer 69

Highly complex process. Four main mechanisms recognised: Stimulation and selection of tumour cells by an antigen Auto-immune disorders, infections e.g. H. Pylori, HCV, Chlamydia Psittaci Infection by an oncogenic virus EBV – Burkitt’s lymphoma, Hodgkin’s disease Immunodeficiency of the host Congenital; AIDS; severe iatrogenic immune suppression Genetics Family history increases the risk of disease

Answer 70

Hodgkin and Non-Hodgkin lymphoma Could be B-cell or T-cell lymphoma Examples of B- cell lymphoma a) diffuse large B cell lymphoma (DLBCL) - most common b) Follicular lymphoma - lymph nodes c) Mantle cell lymphoma (from mantle zone B cells) d) Chronic lymphocytic lymphoma (CLL) involves blood and bone marrow - blood and bone e) Marginal zone lymphoma - associated with chronic inflamm conditions f) Burkitt’s lymphoma (an aggressive form) g)Primary central nervous system lymphoma Examples of T-cell and NK cell lymphoma a) Peripheral T cell lymphoma (can be aggressive and arise from mature T cells) b) Cutaneous T cell lymphoma (involves the skin) c) Anaplastic large cell lymphoma d) Enteropathy associated T cell lymphoma (affect the GIT) e) Nature killer cell lymphoma - URTI and those of Asian descent

Answer 71

First include it in the differential - almost impossible to say any mystery illness is not lymphoma Blood test, blood chemistry History of weight loss, fevers, night sweats (B symptoms) Elevated lactate dehydrogenase in blood tests CT Scan or examination suggests lymphadenopathy or any enlarged organ, Ultrasound scan Positron emission tomography Lymph node biopsy or bone marrow biopsy is vital – no biopsy = no diagnosis Immunohistochemical diagnosis: biopsy of lymph node or extranodal mass B-cell markers (CD19, 20, 22, 79a) T-cell lymphocyte markers (CD2, 3, 5,7) Reed-Sternberg cells (CD15, 30) In CNS involvement, lumbar puncture may be performed

Answer 72

Two peaks in the age-specific incidence: 15-29 60-79 Weight Loss > 10% in 6 months Drenching night sweats (enough to change nightclothes / bed linen) Fevers > 38c Generalised pruritus The bulk of the tumour in HD are ‘normal’ white cells reacting to the presence of tumour cells – Reed Sternberg cells Related to Epstein-Barr virus (EBV) infection - 40%

Answer 73

Originate from B (more common-85%) or T cells Risk factors: age, immunodeficiency, exposure to chemicals, genetics Types: diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma (arises in extra nodal sites), Burkitt's lymphoma (very aggressive), T cell and NK-cell lymphoma (originate from either T cells or NK cells)

Answer 74

Sezary’s cells infiltrate the skin. Symptoms include hair loss, nail pitting. Slow growing, affecting skin and draining lymph nodes – lymphadenopathy Malignant T cells in the dermis of skin giving a red rash that becomes plaques in later stages. Malignant cells can be in blood stream causing abnormal blood count (lymphocytosis) - nuclei resemble Diagnosis: Biopsies, blood test, molecular testing

Answer 75

Slow growing, small cells An example is Follicular lymphoma Most common type of low-grade lymphoma Accounts for 19% of all NHLs Enlarged and painless lymph nodes and patients may experience the B symptoms (fever night sweat and unintentional weight loss) Other examples: Small lymphocytic lymphoma / Chronic lymphocytic leukaemia Same condition SLL if mainly involves lymph nodes CLL if mainly in the blood

Answer 76

Large cells, aggressive growth Aggressive course, require prompt treatment. An example is the diffuse Large B cell Lymphoma –40% of NHL in adults. Can occur in lymph node and extra nodal sites Another example is Burkitt Lymphoma (extremely aggressive).can be endemic or sporadic – 2% of total NHL, but most common NHL in children in UK. Involves jaw, face and abdomen. Another example is the anaplastic large cell lymphoma: associated with genetic abnormalities Another example is the Lymphoblastic lymphoma: common in children and adolescents Rapidly growing lymphadenopathy. Patient may experience B symptoms Extra lymphatic spread – bone marrow, testes, skin, liver, kidneys, paranasal sinuses, CNS Generally good response to chemotherapy - curable disease in >50% of cases

Answer 77

Endemic BL – Equatorial Africa (Uganda, Kenya, Nigeria) and Papua New Guinea Primary affects children and adolescents. Association to malaria incidence EBV ( a member of the herpes virus) DNA detectable in malignant B cells Presents with rapidly growing jaw/facial tumours, abdominal masses, fever, night sweats and weigh loss Histologically – sheets of small round blue lymphoma cells inspersed with macrophages Transcription factor for cell proliferation up- regulated (Oncogene c-MYC)

Answer 78

Can occur anywhere and affects individuals of all ages Less common but it is very aggressive Characterised by rapid growing tumours and abdominal masses Patients experience the B symptoms Same histologically as endemic Burkitt lymphoma EBV less associated (5-10%) Transcription factor for cell proliferation up- regulated (Oncogene c-MYC) Can be cured with high dose chemotherapy in up to 80%

Answer 79

Low grade Lymphoma Localised disease - involved field radiotherapy can be tried and may be curative in a minority of cases; Advanced disease - ‘Watch and wait’ - no survival advantage shown for immediate treatment compared with expectant management in asymptomatic patients Treatment is palliative, and therapies are usually administered intermittently over a period of several years The illness will pursue a remitting - recurring course High grade lymphoma – usually treated with intensive combination chemo-immunotherapy, good chance of cure

Answer 80

Non-Hodgkin lymphoma is divided into four stages based on how far the disease has spread. Stage 1: localised/involvement of a single lymph node Stage 2: involve 2 or more lymph node regions. Stage 3: signifies that lymphoma is present on both sides (above and below) the diaghpram Stage 4: generalised

Answer 81

Autosomal recessive 50% carrier 25% unaffected 25% CF

Answer 82

Cystic fibrosis transmembrane conductance regulator (CFTR) Member of the ABC (ATP binding cassette) superfamily of transporters CFTR is a chloride channel found in membranes of cells that line passageways of the lungs, liver, pancreas, intestines, reproductive tract, and skin.

Answer 83

DF508 (or DF508, F508del) – Deletion of codon 508 for phenylalanine (1st NBD of protein) results in misfolding and the protein being retained in the endoplasmic reticulum G551D – Mis-sense mutation of codon 551 resulting in aspartate rather than glycine (1st NBD) results in normal trafficking of the protein, but the protein has reduced nucleotide binding and ATPase activity G542X – Mutation of codon 542 results in a stop codon in this position. No mature full-length protein is produced 621 + 1G>T – mRNA splicing mutation in intron 4, results in loss of an exon

Answer 84

Protein production mutations (Class 1) Protein processing mutations (Class 2) Improper regulation (Class 3) Improper cl transport (Class 4) Improper synthesis - splicing defect (Class 5) Increased degradation (Class 6) I,II,V,VI - not enough protein III, IV - not enough function

Answer 85

Potentiators increase the flow of Cl– through CFTR (e.g. fix theme II i.e. III, IV) Correctors increase the synthesis, processing and/or delivery of CFTR proteins to the cell surface (e.g. fix theme I i.e. I,II,V,VI)

Answer 86

Females with CF are generally fertile Menstrual cycle may be irregular If good lung function (e.g. over 50%), no liver disease more straightforward Sometimes fertility treatment required Males often infertile Males usually have absent vas deferens Sperm can be aspirated

Answer 87

Children: staph aureus Adults: pseudomonas

Answer 88

Echogenic Bowel

Answer 89

10-15% of CF presents with Meconium Ileus 90% of Meconium Ileus will have CF failure to pass meconium bile stained vomiting abdominal distension - peristalsis echogenic bowel - antenatal US AXR - distended bowel loops mottled inspissated meconium Peritoneal calcification - IU perforation Gastrograffin enema - diagnostic & therapeutic Acetylcysteine Surgery - defunctioning ileostomy

Answer 90

Failure to thrive

Answer 91

Day 5 heel prick - immunoreactive trypsin levels Sweat Test - +ve if Cl >60mmol/L, Na >60mmol/L

Answer 92

Milestone in clinical course of CF 80% adults chronically infected Chronic infection associated with serious disease & reduced survival Initial strains - non-mucoid phenotype Early aggressive treatment may delay chronic infection 3 week treatment nebulised Colomycin & oral Ciprofloxacin Parenteral antibiotics - Aminoglycosides, Ceftazidime, Pipericillin, Meropenem, Aztreonam Indwelling vascular device - “Portacath” Reduce Cross Infection - segregation

Answer 93

Pancreatic Insufficiency -> Malabsorption -> Steatorrhea -> FTT Test for Faecal Elastase Higher energy expenditure Calorie requirement 120-150% of recommended daily allowance; high protein & high fat Pancreatic enzymes - (Creon) enteric coated microspheres Vitamin supplements - Vit A, D & E High calorie nutritional supplements NG feeding Gastrostomy feeding

Answer 94

Distal Intestinal Obstruction Syndrome (Meconium Ileus equivalent) faecal retention abdominal pain Right Iliac fossa mass Insufficient enzymes

Answer 95

Hyperviscus bile -> focal fibrosis -> multilobular cirrhosis

Answer 96

Rare - CFTR expressed in kidney Renal handling of drugs Nephrotoxic drugs Renal stones & Nephrocalcinosis Pseudo- Barters syndrome - metabolic alkalosis associated with Na & K depletion

Answer 97

Previously low electrolytes and/or B1 deficiency Following reintroduction of food -> glucose increases -> increase in anabolic pathways -> decreases micronutrients even more -> organ failure