PathoLecoDeco Flashcards

Question

Microbiology - Zoonoses Salmonella - Reservoir - Transmission

Answer 1

- Poultry - Reptiles / amphibians - Poor hygiene - Contaminated food

Answer 2

Diarrhoea Vomiting Fever Stool culture Diarrhoea Vomiting Fever

Answer 3

Cats Scratches etc Licks of wounds Fleas

Answer 4

Macule at site of innoculation Becomes pustular Regional adenopathy Systemic symptoms Serology Erythromycin, Doxy + Rifampicin IF systemic infection (Bacilliary angiomatosis)

Answer 5

Cats/Sheep Infected meat Faecal contamination

Answer 6

``` Fever Adenopathy Still-birth Progressive visual, hearing, motor, & cognitive issues Seizures Neuropathies ``` Serology Spiramycin Pyrimethamine plus sulfadiazine

Answer 7

Cattle Goats Unpasteurised milk Undercooked meat Mucosal splash Inhalation

Answer 8

``` Fever Back pain Orchitis Focal abscesses (Psoas, liver etc) Symptoms - non-specific. Fever, chills, headache, myalgia, arthralgia, anorexia, fatigue, lymphadenopathy and splenomagaly. ``` Blood/pus culture Serology Doxycycline PLUS Gentamicin OR Rifampicin

Answer 9

Cattle/sheep/goats Aerosolisation/inhalation of secretions, waste, or milk of infected animals Unpasteurised milk

Answer 10

``` Fever ‘Flu-like illness Pneumonia Hepatitis Endocarditis Focal abscesses (Para-vertebral/discitis etc) ``` Serology Doxycycline

Answer 11

Dogs, cats, bats Bites, scratches, fluid

Answer 12

``` Seizures Excessive salivation Agitation Confusion Fever Headache ``` Investigations Serology Brain biopsy (USA saliva PCR) Management Immunoglobulin Vaccine

Answer 13

Clinical presentation Clinical syndrome: 2-10 days after rat bite. Fevers Polyarthralgia Maculopapular progressing to purpuric rash Can progress to endocarditis Investigations Joint fluid microscopy & culture Blood culture Management Penicillins

Answer 14

Mouse/rat Urine/droppings contact Aerosolisation

Answer 15

``` Clinical presentation Fever Myalgia ‘Flulike illness Respiratory failure ``` Bleeding Renal failure Investigations Serology PCR Management Supportive

Answer 16

Caused by a number of viruses – Lassa, Marburg, Ebola, and Congo-Crimean Hemorrhagic Fever Contact with fluid

Answer 17

``` Clinical presentation Fever Myalgia ‘Flulike illness Bleeding ``` Investigations Serology PCR Management Supportive

Answer 18

S.Pneumoniae

Answer 19

``` Streptococcus pneumoniae Haemophilus influenzae Moraxella catarrhalis Staphylococcus aureus Klebsiella pneumoniae ```

Answer 20

E.coli, GBS, Listeria

Answer 21

C.Trachomatis, S Aureus, RSV

Answer 22

Mycoplasma, influenza

Answer 23

S pneumoniae, M pneumoniae

Answer 24

S.pneumoniae | H.Influenza

Answer 25

Splenomegaly, rash, haemolytic anaemia

Answer 26

``` CURB-65 score Confusion Urea >7 mmol/l RR >30 BP <90 systolic <60 diastolic >65 years ``` ``` 2 = ?admit 2-5 = severe ```

Answer 27

Cough, fever, increased sputum production, increased shortness of breath. CXR: normal

Answer 28

H.Influenza

Answer 29

Legionella

Answer 30

Pneumonia caused by an organism without a cell wall - therefore cell-wall ABx will not work

Answer 31

Macrolides Tetracyclines - Inhibit protein synthesis

Answer 32

Legionella Pneumophila

Answer 33

Coxiella Burnetii

Answer 34

Chlamidya Psittaci

Answer 35

``` Empyema / abscess Proximal obstruction (tumour) Resistant organism (incl. Tb) Not receiving / absorbing Abx Immunosuppression Other diagnosis Lung cancer Cryptogenic organising pneumonia ```

Answer 36

Pneumocystis Jirovecii

Answer 37

Aspergillus

Answer 38

Fungal ball often in pre-existing cavity | May cause haemoptysis

Answer 39

Amphotericin B

Answer 40

S. Pneumonia | Legionella Pneumophilia

Answer 41

Chlamydia Legionella - Difficult to culture Collected on presentation + 14 days after.

Answer 42

Amoxicillin | Or Erythromycin / Clarithromycin

Answer 43

Co-Amoxiclav AND clarithromycin IF ALLERGIC Cefuroxime and clarithromycin

Answer 44

Amoxicillin + Clavulanic acid = B lactamase inhibitors

Answer 45

1. Ciprofloxacin +/- Vancomycin | 2. Piptazobactam AND vancomycin

Answer 46

Mycoooooooooobacteeeeeerium

Answer 47

Mycobacterium avium intracellulare (MAI) | AKA M. avium complex (MAC)

Answer 48

M. ulcerans

Answer 49

``` MAI Clarithromycin/azithromycin Rifampicin Ethambutol +/- Amikacin/streptomycin ```

Answer 50

Droplet nuclei/airborne <10µm particles Suspended in air Reach lower airway macrophages Infectious dose 1-10 bacilli

Answer 51

5-10% risk per lifetime >5 years after primary infection

Answer 52

Immunosuppression Chronic alcohol excess Malnutrition Ageing

Answer 53

Non-UK born/recent migrants South Asia 54.8% Sub-Saharan Africa 29.5% HIV Other immunocompromise Homeless Drug users, prison Close contacts Young adults (also higher incidence in elderly)

Answer 54

Fever Weight loss 74% Night sweats 55% Pulmonary symptoms Cough 80% Haemoptysis 6-37% Malaise 68% Anorexia

Answer 55

CXR & other radiology ``` Sputum x3 Induced sputum Bronchoscopy Biopsies EMU ``` Stain for AAFBs (“smear”) Culture NAAT Histology Tuberculin skin test IGRAs

Answer 56

Cannot distinguish between latent and active TB

Answer 57

First line medications Rifampicin (R) Isoniazid (H) Pyrazinamide (Z) Ethambutol (E)

Answer 58

Second line medications ``` Quinolones (Moxifloxacin) Injectables Capreomycin, kanamycin, amikacin Ethionamide/Prothionamide Cycloserine PAS Linezolid Clofazamine ```

Answer 59

Raised transaminases & induces cytochrome P450 | Orange secretions

Answer 60

``` Peripheral neuropathy (pyridoxine 10mg od) Hepatotoxicity ```

Answer 61

Hepatotoxicity

Answer 62

Visual Disturbance

Answer 63

Usually 3/4 for 2months THEN Rifampicin and Isoniazid for 4months CNS TB = 10-12 months

Answer 64

``` Previous TB Rx HIV+ Known contact of MDR TB Failure to respond to conventional Rx >4 months smear +ve/>5 months culture +ve ```

Answer 65

Spanish Flu

Answer 66

2009 200k deaths

Answer 67

True | Requires cleavage of influenza HA protein

Answer 68

Elderly People alive in 1920-1940 had been infected with antigenically similar virus to pH1N1 2009.

Answer 69

High dose, route of exposure Mutant virus (D225G mutation in HA associated with 25% fatal cases in Norway) Bacterial superinfection (Odds ratio of 125 after other factors accounted for in Argentinian study) Co morbidity: Asthma, pregnancy, obesity, diabetes Genetic predisposition: IFITM3 mutation; ethnic bias

Answer 70

Amantadine Targets M2 ion channel Single amino acid mutation in M2 (S31N) renders virus resistant Does not work against influenza B or pH1N1 or seasonal H3N2 Neuraminidase inhibitors and mode of administration: Tamiflu (oseltamivir) oral Relenza (zanamivir) inhaled or iv formulation Peramivir iv Polymerase inhibitors: Favipiravir (licensed in Japan excluding pregnant women) Baloxavir (licensed in Japan)

Answer 71

Trivalent or quadrivalent inactivated vaccine

Answer 72

Live attenuated vaccine, also tri or quadrivalent

Answer 73

Viral replication detected by pattern-recognition receptors (PRRs, Toll-like receptors, RIG-like receptors ) Triggers innate immune responses leading to production of restriction factors such as type 1 interferons (IFNs)

Answer 74

Dorsal Root ganglion

Answer 75

Pneumonitis

Answer 76

Post herpetic neuralgia

Answer 77

Aciclovir (po or iv) Valaciclovir (prodrug of aciclovir, po, high bioavailability) ---------------------------------- Famciclovir 2nd line: Foscarnet or cidofovir for ACV-resistant virus Interfere with viral DNA synthesis

Answer 78

Guanosine analogue Further elongation of the chain is impossible because acyclovir lacks the 3' hydroxyl group necessary for the insertion of an additional nucleotide Affinity for herpesvirus DNA polymerase is 10- to 30- fold higher than for cellular (host) DNA polymerase for ACV-PPP Selective activity means reduced drug toxicity Susceptibility: HSV-1 > HSV-2 >> VZV VZV 10x less sensitive so higher doses required

Answer 79

HSV encephalitis: Start empiric treatment immediately with iv ACV 10mg/kg tds without waiting for test results If confirmed, treat for 21 days HSV meningitis: Treatment recommended if unwell enough to be admitted to hospital, or if immunocompromised Rx example: ACV iv for 2-3 days, then switch to oral for a further 10 days Alternative in the immunocompetent: valaciclovir to avoid cannulation (?)

Answer 80

Chickenpox in adults (risk of complication: pneumonitis) Zoster in adults >50 (risk of complication: post-herpetic neuralgia) 1o infection or reactivation in the immunocompromised Neonatal chickenpox If there is an increased risk of complications

Answer 81

Blood monocytes and dendritic cells Asymptomatic shedding in saliva, urine, semen and cervical secretions

Answer 82

Marrow suppression, retinitis, pneumonitis, hepatitis, colitis, encephalitis…

Answer 83

Ganciclovir (GCV) iv Valganciclovir (VGC) po Foscarnet ( FOS ) iv / intravitreal Cidofovir ( CDV ) iv

Answer 84

Guanosine analogue - Inhibits viral DNA synthesis Indications: CMV disease in immunocompromised (retinitis, pneumonitis), and neonates with congenital CMV Given together with IVIG for CMV pneumonitis in Tx patients

Answer 85

S/E: Less easily tolerated than ACV Bone marrow toxicity (leukopenia, thrombocytopenia, anaemia, pancytopenia) Renal and hepatic toxicity

Answer 86

Non-competitive inhibitor of viral DNA polymerase Does NOT require activation by phosphorylation Activity against CMV, and also occasionally used for HSV (eg if ACV-resistance) Also activity against VZV, EBV and HHV6, but seldom used Indications: CMV disease in patients in whom GCV is contraindicated – ie neutropenic patients (eg pre-engraftment post-BMT); GCV-resistant CMV; CMV retinitis (intravitreal implants).

Answer 87

S/E: Nephrotoxic | Keep well hydrated and monitor electrolytes

Answer 88

Nucleotide (cytidine) analogue Competitive inhibitor of viral DNA synthesis Does NOT require activation by phosphorylation Activity against CMV, and also occasionally used for HSV (eg if ACV-resistance) … …and for other viruses (eg adenovirus, BK virus…) 3RD LINE Rx NEPHROTOXIC

Answer 89

Saliva | - Causes infectious mononucleosis

Answer 90

Associated with EBV infection Breakdown of immunosurveillance Latently infected B cells – polyclonal activation Predispose to lymphoma Diagnosis: EBV viral load in blood (> 105 c/ml), biopsy

Answer 91

``` Reduce immunosuppression (regression in < 50%) Anti-CD20 monoclonal Ab therapy (B cell marker) – rituximab – ```

Answer 92

Ribavirin IVIG Palivizumab

Answer 93

Guanosine analogue Administer po or iv nebulised Inhibits viral RNA synthesis (exact mechanism unclear) – broad activity in vitro: effective for Lassa fever and HEV. Used in combination with other drugs for HCV. Clinical efficacy for RSV is unclear – Lack of good evidence for RSV! Adverse effects include anaemia and possible teratogenicity

Answer 94

Often administered as an adjunct to treatment of viral pneumonitis in the immunocompromised

Answer 95

Prophylaxis: Indication: For the prevention of serious lower respiratory tract disease caused by RSV in infants at high risk: eg born preterm and severe underlying heart or lung disease (such as bronchopulmonary dysplasia), SCID or long term ventilation

Answer 96

``` Paeds transplant recipients Severe multi-organ involvement Rx: Ribavirin Cidofovir iv IVIG Brincidofovir po ```

Answer 97

Use potent drug regimens to achieve maximal suppression of viral replication (combination Rx / HAART) Increase adherence to treatment (low drug burden, once-daily regimens, patient education…)

Answer 98

ACV Mutations usually in viral thymidine kinase (95%), and rarely in the viral DNA polymerase (5%) Nearly always occurs in the context of immunosuppression – TK-deficient strains less virulent

Answer 99

GCV In protein kinase gene (UL97) - most common In the DNA polymerase gene (UL54) - rare Most likely to occur in context of prolonged therapy in immunocompromised

Answer 100

Herd immunity

Answer 101

Inactivated

Answer 102

Attenuated

Answer 103

``` Advantages: Stable Constituents clearly defined Unable to cause the infection Disadvantages Need several doses Local reactions common Adjuvant needed keeps vaccine at injection site activates antigen presenting cells Shorter lasting immunity ```

Answer 104

Advantages Single dose often sufficient to induce long-lasting immunity May stimulate response to multiple protective antigens Strong immune response evoked Local and systemic immunity produced – particularly important for infections where CMI plays an important role. Activation of all components of immune system Disadvantages Potential to revert to virulence Can cause illness directly Contraindicated in immunosuppressed patients Interference by viruses or vaccines and passive antibody Poor stability Potential for contamination

Answer 105

Heterotypic

Answer 106

Live induce more sustained AB responses

Answer 107

Blood cultures for candidaemia, other samples for short term fungal culture. B D Glucan assay (serology) Imaging e.g. for hepatosplenic candidaisis

Answer 108

2 weeks of antifungals from first negative blood cultures. ECHO and fundoscopy Echinicandin empirically and for non-albicans Candida Fluconazole for Candida albicans Ambisome (e.g. CNS), Fluconazole (e.g. urine) or Voriconazole (e.g. CNS) for organ-based disease.

Answer 109

Cryptococcosis

Answer 110

Variation: | Gattii

Answer 111

Cryptococcus!

Answer 112

Detection of Cryptococcal antigen in blood or CSF Often culturable from blood, body fluids

Answer 113

3/52 Amphotericin B +/- flucytosine Repeat LP for pressure management Secondary suppression with fluconazole

Answer 114

Aspergillosis

Answer 115

``` Voriconazole Ambisome Caspofungin/Itraconazole less good At least 6 weeks of therapy Duration based on host/radiological/mycological factors ```

Answer 116

Cellulitis caused by mucor species Occurs in Immunocompromised patients, poorly controlled Diabetes mellitus Cellulitis of the orbit and face progress with discharge of black pus from the palate and nose. Retro-orbital extension produces proptosis, chemosis, ophthalmoplegias and blindness.

Answer 117

Rhizopus spp, Rhizomucor spp, Mucor spp

Answer 118

Cell membrane [ergosterol] DNA synthesis Cell wall

Answer 119

``` Azole antifungals - Ketoconazole - Itraconazole - Fluconazole - Voriconazole - Miconazole, clotrimazole (and other topicals) ``` Polyene antibiotics - Amphotericin B, lipid formulations - Nystatin (topical)

Answer 120

• Pyrimidine analogues | - Flucytosine

Answer 121

• Echinocandins | -Caspofungin acetate (Cancidas)

Answer 122

Azoles bind to lanosterol 14a-demethylase inhibiting the production of ergosterol Some cross-reactivity is seen with mammalian cytochrome p450 enzymes Drug Interactions Impairment of steroidneogenesis (ketoconazole, itraconazole)

Answer 123

inhibition of ß-(1,3) D-glucan synthase | Loss of cell wall glucan results in osmotic fragility

Answer 124

Binds sterols in fungal cell membrane Creates transmembrane channel and electrolyte leakage. Active against most fungi except Aspergillus terreus, Scedosporium spp.

Answer 125

Nephrotoxicity Renovascular and tubular mechanisms Vascular-decrease in renal blood flow leading to drop in GFR, azotemia Tubular-distal tubular ischemia, wasting of potassium, sodium, and magnesium Enhanced in patients who are volume depleted or who are on concomitant nephrotoxic agents

Answer 126

1) Decreased uptake (permease activity) | 2) Altered 5-FC metabolism (cytosine deaminase or UMP pyrophosphorylase activity)

Answer 127

Hep B HIV Rubella Syphilis

Answer 128

May be asymptomatic at birth – 60% but may still go on to suffer long term sequelae Deafness, low IQ, microcephaly ``` 40% symptomatic at birth Choroidoretinitis Microcephaly/hydrocephalus Intracranial calcifications Seizures Hepatosplenomegaly/jaundice ```

Answer 129

Effect on foetus – dependent on time of infection Mechanism – mitotic arrest of cells; angiopathy; growth inhibitor effect Eyes: cataracts; microphthalmia; glaucoma; reintopathy Cardiovascular syndrome; PDA; ASD/VSD Ears; deafness Brain: microcephaly; meningoencephalitis; developmental delay Other: growth retardation; bone disease; hepatosplenomegaly; thrombocytopenia; rash

Answer 130

Infection transmitted during delivery Mother may be asymptomatic Causes neonatal conjunctivitis, or rarely pneumonia Treated with erythromycin

Answer 131

Less maternal IgG NICU care Exposure to microorganisms; colonisation and infection

Answer 132

Group B streptococci E. coli Listeria monocytogenes

Answer 133

Group B streptococci

Answer 134

Bacteraemia Meningitis Disseminated infection e.g. joint infections

Answer 135

In neonates: Bacteraemia Meningitis UTI

Answer 136

``` Maternal: PROM/prem. Labour Fever Foetal distress Meconium staining Previous history ```

Answer 137

``` Baby: Birth asphyxia Resp. distress Low BP Acidosis Hypoglycaemia Neutropenia Rash Hepatosplenomegaly Jaundice ```

Answer 138

``` Full blood count C-reactive protein (CRP) Blood culture Deep ear swab Lumbar puncture (CSF) Surface swabs Chest X-ray (full body) ```

Answer 139

``` As is: Supportive management: Ventilation Circulation Nutrition Antibiotics: e.g. benzylpenicillin & gentamicin ```

Answer 140

Sepsis after 48-72 hours

Answer 141

``` Coagulase negative Staphylococci (CoNS) Group B streptococci E. coli Listeria monocytogenes S. aureus Enterococcus sp. Gram negatives – Klebsiella spp. /Enterobacter spp. /Pseudomonas aeruginosa/Citrobacter koseri Candida species ```

Answer 142

Bradycardia Apnoea Poor feeding/bilious aspirates/ abdominal distension Irritability Convulsions Jaundice Respiratory distress Increased CRP; sudden changes in WCC/platelets Focal inflammation – e.g. Umbilicus; drip sites etc.

Answer 143

``` FBC CRP Blood culture(s) Urine ET secretions if ventilated Swabs from any infected sites ```

Answer 144

NICU-Example of antibiotics for late onset sepsis: 1st line: cefotaxime & vancomycin 2nd line: meropenem Community acquired late onset neonatal infections: cefotaxime, amoxicillin +/-gentamicin

Answer 145

Viral infections are very common e.g. Chickenpox (VZV); Herpes simplex – cold sores/stomatitis; HHV6; HHV8; EBV; CMV; RSV; enteroviruses etc Bacterial infections are important and may cause secondary infection after viral illness e.g. iGAS disease post VZV infection

Answer 146

Meningitis

Answer 147

``` Clinical features Lab tests: Blood cultures Throat swab LP for CSF if possible Rapid antigen screen EDTA blood for PCR Clotted serum for serology if needed later ```

Answer 148

``` N = 5-20 Bacterial = >30 Viral = N / mild increase ```

Answer 149

``` Bacterial = turbid Viral = clear Fungal/TB = fibrin web ```

Answer 150

``` Normal = 0.18-0.45 Bacterial = >1 Viral = <1 Fungal/TB = N ```

Answer 151

``` Normal = 2.5-3.4 Bacterial = <2.2 Viral = N Fungal/TB = 1.6-2.5 ```

Answer 152

``` N = <3 Bacterial = >500 Viral = <1000 Fungal/TB = 100-500 ``` Bacterial - PMNs predominate TB/Fungal - Increase in Monocytes

Answer 153

pneumococcal pneumonia - AKA streptococcus pneumoniae

Answer 154

Account for 1/3 of all childhood illnesses Mostly upper respiratory tract infections Mostly viral Age is important Sputum is often difficult to obtain Often need to give empiric treatment

Answer 155

S. pneumoniae (pneumococcus) is the most important bacterial cause Most UK strains remain sensitive to penicillin or amoxicillin

Answer 156

Mycoplasma pneumoniae tends to affect older children (>4 years) – Macrolides are treatment of choice e.g. Azithromycin

Answer 157

Acquired by droplet transmission person to person. Epidemics occur every 3-4 years. Occurs in school age children and young adults. Incubation period 2-3 weeks

Answer 158

``` Many asymptomatic Classically presents: Fever Headache Myalgia Pharyngitis Dry cough ``` Haemolysis IgM antibodies to the I antigen on erythrocyte Cold agglutinins in 60% patients Neurological (1% cases) Encephalitis most common Aseptic meningitis, peripheral neuropathy, transverse myelitis, cerebellar ataxia Aetiology unknown ?antibodies cross react with galactocerebroside Cardiac Polyarthralgia, myalgia, arthritis Otitis media and bullous myringitis

Answer 159

Whooping cough – Bordetella pertussis especially if unvaccinated TB including MDRTB and XDRTB

Answer 160

E. coli Other coliforms e.g. Proteus species, Klebsiella Enterococcus sp. Coagulase negative Staphylococcus Staph saprophyticus

Answer 161

TERATOGENICITY Decrease in the rate of cell division (structural malformations) Decrease in overall number of cells (small babies) Interference with development of key organs Tissue necrosis due to virus replication Sensorineural hearing loss – commonest sequelae Other neurologic problems psychomotor /mental retardation Meningoencephalitis Microcephaly, intracranial calcifications Ophthalmic problems cataract, glaucoma retinopathy, microphthalmia Intrauterine growth retardation Congenital heart defects such as patent ductus arteriosus and others Hepatosplenomegaly Thrombocytopaenic purpura RISK OF DEAFNESS INCREASED IF INFECTED EARLY IN PREGNANCY

Answer 162

Diagnosis of acute infection Rubella IgG Seroconversion Avidity Rubella IgM Detection of virus Molecular diagnosis (PCR) Respiratory secretions, blood, urine, tissues Immune Status Screen Rubella IgG

Answer 163

The incidence of congenital CMV ranges between 0.2 to 2% of live births Vertical transmission In utero (transplacental) During delivery Breast feeding

Answer 164

Defined as the detection of CMV from body fluids or tissues within 3 weeks of birth Commonest congenital viral infection Leading nongenetic cause of neurosensory hearing loss Transmission to the foetus may occur following primary or recurrent maternal CMV infection May be transmitted to the foetus during all stages of pregnancy

Answer 165

CNS abnormalities - microcephaly, mental retardation, spasticity, epilepsy, periventricular calcification Eye - choroidoretinitis and optic atrophy Ear - sensorineural deafness Liver - hepatosplenomegaly and jaundice which is due to hepatitis. Lung - pneumonitis Heart - myocarditis Thrombocytopenic purpura, Haemolytic anaemia Late sequelae in individuals asymptomatic at birth - hearing defects and reduced intelligence.

Answer 166

Virus Detection (blood, urine, respiratory secretions) Cell culture Detection of Early Antigen Fluorescent Foci DEAFF – accelerated cell culture system CMV DNA (Polymerase Chain Reaction) Serology CMV IgG seroconversion CMV IgG avidity CMV IgM

Answer 167

``` PRE-NATAL Detection of CMV DNA in amniotic fluid at 21 weeks gestation POST-NATAL CMV detection within 3 weeks of life Positive result beyond that time will NOT make a diagnosis of congenital infection Urine/Salivary swab/blood Serology CMV IgM (low sensitivity) ```

Answer 168

cCMV with significant organ disease: - valganciclovir or ganciclovir for 6/12 - audiology f/u until 6 years of age - ophthalmology review

Answer 169

Type of maternal infection Maternal antibody status (neutralizing Ab) Duration of rupture of membranes Integrity of mucocutaneous barriers (e.g., use of foetal scalp electrodes) Mode of delivery (cesarean section versus vaginal)

Answer 170

Neonatal Disease SEM disease: localized to the skin, eyes, and/or mouth 45% of cases CNS disease with or without SEM 30% of cases Disseminated Infection involving multiple organs (CNS, lungs, liver, adrenal glands, skin, eyes,mouth) 25% of cases High mortality Neurologic involvement microcephaly,encephalomalacia, hydranencephaly, and/or intracranial calcification Cutaneous manifestations scarring, active lesions, hypo- and hyperpigmentation Ophthalmologic findings microopthalmia, retinal dysplasia, optic atrophy, and/or chorioretinitis),

Answer 171

Poor prognosis even with antiviral treatment mortality around 30% long-term neurological sequelae in 17% Encephalitis in 60-70% of cases Severe coagulopathy, liver dysfunction, pneumonitis > 20% will NOT have skin lesions

Answer 172

HSV cultures/PCR of skin vesicles (if present), oropharynx, conjunctivae,urine, blood and cerebrospinal fluid Liver transaminase levels (suggest disseminated HSV infection) §

Answer 173

High dose acyclovir at 60 mg/kg/day IV in three divided daily doses ``` Duration of therapy 21 days (minimum) in disseminated or CNS disease Repeat LP and CSF PCR testing Continue with ACV until PCR negative 14 days (minimum) in SEM disease ``` Monitor Neutrophil count

Answer 174

Neutrophils

Answer 175

Resp droplets and direct contact | Highly contagious

Answer 176

pneumonia/encephalitis

Answer 177

Congenital varicella syndrome Neonatal varicella Herpes Zoster during infancy or early childhood

Answer 178

``` Low birth weight Cutaneous scarring Limb hypoplasia Microcephaly Cortical atrophy Chorioretinitis Cataracts ```

Answer 179

Maternal infection during 13-20 weeks' gestation Highest risk (2%)

Answer 180

Mild course of infection Disseminated skin lesions Visceral infection Pneumonia

Answer 181

Live virus vaccine available (give preconception) Avoidance of exposure in pregnancy if susceptible

Answer 182

Varicella-zoster immune globulin (given with 10 days of exposure) Antiviral chemotherapy if exposed (aciclovir from day 7 to 14 post exposure)

Answer 183

Transmission: respiratory, conjuctiva Incubation: 7-18 days (typically 10 days)

Answer 184

prodrome 2-4 days- fever, malaise, congestion, conjuctivitis, koplik’s spots Rash classically starts behind ears & on forehead then spreads

Answer 185

``` Opportunistic bacterial infections Otitis media Pneumonia, bronchitis Encephalitis SSPE ```

Answer 186

``` Rare in pregnant women in UK but causes Foetal loss (miscarriage, IUD) Preterm delivery Increased maternal morbidity No congenital abnormalities to foetus ```

Answer 187

Transmission is by respiratory droplets and by blood | Incubation period is 4 to 20 days

Answer 188

Erythema infectiosum (fifth disease) Transient aplastic crisis Arthralgia Non-immune hydrops foetalis

Answer 189

Unique tropism for rapidly dividing erythrocyte precursors Virus requires the P blood antigen receptor (globoside) to enter the cell Suppression of erythrogenesis No reticulocytes are available to replace aging or damaged erythrocytes as they are cleared by the reticuloendothelial system

Answer 190

Virus crosses the placenta and destroys red cell precursors Foetal anaemia --> high output congestive heart failure --> hydrops fetalis Virus also directly infects and injures myocardial cells

Answer 191

Parvovirus DNA amplification from blood, respiratory samples Serology Parvovirus IgG seroconversion Parvovirus IgM

Answer 192

Foetal blood and amniotic fluid for serology and PCR

Answer 193

Intrauterine transfusion Some cases resolve spontaneously If infant survives the hydropic state, long-term prognosis is usually favorable

Answer 194

``` Red eyes Headache Fever Joint pain Muscle pain Rash 80% ASYMPTOMATIC ```

Answer 195

``` Miscarriage/stillbirth/microcephaly Congenital Zika syndrome is described by 5 features: Severe microcephaly + skull deformity Decreased brain tissue, seizures Retinopathy, deafness Talipes Hypertonia ```

Answer 196

Associated predominantly with travel to Caribbean/Central/South America Top destinations: Antigua, Barbados, Grenada, Jamaica, St Lucia & Trinidad & Tobago

Answer 197

Peptidoglycan layer of cell wall (1) Inhibition of bacterial protein synthesis (2) DNA gyrase and other prokaryote-specific enzymes (3)

Answer 198

(a) B-lactam antibiotics (penicillins, cephalosporins and carbapenems) (b) Glycopeptides (Vancomycin and Teicoplanin)

Answer 199

Inactivate the enzymes that are involved in the terminal stages of cell wall synthesis (transpeptidases also known as penicillin binding proteins) – β-lactam is a structural analogue of the enzyme substrate Bactericidal Active against rapidly-dividing bacteria Ineffective against bacteria that lack peptidoglycan cell walls (e.g. Mycoplasma or Chlamydia)

Answer 200

Ineffective against bacteria that lack peptidoglycan cell walls (e.g. Mycoplasma or Chlamydia)

Answer 201

β-lactamase inhibitors. Protect penicillins from enzymatic breakdown and increase coverage to include S. aureus, Gram negatives and anaerobes

Answer 202

1st = weakest Cephalexin 2nd = cefuroxime 3rd = cefotaxime, ceftriaxone, ceftazidime

Answer 203

Stable to Extended Spectrum β-lactamase (ESBL) enzymes BUT Carbapenemase enzymes becoming more widespread. Multi drug resistant Acinetobacter and Klebsiella species.

Answer 204

Really | dec dose if renal impairment

Answer 205

Large molecules, unable to penetrate Gram –ve outer cell wall Active against Gram +ve organisms

Answer 206

Inhibit cell wall synthesis Important for treating serious MRSA infections (iv only) Oral vancomycin can be used to treat serious C. difficile infection Vancomycin and Teicoplanin are examples of glycopeptides Slowly bactericidal

Answer 207

GFR - nephrotoxic

Answer 208

Aminoglycosides (e.g. gentamicin, amikacin,tobramycin) Tetracyclines Macrolides (e.g. erythromycin) / Lincosamides (clindamycin) / Streptogramins (Synercid) – The MSL group Chloramphenicol Oxazolidinones (e.g. Linezolid)

Answer 209

Bind to 30s subunit of ribosome Rapid, concentration-dependent bactericidal action Require specific transport mechanisms to enter cells (accounts for some intrinsic R)

Answer 210

Ototoxic and nephrotoxic therefore monitor GFR / auditory

Answer 211

Bind to 30s subunit Broad-spectrum agents with activity against intracellular pathogens (e.g. chlamydiae, rickettsiae & mycoplasmas) as well as most conventional bacteria

Answer 212

Do not give to children or pregnant women Light-sensitive rash

Answer 213

Bind to the 50s subunit of the ribosome

Answer 214

Binds to the peptidyl transferase of the 50S ribosomal subunit and inhibits the formation of peptide bonds during translation

Answer 215

Binds to the 23S component of the 50S subunit to prevent the formation of a functional 70S initiation complex (required for the translation process to occur).

Answer 216

Quinolones e.g. Ciprofloxacin, Levofloxacin, Moxifloxacin Nitroimidazoles e.g. Metronidazole & Tinidazole

Answer 217

Act on -subunit of DNA gyrase predominantly, but, together with other antibacterial actions, are essentially bactericidal Use for UTIs, pneumonia, atypical pneumonia & bacterial gastroenteritis

Answer 218

Rapidly bactericidal Active against anaerobic bacteria and protozoa (e.g. Giardia) Nitrofurans are related compounds: nitrofurantoin is useful for treating simple UTIs

Answer 219

Rifamycins, e.g. rifampicin & rifabutin Inhibits protein synthesis by binding to DNA-dependent RNA polymerase thereby inhibiting initiation Monitor LFTs

Answer 220

Resistance develops rapidly Resistance is due to chromosomal mutation. This causes a single amino acid change in the ß subunit of RNA polymerase which then fails to bind Rifampicin.

Answer 221

Act indirectly on DNA through interference with folic acid metabolism Synergistic action between the two drug classes because they act on sequential stages in the same pathway Sulphonamide resistance is common, but the combination of sulphamethoxazole+trimethoprim (Co-trimoxazole) is a valuable antimicrobial in certain situations (e.g. Treating Pneumocystis. jiroveci pneumonia) Trimethoprim is used for Rx community-acquired UTIs

Answer 222

Chemical modification or inactivation of the antibiotic Modification or replacement of target Reduced antibiotic accumulation 1) Impaired uptake 2)Enhanced efflux Bypass antibiotic sensitive step

Answer 223

Dengue, Chikungunya, rickettsial, enteric fever (rose spots), acute HIV, measles

Answer 224

Enteric fever, amoebic liver abscess

Answer 225

Dengue, malaria, rickettsial, enteric, Chikungunya

Answer 226

Viral haemorrhagic fevers (dengue and others), meningococcaemia, letposiprosis, rickettsial

Answer 227

Acute schistosomiasis, drug hypersensitivity, fascioliasis, other parasitic

Answer 228

Bacterial/ viral pathogens, legionellosis, acute schistosomiasis, Q fever

Answer 229

Cerebral malaria, viral or bacterial meningoencephalitis, African trypanosomiasis

Answer 230

EBV, CMV, Toxoplasma, acute HIV

Answer 231

Malaria, enteric fever, EBV, CMV, toxoplasmosis, acute HIV, acute schistosomiasis, brucellosis, TB, Q fever, visceral leishmaniasis (rare)

Answer 232

vivax malaria, acute hepatitis (B,C,E), TB, amoebic liver abscess

Answer 233

``` P. falciparum Invades erythrocytes of all ages, may be drug resistant and can be life threatening P. vivax and P. ovale P. malariae P. knowlesi ```

Answer 234

Severe Malaria

Answer 235

Thick and thin blood smears x3 Field’s or Giemsa stain Thick: screen parasites (sensitive) Thin: identify species & quantify parasitaemia Malaria antigen detection tests Paracheck-Pf® (detect plasmodial HRP-II) OptiMAL-IT (parasite LDH)

Answer 236

Chloroquine – 3 days Primaquine 30mg for 14 days weeks if G6PD normal Hypnozoites Complications in non-falciparum malaria are extremely rare but splenic rupture is well recorded

Answer 237

Not vomiting, Parasitaemia <2%, Ambulant Oral Malarone ™ (atovaquone and proguanil) 4 tablets daily with food for three days ACT – artemisinin combination therapies E.g Riamet/ Co-artem – Artemisinin & Lumefantrine Oral quinine 600mg tds (salt) then doxycycline 100mg od for 1 week

Answer 238

ABC Correct Hypoglycamia Cautious rehydration (avoid overload) Organ support as necessary IV Artesunate in preference to IV Quinine Quinine side effects: cinchonism, arrhythmias, hyperinsulinaemia Daily parasitaemia then PO follow on eg with ACT

Answer 239

Dengue (Fever +)

Answer 240

Investigations: Serology (IgM 5-7 days), PCR. Dengue cross reaction with other flavivirus IgG (JE, yellow fever.)

Answer 241

Identify those at risk of shock. (High Hct, low platelets) Supportive Defevervescence around day 4 – 5 Complications may also develop at this time

Answer 242

Typhoid fever Salmonella Typhi

Answer 243

Complications: | GI bleeding/ perforation/ encephalopathy

Answer 244

``` Empiric Ceftriaxone (2g IV OD) then Azithromycin 500mg BD 7 days ```

Answer 245

Blood cultures have the highest yield within a week of symptoms onset Stool and urine cultures become positive after the first week. Bone marrow cultures have a higher sensitivity than blood culture

Answer 246

Mononucleosis (Fever +)

Answer 247

Rickettsial Disease (Fever +)

Answer 248

doxycycline

Answer 249

Protozoa – Giardia lamblia (malabsorption, Entamoeba histolytica (dysentery/liver cyst) Helminths rarely cause travellers’ diarrhoea

Answer 250

Bacterial/viral

Answer 251

i.v. to p.o. switch is recommended in hospital for most infections if the patient has stabilised after 48 hours i.v. therapy

Answer 252

In general, the length of therapy will be guided by the clinical response of the patient and the improvement in the inflammatory markers.

Answer 253

Flucloxacillin (unless penicillin allergy or MRSA)

Answer 254

Benzyl penicillin x 10 days

Answer 255

Amoxicillin | Co-amoxiclav & clarithromycin

Answer 256

cephalosporin; ciprofloxacin; piperacillin/tazobactam | If MRSA colonised/risk, consider addition of Vancomycin

Answer 257

N. Meningitidis S. pneumoniae +/- Listeria in the very young/elderly/immuno-compromised

Answer 258

Ceftriaxone (+/- amoxycillin if Listeria likely) Baby less than 3 months: Cefotaxime PLUS Amoxicillin (to cover for listeriosis) Note: Ceftriaxone not used in neonates as displaces bilirubin from albumin and because it can cause biliary sludging Neisseria meningitidis: Benzylpenicillin (high dose) or Ceftriaxone/Cefotaxime

Answer 259

Trimethoprim x 3 days

Answer 260

cephalexin or Augmentin Infected urinary catheter: change under gentamicin cover

Answer 261

STOP the offending antibiotic (usually a cephalosporin); If severe, Rx with p.o. metronidazole; If above fails, use p.o. vancomycin

Answer 262

Does the patient really have a bacterial infection? (Have I collected the relevant cultures?) Is there a persistent focus present (e.g. an infected vascular or urinary catheter)? Is there a deep-seated collection (e.g. intra-abdominal) that requires drainage? Could the patient have bacterial endocarditis? Am I using the correct dose of the antimicrobial? Is another infection present (esp consider Candida)?

Answer 263

Intestine Bone ICF Kidney

Answer 264

IC signalling Action potentials Bone

Answer 265

Free-ionised (biologically active) 50% Protein bound (albumin) 40% Complexed (citrate/phosphate bound) 10%

Answer 266

2.2-2.6mmol/L

Answer 267

Serum calcium + 0.02 *(40-serum albumin)

Answer 268

Because some may have a low albumin, therefore a low bound calcium and normal free calcium: corrected calcium corrects for this and tells you that the problem is albumin

Answer 269

Hypocalcaemia detected by PT gland Increased PTH release from PT gland Increases intestinal calcium absorption Increases resorption of calcium from bone Increased reabsorption from kidney Activation of renal 1a-hydroxylase -> increases via D synthesis

Answer 270

Bone Gut (absorption) Kidney (resorption and renal 1 alpha hydroxylase activation)

Answer 271

Bone & renal Ca2+ resorption Stimulates 1,25 (OH)2 vit D synthesis (1α hydroxylation) Also stimulates renal Pi wasting

Answer 272

1a hydroxylase in kidney

Answer 273

1a hydroxylase

Answer 274

Intestinal Ca2+ absorption Also intestinal Pi absorption Critical for bone formation (see later) ? Other physiological effects Vit D receptor controls many genes eg for cell proliferation, immune system etc Vit D deficiency associated with cancer, autoimmune disease, metabolic syndrome

Answer 275

Defective bone mineralisation due to inadequate Vit D

Answer 276

Lack of sunlight exposure Dark skin Dietary malabsorption

Answer 277

50% UK adults

Answer 278

Bone / muscle pain Loosers zones = pseudofractures Rickets: bowed legs, costochondral swelling, widened epiphysis at wrist, myopathy

Answer 279

Low Ca2+, Low phosphate, increased ALP

Answer 280

``` Caused by vitamin D deficiency Renal failure Anticonvulsants induce breakdown of vitamin D Lack of sunlight Chappatis (phytic acid) ```

Answer 281

Reduction in bone density with normal mineralisation | NORMAL BIOCHEMISTRY

Answer 282

NOF Colles - wrist vertebral

Answer 283

osteoporosis

Answer 284

osteopenia

Answer 285

sd from mean of young healthy population (useful to determine  risk)

Answer 286

sd from mean of aged-matched control (useful to identify accelerated bone loss in younger patients)

Answer 287

(useful to identify accelerated bone loss in younger patients)

Answer 288

Lifestyle: sedentary, EtOH, smoking, low BMI/nutritional Endocrine: hyperprolactinaemia, thyrotoxicosis, Cushings Drugs: steroids Others eg genetic, prolonged intercurrent illness Early menopause/childhood illness

Answer 289

Lifestyle Weight-bearing exercise Stop smoking Reduce EtOH ``` Drugs Vitamin D/Ca Bisphosphonates (eg alendronate) –↓ bone resorption Teriparatide (PTH derivative) – anabolic Strontium – anabolic + anti-resorptive (Oestrogens – HRT) SERMs eg raloxifene ```

Answer 290

PTH analogue: | Increased Ca reabsorption + resorption

Answer 291

Dec bone resorption

Answer 292

Polyuria / polydipsia Constipation Neuro – confusion / seizures / coma Unlikely unless Ca2+ > 3.0 mmol/L

Answer 293

SUPPRESSION of PTH

Answer 294

Appropriate PTH response: - Malignancy - common - Rarer: sarcoid, vitamin D excess, thyrotoxicosis, milk alkali syndrome

Answer 295

Primary Hyperparathyroidism | Familial hypocalcuric hypercalcaemia

Answer 296

Parathyroid adenoma / hyperplasia / carcinoma Hyperplasia associated with MEN1 Women > men

Answer 297

↑serum Ca, ↑ or inappropriately N PTH, ↓serum Pi, urine ↑Ca (due to hypercalcaemia)

Answer 298

CaSR mutation Higher “set point” for PTH release -> mild hypercalcaemia Reduced urine Ca2+ CaSR = calcium sensing receptor

Answer 299

Humoral hypercalcaemia of malignancy (eg small cell lung Ca) - PTHrP ``` Bone metastases (eg breast Ca) - Local bone osteolysis ``` ``` Haematological malignancy (eg myeloma) - cytokines ```

Answer 300

Sarcoidosis (non-renal 1α hydroxylation) Thyrotoxicosis (thyroxine -> bone resorption) Hypoadrenalism (renal Ca2+ transport) Thiazide diuretics (renal Ca2+ transport) Excess vitamin D (eg sunbeds…)

Answer 301

Acute management Fluids+++ Fluids+++ Bisphosphonates (if cause known to be cancer) otherwise avoid. Treat underlying cause

Answer 302

``` Neuro-muscular excitability: Increased reflexes Laryngeal spasm Prolonged QT Convulsions Chorioid disk Chvosteks facial nerve tap Trousseaus BP sign ```

Answer 303

Rx: Ca + vit D (usually “activated” ie 1α forms, except simple vit D deficiency)

Answer 304

``` vitamin D deficiency – dietary, malabsorption, lack of sunlight chronic kidney disease (1α hydroxylation)** PTH resistance (“pseudohypoparathyroidism”) ```

Answer 305

Surgical (inc post thyroidectomy) Auto-immune hypoparathyroidism Congenital absence of parathyroids (eg DiGeorge syndrome) Mg deficiency (PTH regulation)

Answer 306

Focal disorder of bone remodeling

Answer 307

Focal PAIN, warmth, deformity, fracture, SC compression, malignancy, cardiac failure Pelvis, femur, skull and tibia Kyphosis Deafness

Answer 308

Treatment = Bisphosphonates for pain

Answer 309

Elevated alkaline phosphatase | Nuclear med scan / XR

Answer 310

Violent Unnatural or sudden Cause of death is unknown

Answer 311

Serum sodium < 135 mmol/L Commonest electrolyte abnormality in hospitalized patients.

Answer 312

Increased EC water

Answer 313

V2 receptors | V1 receptors

Answer 314

V1 receptors vascular smooth muscle vasoconstriction (higher concentrations) alternative name ‘vasopressin’

Answer 315

Insertion of aquaporin-2

Answer 316

Serum osmolality (mediated by hypothalamic osmoreceptors). Blood volume/pressure (mediated by baroreceptors in carotids, atria, aorta)

Answer 317

Clinical assessment of volume status: | EU/Hypo/Hyper

Answer 318

``` Tachycardia Postural hypotension Dry mucous membranes Reduced skin turgor Confusion/drowsiness Reduced urine output Low urine Na+ (<20) ```

Answer 319

Raised JVP Bibasal crackles (on chest examination) Peripheral oedema

Answer 320

Diarrhoea Vomiting Diuretics Salt losing nephropathy

Answer 321

Hypothyroidism Adrenal insufficiency SIADH

Answer 322

Cardiac failure Cirrhosis Nephrotic syndrome

Answer 323

CNS pathology Lung pathology Drugs (SSRI, TCA, opiates, PPIs, carbamazepine) Tumours Surgery

Answer 324

? Hypothyroidism: Thyroid function tests ? Adrenal insufficiency: Short Synacthen test ? SIADH: Plasma & urine osmolality (low plasma & high urine osmolality)

Answer 325

``` Euvolaemia High urine osmolarity > 100 Low plasma osmolarity No Hypovolaemia No Hypothyroidism No Adrenal insufficiency ```

Answer 326

Volume replacement - 0.9% saline

Answer 327

Fluid restriction | Treat the underlying cause

Answer 328

Fluid restriction | Treat the underlying cause

Answer 329

Reduced GCS Seizures Seek expert help (Treat with Hypertonic 3% saline)

Answer 330

Serum Na must NOT be corrected > 8-10 mmol/L in the first 24 hours Risk of osmotic demyelination (central pontine myelionlysis) quadriplegia, dysarthria, dysphgia, seizures, coma, death

Answer 331

Demeclocycline Reduces responsiveness of collecting tubule cells to ADH Monitor U&Es (risk of nephrotoxicity) Tolvaptan V2 receptor antagonist

Answer 332

Serum [Na+] > 145 mmol/L

Answer 333

Unreplaced water loss Gastrointestinal losses, sweat losses Renal losses: osmotic diuresis, reduced ADH release/action (Diabetes insipidus) Patient cannot control water intake e.g. children, elderly

Answer 334

``` Serum glucose (exclude diabetes mellitus) Serum potassium (exclude hypokalaemia) Serum calcium (exclude hypercalcaemia) Plasma & urine osmolality Water deprivation test ```

Answer 335

Fluid replacement Treat the underlying cause Correct water deficit 5% dextrose Correct extracellular fluid volume depletion 0.9% saline Serial Na+ measurements Every 4-6 hours

Answer 336

Variable Hyperglycaemia draws water out of the cells leading to hyponatraemia Osmotic diuresis in uncontrolled diabetes leads to loss of water and hypernatraemia

Answer 337

3.5-5.3 mmol/L

Answer 338

Angiotensin II | Aldosterone

Answer 339

By ACE in the lung

Answer 340

Aldosterone increases number of open Na+ channels in the luminal membrane Increases sodium reabsorption makes the lumen electronegative & creates an electrical gradient Potassium is secreted into the lumen

Answer 341

Angiotensin II | Potassium

Answer 342

Type 4 renal tubular acidosis (diabetic nephropathy) | NSAIDs

Answer 343

``` Rhabdomyolysis Acidosis (H+ enters cells -> release from K+) ```

Answer 344

Renal impairment: reduced renal excretion Drugs: ACE inhibitors, ARBs, spironolactone Low Aldosterone Addison’s disease Type 4 renal tubular acidosis (low renin, low aldosterone) Release from cells: rhabdomyloysis, acidosis

Answer 345

Tented (peaked) T waves

Answer 346

10 ml 10% calcium gluconate 50 ml 50% dextrose + 10 units of insulin Nebulized salbutamol Treat the underlying cause

Answer 347

GI loss Renal loss Hyperaldosteronism, (Excess cortisol) Increased sodium delivery to distal nephron Osmotic diuresis Redistribution into the cells Insulin, beta-agonists, alkalosis Rare causes: Renal tubular acidosis type 1& 2, hypomagnesaemia

Answer 348

Loss of K+ Block Na/K/Cl transporter Increased delivery of Na to distal nephron where Na+ exchanged for K+

Answer 349

Loss of K+ Block Na/Cl transporter Increased delivery of Na to distal nephron where Na+ exchanged for K+

Answer 350

No/defective function of Na/K/Cl transporter

Answer 351

No/defective function of Na/Cl transporter

Answer 352

Muscle Weakness Cardiac arrhythmia Polyuria & polydipsia (nephrogenic DI)

Answer 353

Aldosterone: Renin ratio | >20:1

Answer 354

Serum potassium 3.0-3.5 mmol/L Oral potassium chloride (two SandoK tablets tds for 48 hrs) Recheck serum potassium Serum potassium < 3.0 mmol/L IV potassium chloride Maximum rate 10 mmol per hour Rates > 20 mmol per hour are highly irritating to peripheral veins Treat the underlying cause e.g. spironolactone

Answer 355

Serum potassium < 3.0 mmol/L IV potassium chloride Maximum rate 10 mmol per hour Rates > 20 mmol per hour are highly irritating to peripheral veins

Answer 356

CNS pathology Lung pathology Drugs (SSRI, TCA, opiates, PPIs, carbamazepine) Tumours Surgery

Answer 357

Low pH = acidosis Low CO2 = low bicarbonate Metabolic acidosis

Answer 358

Because brain enzymes cannot function at a very acid pH

Answer 359

Anion gap = Na + K – Cl – bicarb | Normal AG =140+4.0 – 102 – 24 = 18 mM

Answer 360

145 + 5.0 – 96 - 4 = (high) Suggests extra anions (Ketones)

Answer 361

Respiratory alkalosis

Answer 362

What is the anion gap? (normal) What is the diagnosis ? Anxiety caused by hypoglycaemia.

Answer 363

Why is he unconscious : because the brain is VERY dehydrated.

Answer 364

Osmolality = 2(Na+k) + U + G = 296 Anion = 50 Met acidosis Metformin in overdose can cause a lactic acidosis Brain enzymes cannot function at a low pH Lactate = 10 mM (N<2.0) Causes of metabolic acidosis: ``` Methanol Uremia DKA Paracetamol Isoniazid Lactic acidosis Ethanol / ethylene glycol Salicylates ```

Answer 365

``` Methanol Uremia DKA Paracetamol Isoniazid Lactic acidosis Ethanol / ethylene glycol Salicylates ```

Answer 366

Fasting glucose > 7.0 mM Glucose tolerance test (75 grams glucose given at time 0) Plasma glucose > 11.1 mM at 2 hours (2h value 7.8 – 11.1 = impaired glucose tolerance).

Answer 367

Aldosterone

Answer 368

FT4 < 5nM TSH > 50mU/l Suggests thyroid failure. Hypothyroidism can cause profound tiredness. Hypothyroidism does NOT explain the unusual electrolytes: Na: 125, K: 6.5, U 10, Glucose 2.9mM. Hyponatraemia, hyperkalaemia Deficiency of mineralocorticoid. Hypoglycaemia Deficiency of glucocorticoid. Primary hypothyroidism + ADDISONS = SCHMIDTs syndrome

Answer 369

Short SYNACTHEN test. Measure cortisol + ACTH at start of test Administer 250 micrograms synthetic ACTH by IM injection. Check cortisol at 30 and 60 minutes. Results in this patient: ACTH > 100 ng/dl Cortisol < 10 nM Check cortisol at 30 and 60 minutes. Both times, cortisol < 10 nM

Answer 370

Phaeochromocytoma (Adrenal medullary tumour secreting adrenaline). Conn’s syndrome (adrenal tumour secreting aldosterone) Cushing’s syndrome (secretes cortisol) - may just have essential HTN

Answer 371

Adrenal medullary tumour that secretes adrenaline, and can cause severe hypertension, arrhythmias and death. THUS A MEDICAL EMERGENCY Urgent alpha blockade with phenoxybenzamine. Add beta blockade. Finally arrange surgery.

Answer 372

Primary hyperaldosteronism AKA Conn’s syndrome.

Answer 373

The adrenal gland secretes high levels of aldosterone autonomously. This will cause hypertension and this will in turn suppress the renin at the JGA.

Answer 374

9am cortisol 12 midnight cortisol Dexamethasone suppression. This will usually suppress cortisol levels to undetectable levels. Not so in Cushing’s.

Answer 375

Being on oral steroids for something else ``` Pituitary dependent Cushings disease (85%) Ectopic ACTH (5%) Adrenal adenoma (10%) ```

Answer 376

Cushing's syndrome Pituitary dependent = suppresses. Ectopic does not. Next steps: High dose dex test

Answer 377

Pituitary dependent

Answer 378

Oral carbohydrates Rapid acting - juice Longer acting - sandwich Consider IM 1mg glucagon (takes 15-20 mins to act)

Answer 379

Buccal glucose eg glucogel Consider establishing IV access Consider IM 1mg glucagon

Answer 380

IV access 50ml 50% glucose mini-jet or 100mls 20% glucose IM glucagon

Answer 381

Low glucose - <2.5-4.0mmol/L Symptoms: adrenergic: tremors/palpitations/sweating/hunger Neuroglycopaenic: confusions, somnolence, incoordination, seizures, coma Relief of symptoms with glucose

Answer 382

Dec insulin Inc Glucagon ``` CAUSES: Reduce peripheral uptake of glucose Increase glycogenolysis Increase gluconeogenesis Increase lipolysis -- Increases beta-oxidation + ketone body production ``` Low glucose sensed in hypothalamus: sympathetic activation: increased ACTH, cortisol + GH production

Answer 383

Diabetes related ``` W/O diabetes: Fasting or reactive? Paediatric vs. adult Critically unwell Organ failure Hyperinsulinism Post gastric-bypass Drugs Extreme weight loss Factitious ```

Answer 384

``` May be related to: Medications Inadequate CHO intake / missed meal Impaired awareness Excessive alcohol Strenuous exercise Co-existing autoimmune conditions ```

Answer 385

Oral Hypoglycaemic: Sulphonylureas Meglitinides GLP-1 agents Insulin: Rapid acting with meals: inadequate meal Long-acting : hypo’s at night or in between meals Other drugs B-blockers, salicylates, alcohol ( inhibits lipolysis)

Answer 386

``` Biochemical Tests Insulin levels C-peptide Drug screen Auto-antibodies Cortisol /GH Free fatty acids / blood ketones Lactate Other specialist tests – IGFBP/IGF-2/Carnitines etc. ```

Answer 387

CLEAVAGE OF PRO-INSULIN PRODUCES C PEPTIDE INSULIN C-peptide levels are a good marker of beta-cell function

Answer 388

Anorexic poor glycogen stores

Answer 389

exogenous insulin

Answer 390

Hyperinsulinaemic hypoglycaemia

Answer 391

Hypoinsulinaemic hypoglycaemia ``` Appropriate response to hypoglycaemia: Fasting / starvation Strenuous exercise Critical illness Endocrine deficiencies Hypopituitarism Adrenal failure Liver failure Anorexia Nervosa ```

Answer 392

Insulin deficiency Fatty acid oxidation defect Starvation

Answer 393

``` Explainable Premature, co-morbidities, IUGR, SGA Inadequate glycogen and fat stores Should improve with feeding Pathological Inborn metabolic defects ```

Answer 394

``` Inherited metabolic disorders FAOD : no ketones produced GSD type 1 ( gluconeogentic disorder) Medium chain acyl coA dehydrogenase def. Carnitine disorders ``` ``` Good differentiators in neonatal hypoglycaemia Insulin / C-peptide FFA KB Lactate Hepatomegaly ```

Answer 395

``` Islet cell tumours – insulinoma Drugs; insulin, sulphonylurea Islet cell hyperplasia Infant of a diabetic mother Beckwith Weidemann syndrome Nesidioblastosis ```

Answer 396

Low glucose, high insulin and high C-peptide High C-peptide = endogenous insulin production Insulinoma vs. Sulphonylurea abuse Sulphonylurea drug screen – urine or serum Negative sulphonylurea screen required for diagnosing insulinoma

Answer 397

INSULINOMA

Answer 398

Low glucose High insulin Low C-peptide Factitious insulin / oral hypoglycaemic usage : always needs to be considered – more common than we think Suspect in patients with access to insulin / drugs

Answer 399

Non-islet cell tumour hypoglycaemia Tumours that cause a paraneoplastic syndrome Secretion of ‘big IGF-2’ Big IGF2 binds to IGF-1 receptor and insulin receptor ``` Mesenchymal tumours (mesothelioma/fibroblastoma) Epithelial tumours ( carcinoma) ```

Answer 400

Low glucose High insulin High C peptide

Answer 401

``` Hypoglycaemia following food intake Can occur post-gastric bypass Hereditary fructose intolerance Early diabetes In insulin sensitive individuals after exercise or large meal True post-prandial hypo’s Difficult to define ```

Answer 402

Review dosing

Answer 403

Review dosing

Answer 404

YES Give thiazide Using thiazides in 100 people with CAD will save 2 lives over 5 years. The intervention was stopped early after a median follow-up of 3.26 years owing to a significantly lower rate of the primary composite outcome in the intensive-treatment group than in the standard-treatment group (1.65% per year vs. 2.19% per year; hazard ratio with intensive treatment

Answer 405

Intensive lifestyle modification Aspirin High dose statin (Atorvastatin 40-80mg od) Optimal blood pressure control Thiazides are almost free Assessment for probable T2D (check HbA1c)

Answer 406

Evolocumab (PCSK9 monoclonal antibody)

Answer 407

UKPDS trial showed cumulative risk reduction of 25% with intensive But only after about 15 years in NEWLY diagnosed type 2 diabetes 10yr follow up study showed: benefits of an intensive strategy to control blood glucose levels in patients with type 2 diabetes were sustained for up to 10 years after the cessation of randomized interventions a so-called legacy effect

Answer 408

Prevent reabsorption of glucose in the PCT | Increased glucose excretion

Answer 409

Reduction of 0.4% HbA1c,dec 2kg weight, waist circumference decreased by 1.5cm Over 4 yrs Dec CV death by 38% Reduced hospitalisation Relative risk reduction ~14% overall. Substantial effect on CV mortality (30% reduction) Absolute reductions in CV mortality 1% pa NNT is 100 = £48,000 to prevent one death Additional benefits on renal function and heart failure

Answer 410

GLP-1 is secreted from the gut, and signals the pancreas to make even more insulin. It also has a direct effect on appetite and gastric emptying

Answer 411

GLP-1 analogue Increases hypothalamic satiety - Other examples: exanatide, liraglutide, semaglutide

Answer 412

Metformin + lifestyle If non-insulin mono therapy at max tolerated dose doesn't achieve or maintain A1c target after 3 months add a second oral agent, GLP1 antagonist or basal insulin LONGSTANDING T2DM + atherosclerosis = add empagliflozin or liraglutide -> reduce mortality

Answer 413

Hypovolaemic hyponatraemia from diuretic Volume replacement 0.9% saline

Answer 414

Hypervolaemic hyponatraemia - CF Fluid restriction

Answer 415

Hypervolaemic hyponatraemia due to cirrhosis Fluid restriction

Answer 416

Euvolaemic hyponatraemia from hypothyroidism Rx = treat underlying cause Thyroxine replacement

Answer 417

Euvolaemic hyponatramia Addisons Rx = hydrocortisone and fludrocortisone Short synacthen test

Answer 418

Euvolaemia hyponatraemia SIADH Plasma and urine osmolality ``` No Hypovolaemia No Hypothyroidism No Adrenal insufficiency Reduced plasma osmolality AND Increased urine osmolality (>100) ```

Answer 419

CNS pathology Lung pathology Drugs (SSRI, TCA, opiates, PPIs, carbamazepine) Tumours Surgery

Answer 420

Hypernatraemia - cranial diabetes insipidus Fluid restriction

Answer 421

Ureplaced water loss Gastrointestinal losses, sweat losses Renal losses: osmotic diuresis, reduced ADH release/action (Diabetes insipidus) Patient cannot control water intake e.g. children, elderly

Answer 422

``` Serum glucose (exclude diabetes mellitus) Serum potassium (exclude hypokalaemia) Serum calcium (exclude hypercalcaemia) Plasma & urine osmolality Water deprivation test ```

Answer 423

Hyponatreamia + Hyperkalaemia due to ramipril ACEi -> reduces aldosterone -> results in Na+ loss and K+ gain

Answer 424

Rhabdomyolysis Acidosis Renal impairment: reduced renal excretion Drugs: ACE inhibitors, ARBs, spironolactone Low Aldosterone Addison’s disease Type 4 renal tubular acidosis (low renin, low aldosterone) Release from cells: rhabdomyloysis, acidosis

Answer 425

Pealed T waves

Answer 426

10 ml 10% calcium gluconate 50 ml 50% dextrose + 10 units of insulin Nebulized salbutamol Treat the underlying cause

Answer 427

Hypokalaemia due to Conn's syndrome - increased aldosterone Aldosterone:Renin ratio important Give ARB

Answer 428

~120ml/min | Age related decline

Answer 429

Inulin clearance Freely filtered 5.2kD fructose polymer Not processed by tubular cells

Answer 430

Clearance = (urinary x V)/plasma concentration

Answer 431

30-60% reabsorption by tubular cells | Dependent on nutritional state, hepatic function, GI bleed

Answer 432

Generation differs by muscularity, age, sex, ethnicity

Answer 433

Estimated GFR, CCr

Answer 434

Quantitative assessment of proteinuria

Answer 435

Rapid reduction in kidney function, leading to an inability to maintain electrolyte, acid base and fluid metabolism

Answer 436

Pre-renal Intrinsic renal Post-renal

Answer 437

Usually reduced perfusion Selective renal ischaemia ``` True volume depletion Hypotension Oedematous states Selective renal ischaemia Drugs affecting glomerular blood flow ```

Answer 438

Activation of central baroreceptors Activation of RAS Release of vasopressin Activation of sympathetic nervous system Vasoconstriction, increased CO, renal sodium retention

Answer 439

NSAIDs Calcineurin inhibitors ACEi or ARBs Diuretics

Answer 440

Decrease afferent arteriolar dilation

Answer 441

Decrease afferent arteriolar dilation

Answer 442

Decrease efferent arteriolar constriction

Answer 443

Decrease preload + affect tubular function

Answer 444

No, Responds immediately to restoration of circulating volume ..but prolonged insult leads to ischaemic injury -> acute tubular necrosis Doesn't respond to restoration of circulatory volume

Answer 445

Hallmark = obstruction to flow of urine Intra renal obstruction Ureteric obstruction Prostatic / urethral obstruction Blocked urinary catheter

Answer 446

GFR dependent on hydraulic pressure gradient Obstruction results in increased tubular pressure Immediate decline in GFr Immediate relief = no damage Sustained insult = glomerular ischaemia, tubular damage, long term interstitial scarring

Answer 447

Glomerular ischaemia, tubular damage, interstitial scarring

Answer 448

Represents any abnormality in the nephron EG Vascular disease - vasculitis Glomerular - glomerulonephritis Tubular disease - ATN Interstitial disease - analgesic nephropathy

Answer 449

Most commonly ischaemic Endogenous toxins: Myoglobin Immunoglobulins Exogenous toxins: Aminoglycosides Amphotericin Acyclovir

Answer 450

Increase in serum creatinine (SCr) by >0.3mg/dl / 26umol Increase of Screen by >1.5x baseline UO < 0.5ml/kg/hr

Answer 451

``` Increased risk Early damage Reduced GFR Renal Failure Death ```

Answer 452

Mild - 60-90 Mod - 30<60 Sev - 15-29 ESRF <15 or dialysis requiring

Answer 453

``` Diabetes Atherosclerotic renal disease HTN Chronic glomerulonephritis Infective/Ob uropathy Polycystic kidney disease ```

Answer 454

1) Progressive homeostatic failure: Hyperkalaemia, Acidosis 2) Failure of hormone function - anaemia, Renal bone disease 3) CVD - vascular calcification, Uraemic cardiomyopathy 4) Uraemia + DEATH

Answer 455

Failed renal excretion of protons Causes: Increased muscle and protein degradation, osteopenia due to mobilisation of bone calcium stores, cardiac dysfunction Treated with oral sodium bicarb

Answer 456

Worsened hyperkalaemia

Answer 457

Loss of p waves Tented T waves Widened QRS

Answer 458

Progressive decline in erythropoietin producing cells in the renal parenchyma Usually GFR <30 Normochromic, normocytic anaemia

Answer 459

Erythropoietin alfa Erythropoietin beta Darbopoietin

Answer 460

Osteoclastic resorption of calcified bone and replacement by fibrous tissue Driven by hyperparathyroidism

Answer 461

Whereby excessive suppression of PTH leads to low burn turnover and reduced osteoid

Answer 462

``` Phosphate control Dietary Phosphate binders Vit D receptor activators 1-alpha calcidol Paricalcitol Direct PTH suppression Cinacalcet ```

Answer 463

All of the above

Answer 464

``` Liver and bone ALP can be differentiated by: GGT measurement Electrophoretic separation Bone specific ALP immunoassay now available ```

Answer 465

Pregnancy (placental ALP) – 3rd trimester | Childhood- especially during growth spurt

Answer 466

> 5x Upper limit of normal Bone ( Pagets, Osteomalacia) Liver ( cholestasis, cirrhosis) < 5 x Upper Limit Normal Bone ( tumours, fractures, osteomyelitis) Liver (infitrative disease,hepatitis)

Answer 467

Pancreatitis Small increases may be seen in acute abdomen

Answer 468

CK-MM- skeletal muscles CK-MB (1 & 2) – cardiac muscles CK- BB – brain – activity minimal even in severe brain damage CK-MM accounts for almost entire normal plasma activity

Answer 469

Statin related myopathy

Answer 470

Polypharmacy ( fibrates – gemfibrosil, cyclosporin, other drugs metabolised by the CYP 3A4 system) High dose Genetic predisposition Previous history of myopathy with another statin

Answer 471

1. Acute pancreatitis

Answer 472

Statin-related myopathy

Answer 473

Measurement of thiopurine methyltransferase (TPMT) activity is encouraged prior to commencing the treatment of patients with thiopurine drugs such as azathioprine, 6-mercaptopurine and 6-thioguanine

Answer 474

1 day Rise 4-6 hours post MI Peak at 12 -24 hours post MI Remain elevated for 3 -10 days The current marker of choice for myocardial injury (not an enzyme!)

Answer 475

Measure at 6 hours and then at 12 hours post onset of chest pain Sensitivity 17% at 0-6 hours 92% at 6-12 hours 100% at 12 -24 hours

Answer 476

Either one of the following (1) Typical rise and gradual fall (troponin) or more rapid rise and fall (CK-MB) with at least one of the following: (a) ischemic symptoms (b) pathologic Q waves on the ECG (c) ECG changes indicative of ischemia (d) coronary artery intervention (2) Pathologic findings of an acute MI

Answer 477

One International Unit (U) of enzyme activity is defined as the quantity of enzyme that catalyses the reaction of one μmol of substrate per minute Activity of an enzyme is dependent on assay conditions such as temperature, pH

Answer 478

Vitamins ADEK

Answer 479

Rickets / osteomalacia

Answer 480

Defective clotting

Answer 481

Hypercalcaemia

Answer 482

``` B1 - thiamine B2 - riboflavin B6 - pyridoxine B12 - cobalamin C - ascorbate Folate Niacin ```

Answer 483

Beri beri Neuropathy Wernickes syndrome

Answer 484

Dermatitis / anaemia

Answer 485

Pernicious anaemia

Answer 486

Megaloblastic anaemia

Answer 487

Neuropathy

Answer 488

RBC transketolase

Answer 489

RBC glutathione reductase

Answer 490

RBC AST activation

Answer 491

Gotre | Hypothyroid

Answer 492

Dermatitis

Answer 493

Dental Caries

Answer 494

haemochromatosis

Answer 495

Caeruloplasmin

Answer 496

FBC Fe Ferritin TF saturation

Answer 497

LDL-C Increased with saturated fat Decreased with PUFA

Answer 498

``` Fasting glucose >6mmol Waist circumference >102 men 88women Microalbumin + Insulin resistance HTN 135/80 HDL <1.0 men, <1.3 women ```

Answer 499

Adjustable bands Sleeve gastrectomy Roux-en-Y gastric bypass

Answer 500

Bariatric surgery

Answer 501

Kwashiorkor

Answer 502

Intermediary metabolism

Answer 503

Xenobiotic metabolism

Answer 504

``` Vitamin D - hydroxylation Steroid Hormone - conjugation - excretion Peptide Hormone - catabolism ```

Answer 505

Excretion Micelle formation Digestion

Answer 506

Clearance of infection and LPS Antigen presentation Immune modulation cytokines etc.

Answer 507

``` Alanine Transaminase ALT Aspartate Transaminase AST Alkaline Phosphatase ALP Albumin Bilirubin Gamma glutamyl transferase ``` Clotting factors PT Pro-thrombin time Alpha fetoprotein

Answer 508

AST ALT ALP GGT

Answer 509

Albumin Pro-thrombin time (PT) Bilirubin

Answer 510

Alcoholic liver / cirrhosis

Answer 511

contributes to oncotic pressure and binds steroids /drugs/bilirubin/calcium etc

Answer 512

low production (chronic liver disease, malnutrition) loss (eg gut, kidney) sepsis (“3rd spacing”)

Answer 513

Unconjugated

Answer 514

Both conjugated and unconjugated rise, but to a lesser extent

Answer 515

Conjugated

Answer 516

Urobilinogen

Answer 517

Ob Jaundice

Answer 518

Dye tests Indocyanine green / Bromsulphalein Measure excretory capacity of liver Meaure hepatic blood flow Breath tests Aminopyrine / Galactose (carbon 14) measure residual functioning liver cell mass ? predict survival in alcoholic hepatitis ? distinguish cirrhosis without biopsy (70-80%sensitivity) Serum bile acids Elevated esp. in cholestasis 10-100x in cholestasis of pregnancy 25X in PBC/PSC

Answer 519

a diagnosis of drug induced cholestasis was made (intrahepatic / 2Y to Augmentin) the jaundice resolved over the next 3 weeks

Answer 520

“…….in the presence of a painless palpable gallbladder, jaundice is unlikely to be caused by gall stones…” Pancreatic adenocarcinoma CT scan and biopsy confirmed this plus local spread liver looked cirrhotic a palliative stent was placed in the CBD jaundice and itch resolved but he passed away 3 months later

Answer 521

diagnosis acute hepatitis A the jaundice resolved and she made a full recovery AST:ALT - likely viral

Answer 522

Hepatitis C -->> Cirrhosis USS/AFP every 6/12 for ? HCC

Answer 523

Paracetamol OD | N-acetyl-cysteine

Answer 524

Bilirubin level is a test of liver function / urine and blood “split” can help determine underlying cause

Answer 525

``` Primary = inherited Secondary = acquired ```

Answer 526

HIV Measles virus Mycobacterial infection

Answer 527

Malnutrition Specific mineral deficiencies (zinc, iron) Renal impairment

Answer 528

Myeloma Leukaemia Lymphoma

Answer 529

Corticosteroids Anti-proliferative immunosuppressants Cytotoxic agents

Answer 530

``` Two major or one major and recurrent minor infections in one year Unusual organisms Unusual sites Unresponsive to treatment Chronic infections Early structural damage ``` Family history Young age at presentation Failure to thrive

Answer 531

``` Cells Polymorphonuclear cells – neutrophils, eosinophils, basophils Monocytes and macrophages Dendritic cells Natural killer cells ```

Answer 532

Soluble components Complement Acute phase proteins Cytokines and chemokines

Answer 533

Phagocytes

Answer 534

Polymorphonuclear cells (Granulocytes) Neutrophils, Eosinophils and Basophils/Mast cells

Answer 535

Kuppfer | Capable of presenting processed antigen to T cells

Answer 536

Mesangial | Capable of presenting processed antigen to T cells

Answer 537

Osteoclast | Capable of presenting processed antigen to T cells

Answer 538

Sinosoidal lining cell | Capable of presenting processed antigen to T cells

Answer 539

Alveolar macrophage | Capable of presenting processed antigen to T cells

Answer 540

Microglia | Capable of presenting processed antigen to T cells

Answer 541

Histiocyte | Capable of presenting processed antigen to T cells

Answer 542

Langerhans cell | Capable of presenting processed antigen to T cells

Answer 543

Macrophage like synoviocytes | Capable of presenting processed antigen to T cells

Answer 544

Failure to produce neutrophils Failure of stem cells to differentiate along myeloid or lymphoid lineage Mutation in mitochondrial energy metabolism enzyme adenylate kinase 2 (AK2)

Answer 545

reticular dysgenesis

Answer 546

Specific failure of neutrophil maturation

Answer 547

classical form due to mutation in HCLS1-associated protein X-1 (HAX1)

Answer 548

mutation in neutrophil elastase (ELA-2)

Answer 549

Cyclic neutropenia - autosomal dominant episodic neutropenia every 4-6 weeks

Answer 550

In Leukocyte adhesion deficiency the neutrophils lack these adhesion molecules and fail to exit from the bloodstream very high neutrophil counts in blood absence of pus formation CD11a/CD18 (LFA-1) is expressed on neutrophils, binds to ligand (ICAM-1) on endothelial cells and so regulates neutrophil adhesion/transmigration

Answer 551

Failure of oxidative killing mechanisms in neutrophils. Absent respiratory burst Deficiency of one of components of NADPH oxidase Inability to generate oxygen free radicals results in impaired killing Excessive inflammation Persistent neutrophil/macrophage accumulation Failure to degrade antigens Granuloma formation Lymphadenopathy and hepatosplenomegaly

Answer 552

Chronic Granulomatous disease

Answer 553

``` Nitroblue tetrazolium (NBT) test Dihydrorhodamine (DHR) flow cytometry test ``` NBT is a dye that changes colour from yellow to blue, following interaction with hydrogen peroxide DHR is oxidised to rhodamine which is strongly fluorescent, following interaction with hydrogen peroxide

Answer 554

``` Aggressive management of infection Infection prophylaxis Antibiotics – eg Septrin Anti-fungals – eg Itraconazole Oral/intravenous antibiotics as needed ``` ``` Definitive therapy Haematopoietic stem cell transplantation ‘Replaces’ defective population Specific treatment for CGD Interferon gamma therapy ```

Answer 555

Classical NK deficiency

Answer 556

Functional NK deficiency

Answer 557

Herpes virus infection Herpes Simplex virus I and II Varicella Zoster virus Epstein Barr virus Cytomegalovirus Papillomavirus infection

Answer 558

No good trial data Prophylactic antiviral drugs such as acyclovir or gancyclovir Cytokines such as IFN-alpha to stimulate NK cytotoxic function Haematopoietic stem cell transplantation in severe phenotypes

Answer 559

Innate immune cell deficiency ie IFN gamma receptor deficiency Leukocyte adhesion deficiency Chronic granulomatous disease Classical natural killer cell deficiency Kostmann syndrome

Answer 560

Complement

Answer 561

Formation of antibody-antigen immune complexes Results in change in antibody shape – exposes binding site for C1 Binding of C1 to the binding site on antibody results in activation of the cascade Dependent upon activation of acquired immune response (antibody) Joins final common pathway -> forms the MAC

Answer 562

Activated by the direct binding of MBL to microbial cell surface carbohydrates Directly stimulates the classical pathway, involving C4 and C2 but not C1 Not dependent on acquired immune response

Answer 563

Lipopolysaccharide of gram negative bacteria teichoic acid of gram positive bacteria Not dependent on acquired immune response Involves factors B, D and Properidin Factor H – control protein

Answer 564

C3 Triggers the formation of the membrane attack complex via C5-C9

Answer 565

Increases vascular permeability and cell trafficking to site of inflammation Activates phagocytes Promotes clearance of immune complexes Opsonisation of pathogens to promote phagocytosis Promotes mast cell/basophil degranulation Punches holes in bacterial membranes

Answer 566

``` Susceptibility to bacterial infections Especially encapsulated bacteria (NHS) Neisseria meningitides – esp properidin and C5-9 deficiency Haemophilus influenzae Streptococcus pneumoniae ```

Answer 567

Classical complement pathway activation promotes phagocyte mediated clearance of apoptotic/necrotic cells Deficiencies results in increased load of self antigens – particularly nuclear components – which may promote auto-immunity and formation of immune complexes Classical complement pathway activation promotes clearance of immune complexes by erythrocytes Deficiencies result in deposition of immune complexes which stimulates local inflammation in skin, joints and kidneys

Answer 568

C2 C1q, C1r, C1s, C2, C4 deficiency are all described

Answer 569

Yes Active lupus causes persistent production of immune complexes and consequent consumption of complement leading to functional complement deficiency

Answer 570

Nephritic factors are auto-antibodies directed against components of the complement pathway Nephritic factors stabilise C3 convertases resulting in C3 activation and consumption Often associated with glomerulonephritis (classically membranoproliferative) May be associated with partial lipodystrophy

Answer 571

C3, C4 routinely measured C1 inhibitor – decreased in hereditary angiodema Other components not routinely quantified, but can be performed if deficiency is suspected Functional complement tests: CH50 classical pathway AP50 alternative pathway

Answer 572

``` Vaccination Boost protection mediated by other arms of the immune system Meningovax, Pneumovax and HIB vaccines Prophylactic antibiotics Treat infection aggressively Screening of family members ```

Answer 573

Complement deficiency

Answer 574

``` Full blood count Hb 10.7, WBC 5.6, Platelets 320 Electrolytes, Creatinine, Calcium Na 140 K 4.0 Creatinine 100 (60 – 110 umol/l) Calcium 2.00 (2.15 - 2.65 umol/l) Liver function tests ALT 30 (0 – 31 U/L) GGT 15 (8-78 U/L) Alk Phos 400 (30 – 130 U/l) Blood glucose Normal Thyroid function tests Normal ``` Slightly anaemic

Answer 575

ID Thalassaemia ACD

Answer 576

``` Hb - Low Serum iron - low TIBC - High TFsat - Low Ferritin - Low ```

Answer 577

``` Hb - Low Serum iron - low TIBC - High/normal TFsat - N Ferritin - N/H ```

Answer 578

``` Hb - Low / N Serum iron - N TIBC - N TFsat - N Ferritin - N ```

Answer 579

ID anaemia | Thalassaemia

Answer 580

ID anaemia

Answer 581

Aggregated ribosomal material

Answer 582

Beta thalassaemia trait Lead poisoning Alcoholism Sideroblastic anaemia

Answer 583

ID anaemia

Answer 584

Megaloblastic anaemia - reflects impaired DNA synthesis IE B12 deficiency Folate Deficiency Drugs

Answer 585

ID anaemia Thalassaemia Hyposplenism Liver disease

Answer 586

Hyposplenism

Answer 587

Howell-jolly bodies | Target cells

Answer 588

MAJOR - bloodloss Others: Poor diet Malabsorption

Answer 589

Poor diet malabsorption Pernicious anaemia

Answer 590

Absent spleen - Therapeutic (ie radio in Hodgkins) - Trauma Poorly-functioning spleen - Inflammatory bowel disease - Coeliac disease - Sickle cell disease - SLE

Answer 591

Vitamin D deficiency + secondary hyperparathyroidism

Answer 592

Coeliac IBS IBD Pancreatic (unlikely)

Answer 593

Polygenic 75% concordance in monozygotic twins 40% heritability maps to MHC complex gene loci 90% patients (vs 20% controls) carry HLA DQ2 (DQA1*0501 and DQB1*02 alleles) Other patients carry HLA DQ8 (DQA1*03 and DQB1*0302 alleles)

Answer 594

- Peptides from gliadin are deamidated by tissue transglutaminase and presented by APC - CD4 T cells recognise these deamidated peptides presented by HLA DQ2 or DQ8

Answer 595

Intraepithelial lymphocytes

Answer 596

- Increased activation due to IL15 + other cytokines | - Intra-epithelial lymphocytes kill epithelial cells in an NKG2D dependent manner

Answer 597

Anti-gliadin Anti-TTG Anti-endomysial

Answer 598

IgA Anti-TTG > IgA anti-endomysial > IgA/G anti-gliadin

Answer 599

Still need duodenal histology -> gold standard Because of the major implications of this diagnosis - Diet - Complications

Answer 600

Decreased. | Ie less villi to more crypts

Answer 601

- Increased atrophy - Decreased villi height - Hyperplastic crypts VILLOUS ATROPHY RESULTS IN REDUCED SURFACE AREA = MALABSORPTION

Answer 602

Normal <20 / 100 cells | Coeliac >20 / 100 cells

Answer 603

``` Dermatitis herpetiformis Giardiasis Cows milk protein sensitivity IgA deficiency Tropical sprue Post infective malabsorption Drugs (NSAIDs) (Lymphoma) ```

Answer 604

``` Giardiasis Tropical sprue Crohn’s disease Radiation/chemotherapy Bacterial overgrowth Nutritional deficiencies Graft versus host disease Microvillous inclusion disease Common variable immunodeficiency ```

Answer 605

``` Malabsorption Osteomalacia and osteoporosis Neurological disease Epilepsy Cerebral calcification Lymphoma Hyposplenism ```

Answer 606

``` Haematology: Complete blood cell count Iron level, total iron-binding capacity, ferritin Vitamin B12 and folate Prothrombin time ``` ``` Biochemistry: Urea and electrolytes, creatinine Calcium and phosphate Liver function tests Albumin and total serum protein levels ``` Serologic tests: Quantitative IgA anti-transglutaminase antibody or IgA endomysial antibody Imaging: Dual energy x-ray absorptiometry (DEXA) of spine and hip – every 3-5 years

Answer 607

Mortality rate of untreated coeliacs is x 2-3 of general population Malignancy (especially lymphoma) Infection The excess mortality returns to normal after 3-5 years on gluten free diet

Answer 608

Other A/I! Dermatitis herpetiformis (prevalence = 100%) Type 1 diabetes mellitus (prevalence = 7%) Autoimmune thyroid disease Down’s syndrome ``` Systemic lupus erythematosus Autoimmune hepatitis Autoimmune Addison's disease Recurrent aphthous ulceration Sjögren's syndrome Sarcoidosis Vitiligo or alopecia areata IgA deficiency ```

Answer 609

Anaemia, especially iron deficiency Chronic diarrhoea Recurrent mouth ulcers Irritable bowel syndrome ``` Chronic fatigue Unexplained weight loss Short stature Epilepsy Peripheral neuropathy Infertility ``` Family history of coeliac disease Type I diabetes Down’s syndrome Autoimmune thyroid disease or vitiligo

Answer 610

Organs involved in lymphocyte development

Answer 611

Bone marrow Thymus Bone marrow Both T and B lymphocytes are derived from haematopoetic stem cells Site of B cell maturation Thymus Site of T cell maturation. Most active in the foetal and neonatal period, involutes after puberty

Answer 612

Reticular dysgenesis - most severe form of severe combined immunodeficiency (SCID) - mutation in mitochondrial energy metablism enzyme adenylate kinase 2 (AK2) ``` Failure of production of: Lymphocytes Neutrophils Monocyte/macrophages Platelets ```

Answer 613

- mutation in mitochondrial energy metablism enzyme adenylate kinase 2 (AK2 ``` Failure of production of: Lymphocytes Neutrophils Monocyte/macrophages Platelets ```

Answer 614

``` Failure of production of: Lymphocytes Neutrophils Monocyte/macrophages Platelets ```

Answer 615

45% of all severe combined immunodeficiency Mutation of common gamma chain on chromosome Xq13.1 Shared by receptor for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 Inability to respond to cytokines causes early arrest of T cell and NK cell development and production of immature B cells Phenotype Very low or absent T cell numbers Normal or increased B cell numbers but low Igs Very low or absent NK cell numbers

Answer 616

45% of all severe combined immunodeficiency Mutation of common gamma chain on chromosome Xq13.1 Shared by receptor for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 Inability to respond to cytokines causes early arrest of T cell and NK cell development and production of immature B cells Phenotype Very low or absent T cell numbers Normal or increased B cell numbers but low Igs Very low or absent NK cell numbers

Answer 617

16.5% of all severe combined immunodeficiency Adenosine Deaminase Deficiency Enzyme lymphocytes required for cell metabolism Inability to respond to cytokines causes early arrest of T cell and NK cell development and production of immature B cells Phenotype Very low or absent T cell numbers Very low or absent B cell numbers Very low or absent NK cell numbers

Answer 618

16.5% of all severe combined immunodeficiency Adenosine Deaminase Deficiency Enzyme lymphocytes required for cell metabolism Inability to respond to cytokines causes early arrest of T cell and NK cell development and production of immature B cells Phenotype Very low or absent T cell numbers Very low or absent B cell numbers Very low or absent NK cell numbers

Answer 619

``` Unwell by 3 months of age Infections of all types Failure to thrive Persistent diarrhoea Unusual skin disease Colonisation of infant’s empty bone marrow by maternal lymphocytes Graft versus host disease Family history of early infant death ```

Answer 620

Source of circulating IgG in the neonate | - maternal

Answer 621

HLA/Peptide complexes

Answer 622

Low HLA affinity - not selected..inadequate reactivity Intermediate HLA affinity - +ve selection - roughly 10% High HLA affinity - not selected..autoreactivity

Answer 623

CD8+ cytotoxic T cells

Answer 624

CD4+ helper T cells

Answer 625

``` IL12/IFN -> TH1 IL4/6 -> TH2 Acute phase (IL6/23, tgf) -> TH17 Acute phase (IL1/6/TNF) TFH TGF -> Treg ```

Answer 626

22q11.2 deletion syndromeeg DiGeorge syndrome

Answer 627

``` Normal numbers B cells Reduced numbers T cells Homeostatic proliferation with age Immune function usually only mildly impaired and improves with age ```

Answer 628

Defect in one of the regulatory proteins involved in Class II gene expression Regulatory factor X Class II transactivator Absent expression of MHC Class II molecules Profound deficiency of CD4+ cells Usually have normal number of CD8+ cells Normal number of B cells Low IgG or IgA antibody due to lack of CD4+ T cell help BLS type 1 also exists due to failure of expression of HLA class I ``` __________________________ Unwell by 3 months of age Infections of all types Failure to thrive Family history of early infant death ```

Answer 629

``` Viral infections Cytomegalovirus Fungal infection Pneumocystis, Cryptosporidium Some bacterial infections – esp intracellular organisms Mycobacteria tuberculosis, Salmonella Early malignancy ```

Answer 630

Total white cell count and differential Remember that lymphocyte counts are normally much higher in children than in adults Lymphocyte subsets Quantify CD8 T cells, CD4 T cells as well as B cells and NK cells Immunoglobulins If CD4 T cell deficient Functional tests of T cell activation and proliferation Useful if signalling or activation defects are suspected HIV test

Answer 631

Aggressive prophylaxis/treatment of infection Haematopoieitic stem cell transplantation To replace abnormal populations in SCID To replace abnormal cells - class II deficient APCs in BLS Enzyme replacement therapy PEG-ADA for ADA SCID Gene therapy Stem cells treated ex-vivo with viral vectors containing missing components. Transduced cells have survival advantage in vivo. Thymic transplantation To promote T cell differentiation in Di George syndrome Cultured donor thymic tissue transplanted to quadriceps muscle

Answer 632

Lymphocyte deficiency

Answer 633

No recognition of self in bone marrow - survive Recognition of self in BM -> negative selection

Answer 634

Early IgM response

Answer 635

CD4+ T cell help for B cell differentiation Requires CD40L:CD40

Answer 636

Bruton’s X linked agammaglobulinaemia

Answer 637

Bruton’s X linked agammaglobulinaemia

Answer 638

Hyper IgM syndrome (X-linked recessive) | Mutated CD40 = cannot be activated by T cell

Answer 639

``` Mutation in CD40 ligand gene (CD40L, CD154) Member of TNF Receptor family Encoded on Xq26 Involved in T-B cell communication Expressed by activated T cells – NOT on B cells ```

Answer 640

Hyper IgM syndrome (X-linked recessive)

Answer 641

Hyper IgM syndrome (X-linked recessive)

Answer 642

Common variable immune deficiency Low IgG, IgA and IgE Recurrent bacterial infections Cause unknown Heterogenous group of disorders Many different genetic defects – most unidentified Failure of differentiation/function of B lymphocytes Defined by Marked reduction in IgG, with low IgA or IgM Poor/absent response to immunisation Absence of other defined immunodeficiency

Answer 643

Common variable immune deficiency

Answer 644

Total white cell count and differential Remember that lymphocyte counts are normally much higher in children than in adults Lymphocyte subsets Quantify B cells as well as CD4 T cells, CD8 T cells and NK cells Serum immunoglobulins and protein electrophoresis Production of IgG is surrogate marker for CD4 T cell helper function Functional tests of B cell function Specific antibody responses to known pathogens Measure IgG antibodies against tetanus, Haemophilus influenzae B and S. pneumoniae If specific antibody levels are low, immunise with the appropriate killed vaccine and repeat antibody measurement 6–8 weeks later Functional tests have generally superceded IgG subclass quantitation.

Answer 645

Aggressive prophylaxis / treatment of infection Immunoglobulin replacement if required Derived from pooled plasma from thousands of donors Contains IgG antibodies to a wide variety of common organisms Aim of maintaining trough IgG levels within the normal range Treatment is life-long Immunisation For selective IgA deficiency Not otherwise effective because of defect in IgG antibody production

Answer 646

IgA deficiency Common variable immunodeficiency Bruton’s X linked hypogammaglobulinaemia X linked hyper IgM syndrome due to CD40ligand mutation

Answer 647

Autosomal recessive

Answer 648

MEFV gene - Encodes pyrin marenostrin (expressed in neutrophils) Failure to regulate cryopyrin driven activation of neutrophils

Answer 649

Clinical presentation Periodic fevers lasting 48-96 hours associated with: Abdominal pain due to peritonitis Chest pain due to pleurisy and pericarditis Arthritis Rash

Answer 650

Long term risk of AA amyloidosis Liver produces serum amyloid A as acute phase protein Serum amyloid A deposits in kidneys, liver, spleen Deposition in kidney often most clinically important Proteinuria with development of nephrotic syndrome Renal failure

Answer 651

Colchicine 500ug bd - binds to tubulin in neutrophils and disrupts neutrophil functions including migration and chemokine secretion Anakinra (Interleukin 1 receptor antagonist) Etanercept (TNF alpha inhibitor)

Answer 652

Defect in ‘auto-immune regulator’ – AIRE Transcription factor involved in development of T cell tolerance in the thymus Upregulates expression of self-antigens by thymic cells Promotes T cell apoptosis Defect in AIRE leads to failure of central tolerance Autoreactive T and B cells Autosomal recessive disorder

Answer 653

Transcription factor involved in development of T cell tolerance in the thymus Upregulates expression of self-antigens by thymic cells Promotes T cell apoptosis

Answer 654

``` Multiple auto-immune diseases Hypoparathyroidism Addisons Hypothyroidism Diabetes Vitiligo Enteropathy ``` Antibodies vs IL17 and IL22 Candidiasis

Answer 655

Mutations in Foxp3 (Forkhead box p3) which is required for development of Treg cells Failure to negatively regulate T cell responses Autoantibody formation

Answer 656

- Autoimmune diseases Enteropathy Diabetes Mellitus Hypothyroidism

Answer 657

Mutations within FAS pathway Eg mutations in TNFRSF6 which encodes FAS Disease is heterogeneous depending on the mutation Defect in apoptosis of lymphocytes Failure of tolerance Failure of lymphocyte ‘homeostasis’

Answer 658

Defect in apoptosis of lymphocytes Failure of tolerance Failure of lymphocyte ‘homeostasis’ Mutations within FAS pathway Eg mutations in TNFRSF6 which encodes FAS Disease is heterogeneous depending on the mutation

Answer 659

High lymphocyte numbers with large spleen and lymph nodes double negative (CD4-CD8-) T cells Auto-immune disease commonly auto-immune cytopenias Lymphoma

Answer 660

Polygenic Auto-inflammatory Diseases ie crohns

Answer 661

IBD1 gene on chromosome 16 identified as NOD2 (CARD-15, caspase activating recruitment domain -15). NOD2 gene mutations are present in 30% patients (ie not necessary) Abnormal allele of NOD2 increases risk of Crohn’s disease by 1.5-3x if one copy and 14-44x if two copies (ie not sufficient) Mutations also found in patients with Blau syndrome and some forms of sarcoidosis

Answer 662

NOD2 expressed in cytoplasm of myeloid cells - macrophages, neutrophils, dendritic cells Acts as a microbial sensor - recognises muramyl dipeptide – and stimulates NFKb and triggers an inflammatory response Some mutations associated with Crohn’s disease result in a shorter protein that fails to recognise bacteria

Answer 663

NOD2 expressed in cytoplasm of myeloid cells - macrophages, neutrophils, dendritic cells Acts as a microbial sensor - recognises muramyl dipeptide – and stimulates NFKb and triggers an inflammatory response Some mutations associated with Crohn’s disease result in a shorter protein that fails to recognise bacteria

Answer 664

False | NOD2/CARD15

Answer 665

Abdominal pain and tenderness Diarrhoea (blood, pus, mucous) Fevers, malaise

Answer 666

Corticosteroid Azathioprine Anti-TNF alpha antibody Anti-IL12/23 antibody

Answer 667

Mutations in genes encoding proteins involved in pathways associated with innate immune cell function And Mutations in genes encoding proteins involved in pathways associated with adaptive immune cell function HLA associations may be present Auto-antibodies are not usually a feature

Answer 668

True Abnormalities affecting both innate and adaptive immune system resulting in increased tendency to ‘inflammation’ Enhanced inflammation occurs at specific sites where there are high tensile forces (entheses - sites of insertions of ligaments or tendons)

Answer 669

Low back pain and stiffness Large joint arthritis Enthesitis Uveitis

Answer 670

``` Non-steroidal anti-inflammatory drugs Immunosuppression Anti-TNF alpha Anti-IL17 Anti-IL12/23 ```

Answer 671

Mutations in genes encoding proteins involved in pathways associated with adaptive immune cell function HLA associations are common Aberrant B cell and T cell responses in primary and secondary lymphoid organs lead to breaking of tolerance with development of immune reactivity towards self-antigens Auto-antibodies are found

Answer 672

Goodpastures

Answer 673

Graves | SLE

Answer 674

Diabetes T1

Answer 675

Rheumatoid A

Answer 676

``` Peripheral tolerance Regulated expression of co-stimulatory molecules CD40L-CD40, CD80/86-CD28 Regulatory T-cells Tregs, Tr1, CD8 regs Immune privilege Eyes, testes, CNS ```

Answer 677

Type I: Immediate hypersensitivity which is IgE mediated

Answer 678

Type II: Antibody reacts with cellular antigen

Answer 679

Type III: Antibody reacts with soluble antigen to form an immune complex

Answer 680

Type IV: Delayed type hypersensitivity…T-cell mediated response

Answer 681

What type of hypersensitivity reaction?

Answer 682

Complement mediated cell lysis NK cell mediated cytotoxic granule release via Fc receptor Phagocytosis

Answer 683

Type 2 antibody driven hypersensitivity reactions

Answer 684

Noncollagenous domain of basement membrane collagen type IV

Answer 685

Epidermal cadherin

Answer 686

Thyroid stimulating | hormone (TSH) receptor

Answer 687

Acetylcholine receptor

Answer 688

Type III hypersensitivity reactions in autoimmune disease: Immune complex driven autoimmune disease

Answer 689

Type III immune complex driven autoimmune diseases

Answer 690

DNA, Histones, RNP

Answer 691

Fc region of IgG

Answer 692

Type IV hypersensitivity reactions in autoimmunity | CD8 T-cells

Answer 693

Type IV T-cell mediated diseases

Answer 694

Pancreatic b-cell antigen b-cell destruction: CD8+ T-cells

Answer 695

Myelin Basic Protein Proteolipid protein Brain infiltration by CD4+ T-cells,

Answer 696

Myelin oligodendrocyte glycoprotein Brain infiltration by CD4+ T-cells,

Answer 697

Allergic disorder: immunological process that results in immediate and reproducible symptoms after exposure to an allergen.

Answer 698

Allergen is usually a harmless substance that can trigger an IgE mediated immune response and may result in clinical symptoms

Answer 699

Sensitisation is the detection of specific IgE either by skin prick testing or in vitro blood tests: OCCURS MORE OFTEN THAN ALLERGIC DISEASE

Answer 700

*Histamine Prostaglandins *Leukotrienes Proteases biological & drug targets in allergic disorders

Answer 701

T regulatory cells derived from GI mucosa inhibit IgE synthesis to keep immune system in balance

Answer 702

Drug, bees, oral, occupational

Answer 703

Occurs within minutes or up to 3 hours after exposure to allergen and symptoms can include: Skin: angioedema (swelling of lips, tongues, eyelids) , urticaria ( wheals or ‘hives’), flushing and itch Respiratory tract: cough, SOB wheeze, sneezing, nasal congestion and clear discharge, red itch watery eyes Gastrointestinal tract: nausea, vomiting and diarrhoea Vasculature and CNS: symptoms of hypotension (faint, dizzy, blackout) and a sense of impending doom

Answer 704

Elective investigations Skin prick and intradermal tests Laboratory measurement of allergen specific IgE Component-resolved diagnostics Basophil activation test Challenge test Supervised exposure to the putative antigen During acute episode Evidence of mast cell degranulation Serial mast cell tryptase Blood and/or urine histamine

Answer 705

A positive IgE test only demonstrates sensitisation (risk of allergic disease) NOT CLINICAL ALLERGY.

Answer 706

Concentration: higher levels more likely to be associated with symptoms Molecular target within whole extract or even individual epitope can be linked to symptoms Affinity (strength of binding) to target: higher affinity associated with risk Capacity of IgE antibody to induce mast/basophil degranulation

Answer 707

Expose patient to standardised solution of allergen extract through a skin prick to the forearm. Use standard skin test solutions and positive control (histamine) and negative control (diluent) Measure local wheal and flare response to controls and allergens A positive test is indicated by a wheal ≥ 3mm greater than the negative control. Antihistamines should be discontinued for at least 48 hours beforehand Skin prick testing is considered to be more sensitive and specific than blood tests to diagnose allergy in routine clinical practice

Answer 708

Rapid (read after 15-20 minutes) Cheap and easy to do Excellent negative predictive value usually more than > 95% Increasing size of wheals correlates with higher probability for allergy Patient can see the response

Answer 709

Requires experience to interpret Risk of anaphylaxis: 1 in 3000 Poor positive predictive value: high false positive rate Limited value in patients with dermatographism or extensive eczema False negative results with labile commercial food extracts

Answer 710

Allergen bound to sponge in a plastic cap and patient’s serum is added. Specific IgE (if present) binds to allergen. Anti-IgE antibody tagged with a fluorescent label is added. Amount of IgE/Anti-IgE is measured by fluorescent light signal. Blood test are very reliable but can be expensive.

Answer 711

May help diagnosis of allergy in someone with appropriate clinical history Higher values are more likely to be associated with allergic disorder and can be used to triage patients who do not need oral food challenges Results of serum specific IgE do not predict severity of reaction Very good negative predictive value however lot of false positive ( > 80% of patients with peanut specific IgE are asymptomatic) Concentration of specific IgE can be used to predict which children may outgrow allergy and should proceed to oral food challenge Can be used to monitor response to anti-IgE therapy

Answer 712

Patients who can’t stop anti-histamines Patients with dermatographism Patients with extensive eczema History of anaphylaxis Borderline/equivocal skin prick test results

Answer 713

Blood test to detect IgE to single protein components: abundance and stability of protein contribute to risk of allergic disease Useful for diagnosis of peanut and hazelnut allergy: may reduce the needs for food challenges

Answer 714

A Detect primary sensitization Confirm cross reactivity B Define risk of serious reaction for stable allergens C. Improve diagnostic sensitivity on addition of components which are poorly represented in whole food extracts D Improve diagnostic sensitivity for unstable molecules in whole food extracts

Answer 715

Tryptase: pre-formed protein found in mast cell granules Systemic degranulation of mast cells during anaphylaxis results in increase in serum tryptase Peak concentration at 1-2 hours; returns to baseline by 6-12 hours Failure to return to baseline after anaphylaxis may be indicative of systemic mastocytosis Useful if diagnosis of anaphylaxis is not clear (hypotension + rash during anaesthesia Reduced sensitivity for food induced anaphylaxis

Answer 716

Gold standard for food and drug allergy diagnosis Increasing volumes of the offending food/drug are ingested Double blind placebo or open challenge Food challenges take place under close medical supervision. Very expensive in terms of clinical staff time. Can be difficult to interpret mild symptoms Risk of severe reaction

Answer 717

Measurement of basophil response to allergen IgE cross linking Activated basophils increase the expression of CD63, CD203, CD300 protein on cell surface Increasing use in diagnosis of food and drug allergy: surrogate marker for challenge tests Efforts to this standardise test to use n diagnostic laboratories to reduce need fro challenge tests

Answer 718

CORRECT ANSWER | B: Skin prick test

Answer 719

CORRECT ANSWERD. Serial mast cell tryptase

Answer 720

Anaphylaxis: a severe potentially systemic hypersensitivity reaction. Rapid onset, life threatening airway, breathing and circulatory problems which is usually but not always associated with skin and mucosal changes Incidence: 1.5-8/100,000 persons years with studies from UK showing increase in hospital admissions over last 20 years Estimated prevalence based on European studies is 0.3% Skin (hives, itch, swollen lips, tongue, uvula) is most frequent organ involved (84%), then cardiovascular system (collapse, syncope, incontinence symptoms, drop in BP) in 72% cases and respiratory compromise (SOB, wheeze, stridor, fall in PEF, hypoxemia in 68%. Respiratory symptoms occur more often in children and cardiovascular in adults Acute onset of symptoms and/or signs (minutes to several hours)

Answer 721

Anaphylaxis: a severe potentially systemic hypersensitivity reaction. Rapid onset, life threatening airway, breathing and circulatory problems which is usually but not always associated with skin and mucosal changes Incidence: 1.5-8/100,000 persons years with studies from UK showing increase in hospital admissions over last 20 years Estimated prevalence based on European studies is 0.3% Skin (hives, itch, swollen lips, tongue, uvula) is most frequent organ involved (84%), then cardiovascular system (collapse, syncope, incontinence symptoms, drop in BP) in 72% cases and respiratory compromise (SOB, wheeze, stridor, fall in PEF, hypoxemia in 68%. Respiratory symptoms occur more often in children and cardiovascular in adults Acute onset of symptoms and/or signs (minutes to several hours)

Answer 722

Prevalence of anaphylaxis 0.3% of population More common in children aged 0-4 year than other age groups Food more common in children, drug and venom diagnosed more often in adult Idiopathic anaphylaxis seen in 20% cases: hidden causes include shrimp, wheat, and red meat

Answer 723

IgE IgG Complement Pharmacological IgE Food, insect venom, ticks, penicillin IgG Biologicals, Blood and IgG Transfusions Complement Lipid excipients, liposomes, dialysis membranes and PEG Pharmacological NSAID including aspirin, opiates, neuromuscular and quinolones drug

Answer 724

Serial measurement of serum tryptase (a highly specific marker for mast cell degranulation) Samples taken 1 hour, 3 hours and 24 hours post episode of anaphylaxis The rise in tryptase concentration is directly proportional to fall in BP Persistent rise in tryptase 24 hours after allergic reaction suggestive of systemic mast cell disease

Answer 725

α1 receptors: causes peripheral vasoconstriction, reverses low BP and mucosal oedema β1 receptor: increase heart rate and contractility and BP β2 receptor: relaxation bronchial sooth muscle and reduce release of inflammatory mediators

Answer 726

IM adrenaline into outer aspect of thigh and repeat if needed Adjust body position: sit up, supine, lie on side Oxygen 100% Fluid replacement Inhaled Bronchodilators Hydrocortisone 100mg IV ( prevent late phase response) Chlorpheniramine 10mg IV ( skin rash)

Answer 727

Epipen: preloaded adrenaline syringe Contains 300ug adrenaline for adult patients and 150ug adrenaline for children AND Prednisolone 20mg OD Antihistamine tablet Cetirizine 10mg OD Must call for ambulance and attend A&E after using emergency kit

Answer 728

CORRECT ANSWER | A: Intramuscular adrenaline

Answer 729

CORRECT ANSWER | E: ACE inhibitor induced angioedema

Answer 730

Avoidance Education about food labelling, interaction with restaurants, school Nutritional input for dietary balance, growth in children Acknowledge anxiety, potential bullying: mental health support if needed Emergency management Anaphylaxis guidelines Ensure allergic asthma is well controlled Prevention Breast feeding: strong family of allergy LEAP study: early rather than delayed introduction of peanut in high risk children (moderate/severe AD and egg allergy) significantly reduces development of peanut IgE sensitisation and allergy

Answer 731

An IgE mediated food allergy syndromes Limited to oral cavity, swelling and itch: only 1-2% cases progresses to anaphylaxis Sensitisation to inhalant pollen protein lead to cross reactive IgE to food Onset after pollen allergy established: affect adults > young children Respiratory exposure to pollen (birch) results in IgE directed to homologous proteins in stone fruits (apple, pear) vegetables (carrot) and nuts (peanut, hazelnut) Cooked fruits, vegetables and nut cause no symptoms: heat labile allergens detected by component allergen tests

Answer 732

CORRECT ANSWERB: Cross reactive IgE sensitisation between hay fever and apple allergens

Answer 733

Solid organs: Kidney, liver, lungs, heart, pancreas | BM stem cells

Answer 734

Kidney | Then Liver

Answer 735

Kidney | THEN Liver

Answer 736

``` Better surgical techniques Improved PT management: - Drugs - Infections Increased understanding of immunology: - Immunosuppressants - Prevention/Rx of rejection ```

Answer 737

Phase 1: recognition of foreign antigens Phase 2: activation of antigen-specific lymphocytes Phase 3: effector phase of graft rejection

Answer 738

1. ABO blood group | 2. HLA (human leukocyte antigens) coded on chromosome 6 by Major Histocompatibility complex (MHC)

Answer 739

Presentation of foreign antigens on HLA molecules to T cells is central to T cell activation

Answer 740

HLA ABC Expressed on all cells Highly polymorphic

Answer 741

HLA DR, DQ, DP Expressed on APCs - Can be upregulated on cells undergoing stress Highly polymorphic

Answer 742

HLA class I

Answer 743

HLA class II

Answer 744

50% or more

Answer 745

6MM - 25% 3MM - 50% 0MM - 25%

Answer 746

Anti-A or anti-B antibodies are naturally occurring | blood grouping

Answer 747

anti-HLA antibodies are not naturally occurring Pre-formed – previous exposure to epitopes (previous transplantation, pregnancy, transfusion) Post-formed - arise after transplantation

Answer 748

Neutralisation of microbes -> phago Opsonisation of microbes -> phago Antibody dependent cytotoxicity -> NK cells Complement activation: - Lysis - Complement mediated phagocytosis (C3b) - Inflammation (ie activate endothelial cells)

Answer 749

A + B (blood grouping)

Answer 750

Any combination

Answer 751

A. AB/HLA matching B. Screening for anti-HLA antibodies C. Immunosuppression: dampen the immune system of the recipient

Answer 752

Always balance the need for immunosuppression with the risk of infection/malignancy/drug toxicity

Answer 753

BM | Kidney

Answer 754

Heart | Lung

Answer 755

PCR-based DNA sequence analysis determines the individuals genotype

Answer 756

Before transplantation At time of transplantation: when a specific deceased donor kidney has been assigned to the patient After transplantation, repeat measurements to check for new antibody production

Answer 757

Cytotoxicity assays Flow cytometry Solid phase assays

Answer 758

Recipient serum exposed to donor lymphocytes in presence of complement. If donor lymphocytes are killed + antibody present -> negative cross match If donor lymphocytes are viable and no antibodies -> positive cross match

Answer 759

Serum incubated with donor lymphocytes FITC labelled anti-human IgG added Flow cytometry detects if antibody is present (and thus crossmatch)

Answer 760

Recombinant HLA molecules are attached to beads Recipient serum is added Bound antibodies are detected by adding flourescantly labelled human anti-IgG

Answer 761

Induction agent ex. OKT3/ATG, anti-CD52, anti-CD25 (anti-IL2R) Base-line immunosuppression: CNI inhibitor + MMF or Aza, with or without steroids Treatment of episodes of acute rejection: Cellular: steroids (MP IV 3x 60mg/kg then oral), ATG/OKT3 Antibody-mediated: IVIG, plasma exchange, anti-C5, anti-CD20

Answer 762

Allogeneic HSCT leads to reaction of donor lymphocytes against host tissues Related to degree of HLA-incompatibility

Answer 763

GVHD prophylaxis: Methotrexate/Cyclosporine

Answer 764

Corticosteroid

Answer 765

Skin: rash Gut: nausea, vomiting, abdominal pain, diarrheoa, bloody stool Liver: jaundice Treat with corticosteroids

Answer 766

``` Viral associated (x 100) Kaposi’s sarcoma (HHV8) Lymphoproliferative disease (EBV) Skin Cancer (x20) Risk of other cancers eg lung, colon also increased (x 2-3) ```

Answer 767

Following infection, residual pool of specific cells with enhanced capacity to respond if re-infection occurs

Answer 768

``` TH1 TH2 Treg TfH TH17 ```

Answer 769

IL12, IFN-y

Answer 770

IL6, TGF-b, IL23

Answer 771

IL1-b, IL6, TNFa | - AKA the acute phase cytokines (induce expansion)

Answer 772

IL2, IFNy, TNFa, IL10

Answer 773

IL17, IL21, IL22

Answer 774

IL10, FOXp3, CD25

Answer 775

IL4,5,9,13

Answer 776

Memory T cells are maintained for a long time without antigen by continual low-level proliferation in response to cytokines

Answer 777

These allow memory cells to access non-lymphoid tissues, the sites of microbial entry.

Answer 778

HA - haemaglutinin

Answer 779

RBC and virus are plated Antibody functions to protect binding of influenza to RBC Therefore no hemaglutiniation if antibodies Different dilutions of serum added

Answer 780

Inject 0.1 ml of 5 tuberculin units of liquid tuberculin intradermally. The tuberculin used in the Mantoux skin test is also known as purified protein derivative, or PPD. The patient's arm is examined 48 to 72 hours after the tuberculin is injected. The reaction is an area of induration (swelling that can be felt) around the site of the injection.

Answer 781

6 months Antibody protection begins within 7 days after immunization. Protection can last for approximately 6 months or longer in the general population.

Answer 782

Protection in the UK after BCG lasts about 10-15 years.

Answer 783

Examples: MMR BCG Yellow fever Typhoid (oral) Polio (Sabin oral) Vaccinia

Answer 784

Establishes infection – ideally mild symptoms Raises broad immune response to multiple antigens – more likely to protect against different strains Activates all phases of immune system. T cells, B cells – with local IgA, humoral IgG Often confer lifelong immunity after one dose

Answer 785

Storage problems Possible reversion to virulence (recombination, mutation). Vaccine associated paralytic poliomyelitis (VAPP, ca. 1: 750,000 recipients) Spread to contacts Spread to contacts of vaccinee who have not consented to be vaccinated Spread to immunosuppressed/immunodeficient patients

Answer 786

Influenza, Cholera, Bubonic plague, Polio (Salk), Hepatitis A, Pertussis, Rabies.

Answer 787

Diphtheria, Tetanus.

Answer 788

Hepatitis B (HbS antigen), HPV (capsid), Influenza (haemagglutinin, neuraminidase).

Answer 789

No mutation or reversion Can be used with immunodeficient patients Can lead to elimination of wild type virus from the community Storage easier Lower cost

Answer 790

Often do not follow normal route of infection Some components have poor immunogenicity May need multiple injections May require conjugate protein carrier or adjuvants to enhance immunogenicity

Answer 791

Polysaccharide plus protein carrier Polysaccharide alone induces a T cell independent B cell response – transient Addition of protein carrier promotes T cell immunity which enhances the B cell/antibody response

Answer 792

Haemophilus Influenzae B Meningococcus Pneumococcus

Answer 793

Adjuvant increases the immune response without altering its specificity Mimic action of PAMPs (pathogen associated molecular patterns) on TLR (toll-like receptors) and other PRR (pattern recognition receptors)

Answer 794

``` Aluminium salts (humans) Lipids – monophosphoryl lipid A (humans) Oils -Freund’s adjuvant (animals) ISCOMS CpG DNA ```

Answer 795

Immune stimulating complexes Cage-like structure composed of Quillaja saponins, cholesterol, phospholipids, and protein Mixed with antigen to provide multimeric presentation with built-in adjuvant Enhance cell mediated immune response Experimental ISCOMS – induce protective immunity to viruses, parasites, bacteria in several species

Answer 796

"CpG" stands for cytosine and guanine separated by a phosphate which links the two nucleotides together in DNA Stimulatory DNA; TCC ATG ACG TTC Adjuvant activity is linked to DNA motifs that are rich in CpG dinucleotides which should be unmethylated CpG motifs bind via pattern recognition receptors (TLR-9).

Answer 797

Mimics a virally infected cell | Stimulates T cell responses

Answer 798

Possible plasmid integration into host DNA | Possible response to DNA could lead to autoimmune diseases such as SLE

Answer 799

``` Prepared from pools of >1000 donors Contains preformed IgG antibody to a wide range of unspecified organisms Blood product: Donors screened for Hep B, Hep C and HIV Further treated to kill any live virus Administration IV or SC ```

Answer 800

Primary antibody deficiency X linked agammaglobulinaemia X linked hyper IgM syndrome Common variable immune deficiency ``` Secondary antibody deficiency Haematological malignancies Chronic lymphocytic leukaemia Multiple myeloma After bone marrow transplantation ```

Answer 801

Human immunoglobulin used for post-exposure prophylaxis (passive immunisation) Derived from plasma donors with high titres of IgG antibodies to specific pathogens Hepatitis B immunoglobulin Tetanus immunoglobulin Rabies immunoglobulin Varicella Zoster immunoglobulin

Answer 802

Immunosuppression results in failure to control infection with persistent viruses – CMV, EBV Patients develop CMV pneumonitis, retinitis….. Patients develop EBV related B cell lymphoproliferative disease

Answer 803

Virus-specific T cells Autologous T cells expanded in vitro and then re-infused Donor (HLA matched) T cells expanded in vitro and then infused ‘Banks’ of HLA matched, virus specific T cells being developed

Answer 804

Interferon alpha: Hepatitis C, Hepatitis B, Kaposi’s sarcoma Hairy cell leukaemia, chronic myeloid leukaemia, multiple myeloma

Answer 805

Interferon beta: Behcet’s Relapsing multiple sclerosis (past)

Answer 806

Interferon gamma: | Chronic granulomatous disease

Answer 807

PD-1 Action Antibody binds to PD-1 Blocks immune checkpoint Allows T cell activation Indications and dosing Advanced melanoma

Answer 808

Action Antibody binds to CTLA4 Blocks immune checkpoint Allows T cell activation Indications - Advanced melanoma

Answer 809

Corticosteroids inhibit phospholipase A2 | - Blocks arachidonic acid and prostaglandin formation and so reduces inflammation

Answer 810

Decreased traffic of phagocytes to inflamed tissue Decreased expression of adhesion molecules on endothelium Blocks the signals that tell immune cells to move from bloodstream and into tissues Results in transient increase in neutrophil counts Decreased phagocytosis Decreased release of proteolytic enzymes

Answer 811

Lymphopenia Sequestration of lymphocytes in lymphoid tissue Affects CD4+ T cells > CD8+ T cells > B cells Blocks cytokine gene expression Decreased antibody production Promotes apoptosis

Answer 812

Diabetes, central obesity, moon face, lipid abnormalities, osteoporosis, hirsuitism, adrenal suppression Cataracts, glaucoma, peptic ulceration, pancreatitis, avascular necrosis

Answer 813

Cytotoxic agents Inhibit DNA synthesis Cells with rapid turnover most sensitive

Answer 814

Cyclophosphamide Mycophenolate Azathioprine

Answer 815

Bone marrow suppression Infection Malignancy Teratogenic

Answer 816

Mechanism of action – Alkylating agent Alkylates guanine base of DNA Damages DNA and prevents cell replication Affects B cells > T cells, but at high doses affects all cells with high turnover

Answer 817

Multisystem connective tissue disease or vasculitis with severe end-organ involvement eg GPA (Wegener’s granulomatosis), SLE Anti-cancer agent

Answer 818

``` Toxic to proliferating cells Bone marrow depression Hair loss Sterility (male>>female) Haemorrhagic cystitis Toxic metabolite acrolein excreted via urine Malignancy Bladder cancer Haematological malignancies Non-melanoma skin cancer Infection Pneumocystis jiroveci ```

Answer 819

Mechanism of action – Anti-metabolite - purine Metabolised by liver to 6 mercaptopurine Purine analogue Interferes with DNA production – inhibits proliferating cells Affects T cells>B cells

Answer 820

Transplantation Auto-immune disease Auto-inflammatory diseases, eg Crohn’s, ulcerative colitis

Answer 821

Bone marrow suppression Cells with rapid turnover (leucocytes and platelets) are particularly sensitive 1:300 individuals are extremely susceptible to bone marrow suppression s Thiopurine methyltransferase (TPMT) polymorphisms Unable to metabolise azathioprine Check TPMT activity or gene variants before treatment if possible; always check full blood count after starting therapy Hepatotoxicity - Idiosyncratic and uncommon Infection - Serious infection less common than with cyclophosphamide

Answer 822

Mechanism of action – Anti-metabolite - purine Blocks de novo guanosine nucleotide synthesis – prevents replication of DNA Prevents T>B cell proliferation

Answer 823

Widely used in transplantation as alternative to azathioprine Also used in auto-immune diseases and vasculitis as alternative to cyclophosphamide

Answer 824

Widely used in transplantation as alternative to azathioprine Also used in auto-immune diseases and vasculitis as alternative to cyclophosphamide

Answer 825

Aim: removal of pathogenic antibody Patient’s blood passed through cell separator Own cellular constituents reinfused Plasma treated to remove immunoglobulins and then reinfused (or replaced with albumin in ‘plasma exchange’)

Answer 826

Rebound antibody production limits efficacy, therefore usually given with anti-proliferative agent

Answer 827

Many indications are type II hypersensitivity reactions –the antibody itself is directly pathogenic Goodpastures syndrome Anti-glomerular basement membrane antibodies Severe acute myasthenia gravis Anti-acetyl choline receptor antibodies Severe vascular rejection Antibodies directed at donor HLA molecules

Answer 828

Ciclosporin Tacrolimus - Prevent activation of T cells by preventing calcinurin activation and blocking cytokine transcription

Answer 829

``` Nephrotoxicity Hypertension Neurotoxic Diabetogenic Dysmorphic features ```

Answer 830

Nephrotoxicity Hypertension Neurotoxic Diabetogenic

Answer 831

Inhibition of PDE4 leads to increase in cAMP Influences gene transcription via protein kinase A pathway Modulates cytokine production Effective in psoriasis and psoriatic arthritis

Answer 832

An infusion of horse or rabbit-derived antibodies against human T cells, which is used in the prevention and treatment of acute rejection in organ transplantation and therapy of aplastic anemia. ``` Contains Specificities include CD2 CD3 CD4 CD8 CD28 CD11a HLA class I and II ```

Answer 833

Action Lymphocyte depletion Modulation of T cell activation Modulation of T cell migration

Answer 834

Infusion reactions Leukopenia Infection Malignancy

Answer 835

CD25 Indications and dosing Prophylaxis of allograft rejection Intravenous given before and after transplant surgery Action Inhibits T cell proliferation

Answer 836

Indications and dosing Prophylaxis of allograft rejection Intravenous given before and after transplant surgery

Answer 837

Abatacept Reduces T cell activation by APC

Answer 838

RHA IV 4w SC 1w

Answer 839

Rituximab Depletes mature B cells Infusion reactions Infection (PML) Exacerbation CV disease

Answer 840

Lymphoma Rheumatoid arthritis SLE - 2 doses intravenous every 6-12 months (RA) Depletes mature B cells Infusion reactions Infection (PML) Exacerbation CV disease

Answer 841

Natalizumab

Answer 842

a4 expressed with b1 or b7 integrin Bind to VCAM1 and MadCAM1 to mediate rolling/arrest of leukocytes Bind to non-endothelial VCAM1 in lymphoid tissue Inhibits T cell migration Infusion reactions Infection (PML) Hepatotoxic Concern re malignancy

Answer 843

Tocilizumab ``` SE Infusion reactions Infection Hepatotoxic Elevated lipids - Caution wrt malignancy ```

Answer 844

Antibody directed at IL-6 receptor ``` SE Infusion reactions Infection Hepatotoxic Elevated lipids - Caution wrt malignancy ```

Answer 845

Reduces macrophage, T cell, B cell, neutrophil activation ``` SE Infusion reactions Infection Hepatotoxic Elevated lipids - Caution wrt malignancy ```

Answer 846

Castleman’s disease Rheumatoid arthritis Intravenous every 4 weeks ``` SE Infusion reactions Infection Hepatotoxic Elevated lipids - Caution wrt malignancy ```

Answer 847

Etanercept – TNF receptor

Answer 848

``` Infusion or injection site reactions Infection (TB, HBV, HCV) Lupus-like conditions Demyelination Malignancy ```

Answer 849

Indications and dosing - Rheumatoid arthritis - Ankylosing spondylitis - Psoriasis and psoriatic arthritis - Inflammatory bowel disease - Subcutaneous or intravenous

Answer 850

Ustekinumab Toxicity Injection site reactions - Infection (TB) - Concern re malignancy

Answer 851

Antibody to p40 subunit of IL-12 and IL-23 Toxicity Injection site reactions - Infection (TB) - Concern re malignancy

Answer 852

Indications and dosing Psoriasis, psoriatic arthritis Crohns disease Subcutaneous every 12 weeks

Answer 853

Toxicity Injection site reactions - Infection (TB) - Concern re malignancy

Answer 854

Secukinumab

Answer 855

Antibody to IL17 A

Answer 856

Indications and dosing Psoriasis and psoriatic arthritis Ankylosing spondylitis SC load and then monthly

Answer 857

Infection - TB risk

Answer 858

Denosumab Inhibits RANK mediated osteoclast differentiation and function Toxicity Injection site reactions Infection – mildly immunosuppressive - Avascular necrosis of jaw

Answer 859

Antibody directed at RANK ligand Inhibits RANK mediated osteoclast differentiation and function Toxicity Injection site reactions Infection – mildly immunosuppressive - Avascular necrosis of jaw

Answer 860

Osteoporosis: SC 6monthly Inhibits RANK mediated osteoclast differentiation and function Toxicity Injection site reactions Infection – mildly immunosuppressive - Avascular necrosis of jaw

Answer 861

Toxicity Injection site reactions Infection – mildly immunosuppressive - Avascular necrosis of jaw

Answer 862

Infusion reactions

Answer 863

Urticaria, hypotension, tachycardia, wheeze – IgE mediated Headaches, fevers, myalgias – not classical type I hypersensitivity Cytokine storm

Answer 864

Peak reaction at ~48 hours May also occur at previous injection sites (recall reactions) Mixed cellular infiltrates, often with CD8 T cells Not generally IgE or immune complexes

Answer 865

Tuberculosis - History, Residence, Travel, Contacts, CXR, TB Elispot - Prophylaxis or treatment if required HBV and HCV Check Hep B core antibody pre-treatment Check Hep C antibody pre-treatment Further investigate for active virus infection if serology is positive HIV - Check HIV serology pre-treatment - Balance benefits against possible risks John Cunningham Virus (JCV) Common polyomavirus that can reactivate - Infects and destroys oligodendrocytes - Progressive multifocal leukoencephalopathy

Answer 866

Malignancy Lymphoma (EBV) Non melanoma skin cancers (Human papilloma virus) Melanoma (increased in cohort treated with anti-TNF alpha) - Risks appear lower with targeted forms of immunosuppression than with regimes used in transplantation

Answer 867

Reverse transcriptase

Answer 868

TH cells - CD4+ Induces a selective loss of CD4+ T helper cells.

Answer 869

Diploid + ssRNA genome

Answer 870

``` 9 genes (e.g. env, gag, pol) (tat, rev, nef) (vif, vpr, vpu) encoding: 15 Structural, Regulatory & Auxiliary Proteins. Proteins e.g. gp120 & gp41; p17,p24,p9,p7; RT, IN, PR. ```

Answer 871

CD4 molecule/Ag

Answer 872

CCR5 and CXCR4

Answer 873

Sexually. The virus enters through mucosal surfaces. Increased by factors which damage such surfaces. Infects CD4+ cells, but also DC in the mucosa may bind to and carry the virus from the site of infection to the LNs where other immune cells become infected. Infected blood - transfusion, sharing needles, blood products. Mother to child before or during birth or via breast milk.

Answer 874

Anti-gp120 and anti-gp41 (Nt) antibodies are thought to be important in protective immunity. Non-neutralising anti-p24 gag IgG also produced.

Answer 875

F | HIV remains infectious even when coated with antibodies.

Answer 876

CD8+ T cells White blood cells that kill cells infected with HIV or other viruses, or transformed by cancer (CTL). Also able to suppress viral replication. Secrete soluble molecules (cytokines and chemokines such as MIP-1a, MIP-1b, and RANTES) which are able to prevent infection by blocking entry of virus into CD4+ T cells. Recognise processed antigen - (peptides) - in the context of class I HLA molecules.

Answer 877

Interferes with: Activated infected CD4+ helper T cells die and are lost Infected CD4+ T cells are also disabled (ANERGISED) by the virus MO/DC are not activated by the CD4+ T cells and can not prime naïve CD8+ CTL CD8+ T cell and B cell responses are diminished without help CD4+ T cell memory is lost Infected MO/DC are killed by virus or CTL Defect in antigen presentation Failure to activate memory CTL

Answer 878

High error rates of: i) RT & ii) RNA polymerase II. Reverse Transcriptase lacks the proof reading mechanisms associated with cellular DNA polymerases and therefore genomes of retroviruses are copied into DNA with low fidelity. Transcription of DNA into RNA copies is also of low fidelity.

Answer 879

1. Attachment/Entry 2. Reverse Transcription & DNA Synthesis 3. Integration 4. Viral Transcription 5. Viral Protein Synthesis 6. Assembly of Virus & Release of Virus 7. Maturation

Answer 880

Attachment inhibitors | Fusion inhibitors

Answer 881

Reverse-transcriptase inhibitors

Answer 882

Integrase inhibitors

Answer 883

Protease inhibitors

Answer 884

10% | 3 Years

Answer 885

Slow progressor HLA profile Heterozygosity for 32-bp deletion in chemokine receptor CCR5 Mannose binding lectin alleles Tumor necrosis factor c2 microsatellite alleles Gc vitamin D-binding factor alleles

Answer 886

Effective CTL & HTL responses Secretion of CD8 antiviral factor Secretion of chemokines that block HIV entry co-receptors CCR5 (e.g., MIP-1a, MIP-1b, and RANTES) and CXCR4 (e.g., SDF-1) Secretion of IL-16 Effective humoral immune response Maintenance of functional lymphoid tissue architecture

Answer 887

Infection with attenuated strains of HIV

Answer 888

anti-HIV antibodies (ELISA) or by the presence of the virus itself (viral load) using polymerase chain reaction (PCR) which detects viral RNA.

Answer 889

The initial baseline plasma viral load (that is when the patient is first monitored for virus number) is a good predictor of the time it will take for disease to appear.

Answer 890

The course of HIV-1 disease in the patient is also followed by monitoring CD4+ T cell levels (Flow cytometry). The onset of AIDS correlates with the diminution of the number of CD4+ T cells.

Answer 891

Phenotypic: Viral replication is measured in cell cultures under selective pressure of increasing concentrations of antiretroviral drugs – compared to wild-type Genotypic: Mutations determined by direct sequencing of the amplified HIV genome (so far limited to sequencing of RT and P)

Answer 892

2 BACKBONES + 1 BINDING AGENTS Backbone = integrase inhibitors Binding agents = attachment inhibitors and fusion inhibitors

Answer 893

Effective HAART does not eradicate latent HIV-1 in the host Fails to restore HIV-specific T-cell responses Is dogged by the threat of drug resistance Significant Toxicities High pill burden Adherence problems Quality of life issues Cost (>40%)

Answer 894

Excessive production of thyroid hormones Mediated by IgG antibodies which stimulate the TSH receptor Evidence Antibodies stimulate thyrocytes in vitro Passive transfer of IgG from patients to rats often produces similar symptoms (!) Babies born to mothers with Graves' may show transient hyperthyroidism

Answer 895

Type 2 [antibody mediated]

Answer 896

Hypothyroidism | [Hashimotos - most common in iodine replete areas]

Answer 897

Associated with anti-thyroid peroxidase antibodies Presence correlates with thyroid damage and lymphocyte inflammation Some shown to induce damage to thyrocytes Associated with presence

Answer 898

Type II + IV

Answer 899

Few indications: Many women >65 have them with NO hypothyroidism Some have subclinical hypothyroidism Small proportion of postmenopausal women with anti-thyroid antibodies have overt hypothyroidism

Answer 900

Insulin dependent diabetes mellitus

Answer 901

``` Auto-antigens Glutamic acid dehydrogenase (GAD 65) Islet antigen 2 (IA2) Anti-insulin anti-islet cell antibodies ``` CD8+ T-cell infiltration of pancreas T cell clones have specificity for islet antigens Therefore type 4

Answer 902

Anti-islet cell antibodies Anti-insulin antibodies Anti-GAD antibodies Anti-IA-2 antibodies Individuals with 3-4 of the above are highly likely to develop type I diabetes Detection of antibodies does not currently play a role in diagnosis

Answer 903

Pernicious anaemia

Answer 904

anti-Intrinsic factor | Antibodies to gastric parietal cells

Answer 905

Myaesthenia Gravis Antibodies against ACh receptor

Answer 906

Anti ACh receptor

Answer 907

Myaesthenia gravis

Answer 908

Goodpastures

Answer 909

RhA Peptidylarginine deiminases PAD type 2 and 4 Enzymes involved in deimination of arginine to create citrulline. Polymorphisms are associated with increased citrullination - This creates a high load of citrullinated proteins

Answer 910

Smoking associated with development of erosive disease Smoking associated with increased citrullination Gum infection with Porphyromonas gingivalis associated with rheumatoid arthritis P gingivalis is only bacterium known to express PAD enzyme and thus promote citrullination

Answer 911

Antibodies to cyclic citrullinated peptide Bind to peptides in which arginine has been converted to citrulline by peptidylarginine deiminase (PAD)

Answer 912

A rheumatoid factor is an antibody directed against the common (Fc) region of human IgG IgM anti-IgG antibody is most commonly tested although IgA and IgG rheumatoid factors may also be present in some individuals

Answer 913

Type II response Antibody binding to citrullinated proteins may lead to: Activation of complement Activation of macrophages via Fc R and complement receptors NK cell activation with ADCC + Type III response Immune complex formation (RF and anti-CCP) and deposition with complement activation +Type IV

Answer 914

Inflamed synovial tissue forms a ‘pannus’ overlaying and invading articular cartillage and adjacent bone tissues.

Answer 915

Abnormalities in clearance of apoptotic cells = Polymyorphisms in genes encoding complement, MBL, CRP Abnormalities in cellular activation = Polymorphisms in genes encoding/controlling expression of cytokines, chemokines, co-stimulatory molecules, intracellular signalling molecules B cell hyperactivity and loss of tolerance Antibodies directed particularly at intracellular proteins ? Debris from apoptotic cells that have not been cleared Nuclear antigens - DNA, histones, snRNP Cytoplasmic antigens - Ribosome, scRNP

Answer 916

Type III Antibodies bind to antigen to form immune complexes Immune complexes deposit in tissues Skin, joints, kidney Immune complexes activate complement (classical pathway) Immune complexes stimulate cells expressing Fc and complement receptors

Answer 917

Measured by titre (the minimal dilution at which the antibody can be detected) or by concentration in standardised units Therefore 1:640

Answer 918

ANA DsDNA Anti-Ro/La/Sm/RNP Anti-cardiolipin antibody Lupus anti-coagulant

Answer 919

SLE | Sjogrens

Answer 920

Both normal in inactive disease Active disease = Normal C3, Low C4 Severe disease = Low C3+4

Answer 921

Anti-cardiolipin

Answer 922

Lupus anti-coagulant

Answer 923

Anti-cardiolipin antibody immunoglobulins directed against phospholipids, and β2 glycoprotein-1 Lupus anti-coagulant Prolongation of phospholipid-dependent coagulation tests cannot be assessed if the patient is on anticoagulant therapy Note that 40% of patients have discordant antibodies If there is a clinical suspicion of the antiphospholipid syndrome, both tests should be performed.

Answer 924

Systemic sclerosis

Answer 925

Inflammation with Th17 and Th2 cells dominating Cytokines lead to activation of fibroblasts and development of fibrosis Polymorphisms within type I collagen alpha 2 chains and fibrillin 1 may be important Polymorphisms in TGF-b have also been described Cytokines lead to activation of endothelial cells and contribute to microvascular disease Loss of B cell tolerance to nuclear antigens

Answer 926

Limited Cutaneous Systemic Sclerosis (CREST) Skin involvement does not progress beyond forearms (although it may involve peri-oral skin) ``` Calcinosis Raynauds Oesophageal dysmotility Sclerodactyly Telangectasia ``` Primary pulmonary hypertension

Answer 927

Diffuse Cutaneous Systemic Sclerosis Skin involvement does progress beyond forearms - CREST features - More extensive gastrointestinal disease - Interstitial pulmonary disease - Scleroderma kidney / renal crisis

Answer 928

Anti-centromere antibodies

Answer 929

Anti-topoisomerase antibodies (Scl70)

Answer 930

Idiopathic inflammatory myopathy: Dermatomyositis Within muscle – perivascular CD4 T cells and B cells Immune complex mediated vasculitis – Type III response Polymositis Within muscle – CD8 T cells surround HLA Class I expressing myofibres CD8 T cells kill myofibres via perforin / granzymes – Type IV response

Answer 931

Dermatomyositis

Answer 932

Polymositis

Answer 933

Positive ANA (in some patients) Anti-aminoacyl transfer RNA synthetase antibody eg Jo-1 (cytoplasmic) (DM) Anti-signal recognition peptide antibody (nuclear and cytoplasmic) (PM) Anti-Mi2 (nuclear) (DM>PM)

Answer 934

polymyositis

Answer 935

Vasculitis

Answer 936

Microscopic polyangiitis / Microscopic polyarteritis / MPA Granulomatosis with polyangiitis / Wegener’s granulomatosis / GPA Eosinophilic granulomatosis with polyangiitis / Churg-Strauss syndrome / eGPA

Answer 937

Anti-neutrophil cytoplasmic antibody

Answer 938

ANCA: Anti-neutrophil cytoplasmic antibodies

Answer 939

Anaphylaxis | Definition: “A systemic hypersensitivity reaction in which the response is so overwhelming as to be life-threatening”

Answer 940

Mechanism: Type I hypersensitivity response Cross-linking of IgE on surface of mast cells Causes mast cells to degranulate Results in release of specific biological mediators including histamine and leukotrienes Increase in vascular permeability Smooth muscle contraction Inflammation, increased mucus production

Answer 941

``` Flushing Urticaria Wheeze, bronchoconstriction Itch of palms, soles of feet and genitalia Vomiting Diarrhoea Abdominal pain Hypotension Cardiac arrhythmias Myocardial infarct Laryngeal obstruction, Stridor Angioedema of lips and mucous membranes feeling of impending doom, loss of conciousness, death Conjunctival injection, rhinorrhea, angioedema ``` __________________ Percentages of symptoms: ``` Urticaria and angioedema 88 Upper airway oedema 56 Breathlessness and wheezing 47 Flushing 46 Dizziness, syncope, and hypotension 33 Gastrointestinal symptoms 30 Rhinitis 16 Headache 15 Substernal pain 6 Itch without rash 4.5 Seizure 1.5 ```

Answer 942

Percentages of symptoms: ``` Urticaria and angioedema 88 Upper airway oedema 56 Breathlessness and wheezing 47 Flushing 46 Dizziness, syncope, and hypotension 33 Gastrointestinal symptoms 30 Rhinitis 16 Headache 15 Substernal pain 6 Itch without rash 4.5 Seizure 1.5 ```

Answer 943

Causes of collapse ``` Anaphylaxis Myocardial infarction Cardiac arrythmia Acute asthmatic attack Pulmonary embolus Vasovagal attack Epilepsy ```

Answer 944

May require respiratory support Intubation may be required for severe bronchoconstriction Tracheostomy if develops upper respiratory tract obstruction (eg laryngeal swelling, or severe swelling of tongue) Oxygen by mask Improve oxygen delivery Adrenalin im (0.5mg for adult and may repeat) Acts on B2 adrenergic receptors to constrict arterial smooth muscle Increases blood pressure Llmits vascular leakage Bronchodilator Intravenous anti-histamines (10mg Chlorpheniramine) Acts to oppose the effects of mast-cell derived histamine Nebulised bronchodilators Improve oxygen delivery through bronchial dilatation Intravenous corticosteroids (Hydrocortisone 200mgs) Systemic anti-inflammatory agent. Effect takes about 30minutes to start, and does not peak for several hours. Important in preventing rebound anaphylaxis Intravenous fluids Increase circulating blood volume and therefore increase blood pressure

Answer 945

IgE mediated mast cell degranulation ``` Foods Peanuts Tree nuts Fish and shellfish Milk Eggs Soy products Insect stings Bee venom Wasp venom Chemicals, drugs and other foreign proteins Penicillin and other antibiotics Intravenous anaesthetic agents, eg suxamethonium, propofol Latex ```

Answer 946

What was he doing immediately prior to the onset of symptoms? As his first symptom was lip swelling, specifically ask what had his lips been in contact with, & what he had eaten. Does he have any known allergies? Has anything like this happened before? How is his general health?

Answer 947

Latex | = milky fluid produced by rubber trees (Hevea brasiliensis)

Answer 948

Type I hypersensitivity Acute onset of classical allergic symptoms after exposure e.g. wheeze, urticaria, angioedema, anaphylaxis. Spectrum of severity Mucosal route is associated with more severe reactions Different rubber products vary significantly in their allergenic content Type IV hypersensitivity Contact dermatitis Usually affect hands (glove usage) or feet (due to rubber in footwear) Mainly due to rubber additives eg thiuram rather than latex itself

Answer 949

Whereby individuals with type 1 hypersensitivity to latex cross react with any or all of the following: ``` Avocado Apricot Banana Chestnut Kiwi Passion fruit Papaya Pear Pineapple ```

Answer 950

In vitro tests for specific IgE to latex History of anaphylaxis - therefore blood tests are preferable to skin tests because of the small but significant risk of inducing anaphylaxis But poor sensitivity (70-80%) and specificity (60-80%) Blanket testing to other allergens which have not been implicated will not aid diagnosis It is POSSIBLE to do skin tests: Skin prick testing Commercial latex extracts at a range of concentrations Some non-standard tests are available for use in specialised centres individualised skin test with particular glove/other products used by patient

Answer 951

Patch tests Moisten blotting paper with suspected allergen Tape to area of healthy skin for 24-48 hours Eczema will be seen where the substance is in contact with skin Biopsy Infiltrating T lymphocytes Granuloma

Answer 952

All patients with anaphylaxis should be referred to an allergist/immunologist Given occupational implications, a plan of avoidance should be made in conjunction with occupational physician Medic-Alert bracelet Self injectable adrenalin e.g. EpiPen Alert health professionals prior to any procedure, especially dentists! Written plan for surgical or dental procedures Latex-free equipment Patient should be first on the list to reduce risk of latex exposure Peri-operative antihistamines and corticosteroids may be considered Avoidance of cross reactive foods May need assistance of specialist dietician Major occupational health issue

Answer 953

No, desensitisation only works for insect venom and some aero-allergens (eg grass pollen).

Answer 954

Immunological: - Complement deficiency Recurrent infection with encapsulated organisms Neisseria meningitidis, Neisseria gonorrhoeae, Haemophilus influenzae type B, Pneumococcus - Antibody deficiency Recurrent bacteria infections, especially of upper and lower respiratory tract Neurological: Any disruption of blood brain barrier Occult skull fracture Hydrocephalus

Answer 955

``` Hx of infections: SPUR Serious Persistent Unusual Recurrent ``` PMH: Specifically ask about neurological disease and head injury General health: Energy, weight loss, sleep, work status FHx: Consanguinuity History of meningitis

Answer 956

Complement C3 and C4 CH50 AP50 Immunoglobulins Serum IgG, IgA and IgM Protein electrophoresis

Answer 957

Meningovax, Pneumovax and HIB vaccines Daily prophylactic penicillin High level of suspicion Any deficiency of the complement pathway may be associated with recurrent meningococcal infection Particularly alternative pathway and final common pathway deficiencies Generally suggested that adults with sporadic meningococcal disease should be screened for complement deficiency CH50 and AP50

Answer 958

Functional test of integrity of the classical complement cascade All components of the cascade need to be in place for the test to give a positive (normal) result

Answer 959

Functional test of integrity of the alternative complement cascade All components of the cascade need to be in place for the test to give a positive (normal) result

Answer 960

If a patient is ANA+ then the following must be assessed (all ANAs): dsDNA - SLE ENAs: Ro,La,SM,RNP - SLE, sjogrens SCL70, RNApol, Fibrillarin - diffuse cutaneous sclero Mi2, SRP - myositis Cytoplasmic: Jo1, SRP - myositis Mitchondria - PBC Anticentromere - lim cut sclerosis c3 testing c4 testing

Answer 961

NO: Remember the following is possible: Urinalysis: Proteinuria Microscopic haematuria Urine microscopy: Red cells Red cell casts Renal biopsy: Diffuse proliferative nephritis Immune complex and complement deposition

Answer 962

Prednisolone Yes Widely used immunosuppressant Pegylated IFN alpha No Effective in some inflammatory diseases eg Behcet’s Azathioprine Yes Widely used anti-proliferative immunosuppresant Check TPMT status before use Hydroxychloroquine Yes Alters pH and affects antigen presentation / processing. Inhibits production of some cytokines. Upregulates apoptosis / clearance. Allopurinol No Xanthine oxidase inhibitor used in gout Rituximab Yes Antibody to CD20 that depletes B cells ``` IVIG Yes Effective immunosuppressive agent Precise mechanisms unclear Used in SLE, DMy, Pemphigus….. ``` Mycophenolate Mofetil Yes Anti-proliferative immunosuppressant with preferential effect on lymphocytes Adalimumab No Anti-TNF alpha antibody. May precipitate cutaneous lupus Cyclophosphamide Yes Cytotoxic immunosuppressant Colchicine No Inhibits neutrophils – used in gout, Behcets

Answer 963

Diagnosis Community acquired pneumonia Treatment Intravenous penicillin

Answer 964

Serum sickness T3 hypersensitivity Mechanism Penicillin can bind to cell surface proteins Acts as “neo-antigen”: stimulates very strong IgG antibody response Individual is “sensitised” to penicillin Complement activation Immune complex deposition in small vessels - ie glomerulus Infiltration of macrophages and neutrophils Deposition of IgG immune complexes in glomeruli causes renal dysfuntion Immune complex deposition in joints causes arthralgia Immune complex deposition in skin causes vasculitis with local haemorrhage = purpuric

Answer 965

Low serum C3 and C4: Indicative of classical complement pathway activation (Immune complex measurements unreliable) Specific IgG to penicillin: Can be performed if specifically indicated, but takes time Characteristic biopsy features (skin, kidney): Infiltration of macrophages and neutrophils Deposition of IgG, IgM and complement

Answer 966

Why did his renal function deteriorate? Deposition of immune complexes causes local complement activation and neutrophil and macrophage infiltration Results in inflammation of the glomeruli Results in increase in serum creatinine, proteinuria and haematuria Why did he become disorientated? Small vessel vasculitis affecting cerebral vessels may compromise oxygen supply to the brain Why did he develop purpura? Inflamed blood vessels are likely to leak results in local haemorrhage Also become plugged with clots, further compromising oxygen delivery.

Answer 967

Discontinue penicillin immediately Decrease systemic inflammation Corticosteroids Ensure appropriate fluid balance

Answer 968

Immunodeficiency

Answer 969

Immunodeficiency

Answer 970

``` X-linked agammaglobulinaemia Failure of pre-B cells to mature in bone marrow Failure to produce any immunoglobulin Management Immunoglobulin replacement therapy Pooled serum immunoglobulin Administered every 3 weeks Indefinite treatment ```

Answer 971

``` X ray pelvis Fracture of neck of femur, through area of decreased bone density FBC HB 75 g/l: normocytic, normochromic normal wcc and platelet count ESR 100 CRP <6 (Normal range <6 mg/l) LFTs Normal ```

Answer 972

Multiple myeloma Osteoporosis and Sjogren’s syndrome Osteoporosis and SLE

Answer 973

Multiple myeloma Definition: neoplastic proliferation of plasma cells Results in massive expansion of single plasma cell clone Production of excess amounts of a single immunoglobulin molecule with single specificity (usually both heavy chain and light chain) Increased numbers of abnormal plasma cells in bone marrow Lytic lesions of bone

Answer 974

Multiple myeloma Definition: neoplastic proliferation of plasma cells Results in massive expansion of single plasma cell clone Production of excess amounts of a single immunoglobulin molecule with single specificity (usually both heavy chain and light chain) Increased numbers of abnormal plasma cells in bone marrow Lytic lesions of bone

Answer 975

Suppression of production of normal immunoglobulin by the malignant clone results in functional antibody deficiency Sometimes known as “immune paresis” majority is the single (useless) malignant clone

Answer 976

Anaemia is found in majority of patients with multiple myeloma Mechanism: Space limitation Expansion of malignant clone crowds out normal red cell and white cell precursors in bone marrow Inhibitors Tumour may produce local cytokines which inhibit normal bone marrow function

Answer 977

ESR: measures the rate of fall of erythrocytes through plasma Normally, erythrocytes do not clump Repellent negative surface charge > attractant charge of plasma constituents However, if protein constituents of plasma increase or change Increases attractant charge Causes erythrocytes to clump together Clumped erythrocytes fall more quickly through plasma higher ESR AKA why you see rouleaux in MM

Answer 978

ESR: measures the rate of fall of erythrocytes through plasma Normally, erythrocytes do not clump Repellent negative surface charge > attractant charge of plasma constituents However, if protein constituents of plasma increase or change Increases attractant charge Causes erythrocytes to clump together Clumped erythrocytes fall more quickly through plasma higher ESR AKA why you see rouleaux in MM

Answer 979

Rheumatoid arthritis

Answer 980

Rheumatoid arthritis

Answer 981

Rheumatoid factor

Answer 982

HLA DR - HLA DR4 present in 60-70% patients cf 20-35% controls (caucasian) - only specific DR4 subtypes, ie Dw4, Dw14, Dw15, are RA associated - HLA DR1 also predisposes to RA - Predisposing HLA class II molecules share common sequence at positions 70-74, an area predicted to lie within the alpha helix forming the wall of the peptide-binding groove - ? Peptide presentation by disease associated HLA class II molecules may be involved in disease pathogenesis PADI type 2 and 4 - Peptidylarginine deiminase polymorphisms increase citrullination of proteins - Suggests increased load of citrullinated proteins may increase likelihood of developing rheumatoid arthritis. Note the loss of B cell tolerance to citrullinated proteins in patients who develop rheumatoid arthritis PTPN 22 - Protein tyrosine phosphatase non-receptor 22 is a lymphocyte specific tyrosine phosphatase which suppresses T cell activation.1858T allele increases susceptibility to rheumatoid arthritis, SLE, type 1 diabetes - Suggests T cell activation is involved in pathogenesis of rheumatoid arthritis

Answer 983

First line treatment - Disease modifying drugs to include methotrexate. - Sulphasalazine, hydroxychloroquine, leflunomide also frequently used in addition or if methotrexate not tolerated. Further treatment - TNFalpha antagonist. Inhibits downstream events in inflammation. - Rituximab. Antibody specific for CD20. Depletes B cells (not plasma cells). - Abatacept. CTLA-4 – Ig fusion protein. Binds to ligands of CD28 (CD80 and CD86) and thereby inhibits T cell activation. - Tocilizumab. Antibody specific for IL-6 receptor – widespread effects

Answer 984

Before subjecting a patient to immunosuppression ensure you have balanced the benefits vs the risks Consider risk of infection especially prior to use of ‘biologic’ agents - Screen for exposure to TB using CXR and TB ELISPOT - Screen for exposure to Hepatitis B - Screen for exposure to Hepatitis C - Consider possibility of HIV infection - Prior history of septic arthritis/infected joint prosthesis - Educate patient to stop drug and seek advice if acute infection - Consider need for vaccinations Consider risk of malignancy - Prior history of malignancy - Advise re sun exposure/skin protection

Answer 985

Before subjecting a patient to immunosuppression ensure you have balanced the benefits vs the risks Consider risk of infection especially prior to use of ‘biologic’ agents - Screen for exposure to TB using CXR and TB ELISPOT - Screen for exposure to Hepatitis B - Screen for exposure to Hepatitis C - Consider possibility of HIV infection - Prior history of septic arthritis/infected joint prosthesis - Educate patient to stop drug and seek advice if acute infection - Consider need for vaccinations Consider risk of malignancy - Prior history of malignancy - Advise re sun exposure/skin protection

Answer 986

portal vein | hepatic artery

Answer 987

Stellate cells

Answer 988

1. whole liver involved 2. fibrosis 3. nodules of regenerating hepatocytes 4. distortion of liver vascular architecture: intra- and extra- hepatic (e.g. gastro-oesophageal) shunting of blood

Answer 989

Histological definition of cirrhosis

Answer 990

Intra/extra hepatic

Answer 991

a) according to nodule size: micronodular or macronodular b) according to aetiology: 1) alcohol / insulin resistance 2) viral hepatitis etc.

Answer 992

nodules of regenerating hepatocytes

Answer 993

1. Portal hypertension 2. Hepatic encephalopathy 3. Liver cell cancer

Answer 994

1. viruses | 2. drugs

Answer 995

Acute hepatitis

Answer 996

1. viral hepatitis 2. drugs 3. auto-immune

Answer 997

severity of inflammation

Answer 998

severity of fibrosis

Answer 999

Interface hepatitis

Answer 1000

1) fatty liver 2) alcoholic hepatitis 3) cirrhosis

Answer 1001

Ballooning ( +/- Mallory Denk Bodies) Apoptosis Pericellular fibrosis Mainly seen in Zone 3

Answer 1002

Mainly seen in Zone 3

Answer 1003

Non-alcoholic fatty liver disease (NAFLD) including non-alcoholic steatohepatitis (NASH)

Answer 1004

PRIMARY BILIARY CHOLANGITIS Diagnostic test is detection of anti-mitochondrial antibodies

Answer 1005

Bile duct loss associated with chronic inflammation (with granulomas)

Answer 1006

Diagnostic test is detection of anti-mitochondrial antibodies

Answer 1007

M Periductal bile duct fibrosis leading to loss Associated with ulcerative colitis Increased risk of cholangiocarcinoma Diagnostic test is bile duct imaging

Answer 1008

Periductal bile duct fibrosis leading to loss

Answer 1009

PSC Periductal bile duct fibrosis leading to loss Associated with ulcerative colitis Increased risk of cholangiocarcinoma Diagnostic test is bile duct imaging

Answer 1010

HAEMOCHROMATOSIS

Answer 1011

Gene on chromosome 6 (HFe) Genetically determined increased gut iron absorption Parenchymal damage to organs secondary to iron deposition (bronzed diabetes)

Answer 1012

Genetically determined increased gut iron absorption Gene on chromosome 6 (HFe) Parenchymal damage to organs secondary to iron deposition (bronzed diabetes)

Answer 1013

Haemosiderosis

Answer 1014

accumulation of iron in macrophages post blood transfusion / idiopathic

Answer 1015

post blood transfusion / idiopathic

Answer 1016

Accumulation of copper due to failure of excretion by hepatocytes into the bile Assessed by biopsy or biochemistry Genes on chromosome 13 Accumulates in the liver and CNS (hepato-lenticular degeneration) including Kayser-Fleishcer rings

Answer 1017

Wilsons disease

Answer 1018

Wilsons disease

Answer 1019

rhodanine stain

Answer 1020

Stain in wilsons

Answer 1021

ANA+ | ASMA+

Answer 1022

Steroid responsive

Answer 1023

ALPHA-ONE ANTITRYPSIN DEFICIENCY

Answer 1024

ALPHA-ONE ANTITRYPSIN DEFICIENCY

Answer 1025

Failure to secrete alpha-one antitrypsin Intra-cytoplasmic inclusions due to misfolded protein Hepatitis and cirrhosis

Answer 1026

``` Specific causes: PBC drugs General causes TB Sarcoid etc ```

Answer 1027

1) liver cell adenoma 2) bile duct adenoma 3) haemangioma

Answer 1028

Lots of separate distinct nodules of growth

Answer 1029

1. hepatocellular carcinoma 2. hepatoblastoma 3. cholangiocarcinoma 4. haemangiosarcoma

Answer 1030

PSC Worm infections Cirrhosis

Answer 1031

Both: Can arise from: intrahepatic ducts extrahepatic ducts (including gall bladder)

Answer 1032

Acute pancreatitis

Answer 1033

``` Duct obstruction Drugs/metabolic/toxic Poor blood supply Infection/inflammation Autoimmune Idiopathic (15%) ```

Answer 1034

Gall stones (50%) Trauma Tumours

Answer 1035

Alcohol (33%) - 5% of alcoholics develop acute pancreatitis Drugs (e.g. thiazides) Hypercalcaemia Hyperlipidaemia

Answer 1036

Shock / hypothermia

Answer 1037

Gallstone stuck distal to where the common bile duct and pancreatic ducts join leads to: reflux of bile up the pancreatic duct followed by damage to acini and release of proenzymes which then become activated

Answer 1038

Alcohol leads to spasm/oedema of Sphincter of Oddi and the formation of a protein rich pancreatic fluid which obstructs the pancreatic ducts

Answer 1039

Periductal - necrosis of acinar cells near ducts (usually secondary to obstruction) Perilobular – necrosis at the edges of the lobules (usually due to poor blood supply) Panlobular – develops from 1. and 2.

Answer 1040

Periductal - necrosis of acinar cells near ducts (usually secondary to obstruction)

Answer 1041

Perilobular – necrosis at the edges of the lobules (usually due to poor blood supply)

Answer 1042

Pancreatic : pseudocyst, abscess | Systemic: shock, hypoglycaemia, hypocalcaemia

Answer 1043

Overall mortality up to 50% for haemorrhagic pancreatitis

Answer 1044

Chronic pancreatitis

Answer 1045

``` Metabolic/toxic Duct obstruction Tumours Idiopathic Autoimmune ```

Answer 1046

Alcohol 80% | Haemochromatosis

Answer 1047

Gallstones Abnormal pancreatic duct anatomy Cystic fibrosis (“mucoviscoidosis”)

Answer 1048

Pattern of chronic pancreatic injury

Answer 1049

Chronic inflammation with parenchymal fibrosis and loss of parenchyma Duct strictures with calcified stones with secondary dilatations

Answer 1050

Malabsorption Diabetes mellitus Pseudocyts Carcinoma of the pancreas

Answer 1051

Pancreatic pseudocyst

Answer 1052

Associated with acute and/ or chronic pancreatitis Lined by fibrous tissue (no epithelial lining), contain fluid rich in pancreatic enzymes or necrotic material Connect with pancreatic ducts May resolve, compress adjacent structures, become infected or perforate

Answer 1053

Characterised by large numbers of IgG4 positive plasma cells. May involve the pancreas, bile ducts and almost any other part of the body.

Answer 1054

Ductal (85% of all neoplasms) | Acinar

Answer 1055

Serous cystadenoma | Mucinous cystic neoplasm

Answer 1056

Pancreatic neuroendocrine tumour

Answer 1057

Ductal carcinoma

Answer 1058

Smoking BMI and dietary factors Chronic pancreatitis Diabetes

Answer 1059

Pancreatic Intraductal Neoplasia (PanIN) Intraducal Mucinous Papillary Neoplasm IMPN

Answer 1060

Pancreatic ductal carcinoma

Answer 1061

Head (60%) Body Tail Diffuse

Answer 1062

Direct: Bile ducts, duodenum Lymphatic: Lymph nodes Blood: Liver Serosa: Peritoneum

Answer 1063

Due to spread Chronic pancreatitis Venous thrombosis (“migratory thrombophlebitis”)

Answer 1064

Cystic tumours

Answer 1065

Pancreatic Endocrine Neoplasms

Answer 1066

Chromogranin

Answer 1067

Insulinomas (derived from beta cells) the commonest type of secretory tumour

Answer 1068

20% of adults in the West Age and gender: increasing age, F>M Ethnic and geographic: e.g. Native Americans Hereditary: e.g. disorders of bile metabolism Drugs e.g. oral contraceptive Acquired disorders e.g. rapid weight loss

Answer 1069

Cholesterol (more than 50% cholesterol) May be single, mostly radiolucent Pigment (contain calcium salts of unconjugated bilirubin) Multiple, mostly radio-opaque

Answer 1070

Bile duct obstruction Acute and chronic cholecystitis Gall bladder cancer Pancreatitis

Answer 1071

Acute inflammation | 90% associated with gall stones

Answer 1072

Chronic cholecystitis

Answer 1073

Adenocarcinomas | 90% associated with gall stones

Answer 1074

Excretion of metabolic waste products and foreign chemicals (including drugs) Regulation of fluid, electrolyte and acid/base balance Regulation of blood pressure Renin Regulation of calcium and bone metabolism 1,25 Dihydroxycholecalciferol Regulation of haematocrit Erythropoietin

Answer 1075

``` Retroperitoneal T12 to L3 on left; right is lower Mean length 11cm Normal weight 125-170g (male), 115-155g (female) Receive around 20% of cardiac output ```

Answer 1076

The Proximal Convoluted Tubule actively resorbs sodium Hydrogen exchange to allow carbonate resorption Co-transport of amino acids, phosphate, glucose Potassium is also reabsorbed

Answer 1077

Descending / thin ascending limb permeable to water but not ions or urea; ascending limb actively resorbs sodium and chloride Countercurrent Multiplier; aligned with vasa recta

Answer 1078

The Distal Convoluted Tubule is impermeable to water Regulates pH via active transport (proton / bicarbonate) Regulates sodium, potassium via active transport (aldosterone) Regulates calcium (parathyroid hormone, 1,25 dihydroxycholecalciferol

Answer 1079

``` Collecting Duct Resorbs water (principal cells, antidiuretic hormone) Regulates pH (intercalated cells, proton excretion) ```

Answer 1080

``` Haematuria Proteinuria Uraemia Hypertension Oliguria / Anuria Polyuria Oedema Colic ```

Answer 1081

Genitourinary Malformations and the Kidney

Answer 1082

``` Agenesis Renal Fusion (e.g. horse-shoe) Ectopic Kidney Renal Dysplasia Pelvi-ureteric Junction Obstruction Ureteral Duplication Vesicoureteral Reflux Posterior urethral Valves ```

Answer 1083

Adult (Dominant) Polycystic Kidney Disease 1:500 10% of end-stage renal failure Presents in adulthood with hypertension, flank pain and haematuria PKD1, PKDS2 Berry aneurysm…

Answer 1084

Adult (Dominant) Polycystic Kidney Disease 1:500 10% of end-stage renal failure Presents in adulthood with hypertension, flank pain and haematuria PKD1, PKDS2 Berry aneurysm…

Answer 1085

Cysts commonly develop in patients with end stage renal disease who are on dialysis Multiple Bilateral Cortical and Medullary

Answer 1086

Acute Renal Failure (Acute Kidney Injury) Nephrotic Syndrome Isolated Urinary Abnormalities Chronic Kidney Disease

Answer 1087

Acute Renal Failure

Answer 1088

Failure of perfusion: Hypovolaemia Shock Severe RAS

Answer 1089

Acute tubular injury Acute glomerulonephritis Thrombotic microangiopathy

Answer 1090

Obstruction by stones / tumours

Answer 1091

Commonest cause of acute renal failure Tubular epithelial cells damaged by: Ischaemia Toxins (contrast, haemoglobin, myoglobin, ethylene glycol) Drugs Common in critical illness Drugs that inhibit vasodilatory prostaglandins predispose NSAIDs Failure of Glomerular Filtration Blockage of tubules by casts Leakage of tubules to interstitial space Secondary haemodynamic changes

Answer 1092

Drugs that inhibit vasodilatory prostaglandins predispose | NSAIDs

Answer 1093

Immune injury to tubules and interstitium Heavy interstitial inflammatory infiltrate with tubular injury Can see eosinophils, granulomas

Answer 1094

``` Can also be due to infection and drugs NSAIDs Antibiotics Diuretics Allopurinol Proton Pump Inhibitors ```

Answer 1095

Acute Glomerulonephritis

Answer 1096

Acute inflammation of glomeruli | Presents with oliguria with urine casts containing erythrocytes and leucocytes

Answer 1097

Acute inflammation of glomeruli Presents with oliguria with urine casts containing erythrocytes and leucocytes When sufficient to cause acute renal failure, there are almost always crescents Proliferation of cells within Bowman’s space

Answer 1098

Acute Crescentic Glomerulonephritis

Answer 1099

Aetiologies include SLE, IgA nephropathy and Post-Infectious Glomerulonephritis

Answer 1100

Rare and severe disease caused by antibodies directed against the glomerular basement membrane C-terminal domain of Type IV collagen May cross-react with alveolar basement membrane leading to pulmonary haemorrhage Antibody may be detected with serology Linear deposition of IgG demonstrable on glomerular basement membrane

Answer 1101

Anti-GBM Disease

Answer 1102

Linear deposition of IgG demonstrable on glomerular basement membrane

Answer 1103

Only scanty glomerular immunoglobulin deposits Usually ANCA-associated Trigger neutrophil activation and glomerular necrosis Vasculitis elsewhere

Answer 1104

Pauci-Immune Crescentic Glomerulonephritis

Answer 1105

Thrombotic Microangiopathy

Answer 1106

Damage to endothelium in glomeruli, arterioles, arteries leading to thrombosis Red cells may be damaged by fibrin Microangiopathic haemolytic anaemia Haemolytic Uremic Syndrome

Answer 1107

Microangiopathic haemolytic anaemia Haemolytic Uremic Syndrome Diarrhoea associated Bacterial gut infection such as with E. coli Toxins released that target renal endothelium Non-Diarrhoea associated Defects in regulation of complement Deficiency in ADAMTS13 Drugs (calcineurin inhibitors) Radiation Hypertension Scleroderma Antiphospholipid Antibody Syndrome (+/- SLE) ___________________ Damage to endothelium in glomeruli, arterioles, arteries leading to thrombosis Red cells may be damaged by fibrin

Answer 1108

Bacterial gut infection such as with E. coli | Toxins released that target renal endothelium

Answer 1109

``` Defects in regulation of complement Deficiency in ADAMTS13 Drugs (calcineurin inhibitors) Radiation Hypertension Scleroderma Antiphospholipid Antibody Syndrome (+/- SLE) ```

Answer 1110

Breakdown in selectivity of glomerular filtration barrier leading to protein leak Proteinuria (>3.5g/day) Hypoalbuminemia Oedema Hyperlipidaemia

Answer 1111

Nephrotic Syndrome

Answer 1112

``` Primary Glomerular Disease, Non-Immune Complex Related Minimal Change Disease Focal Segmental Glomerulosclerosis Primary Renal Disease, Immune Complex Mediated Membranous Glomerulonephritis Systemic Disease Diabetes mellitus Amyloidosis SLE ```

Answer 1113

Non-Immune Complex Related Minimal Change Disease Focal Segmental Glomerulosclerosis

Answer 1114

Immune Complex Mediated | Membranous Glomerulonephritis

Answer 1115

Diabetes mellitus Amyloidosis SLE

Answer 1116

Minimal Change Disease

Answer 1117

Focal Segmental Glomerulosclerosis

Answer 1118

Associated with immune deposits on outside of glomerular basement membrane Subepithelial Common cause of nephrotic syndrome in adults Primary disease is autoimmune Antibody against phospholipase A2 type M receptor (PLA2R) in 75% of cases Need to exclude possibility of a secondary disease Epithelial malignancy, drugs, infections, SLE Interpret findings in clinical and serological context

Answer 1119

Membranous Glomerulonephritis

Answer 1120

Associated with immune deposits on outside of glomerular basement membrane Subepithelial Common cause of nephrotic syndrome in adults Primary disease is autoimmune Antibody against phospholipase A2 type M receptor (PLA2R) in 75% of cases Need to exclude possibility of a secondary disease Epithelial malignancy, drugs, infections, SLE Interpret findings in clinical and serological context

Answer 1121

Antibody against phospholipase A2 type M receptor (PLA2R) in 75% of cases

Answer 1122

Membranous Glomerulonephritis

Answer 1123

Diabetic Nephropathy

Answer 1124

Nodular Glomerulosclerosis caused by high glucose levels Typically starts as microalbuminuria before progression to proteinuria and nephrotic syndrome

Answer 1125

Stage 1 – Thickening of basement membrane on EM Stage 2 – Increase in mesangial matrix, without nodules Stage 3 – Nodular lesions / Kimmelstiel-Wilson Stage 4 – Advanced glomerulosclerosis

Answer 1126

Amyloidosis

Answer 1127

AA, derived from serum amyloid associated protein (SAA), an acute phase protein; patients tend to have a chronic inflammatory state AL, derived from immunoglobin light chains; 80% of patients have multiple myeloma

Answer 1128

Microscopic Haematuria Thin basement membranes IgA Nephropathy Asymptomatic Proteinuria May be associated with a broad range of glomerular structural abnormalities or immune complex deposition Diagnosis often requires renal biopsy for histology, immunohistochemistry and electron microscopy

Answer 1129

Hereditary defect in Type IV collagen synthesis Basement membrane <250nm thickness Haematuria is only consequence in most cases

Answer 1130

Alport’s Syndrome X-linked dominant mutations affecting ⍺5 subunit Forms exist in which mutation affects ⍺3 or ⍺4 subunit Typically progressive, renal failure in middle age Often have deafness, ocular disease

Answer 1131

X-linked dominant mutations affecting ⍺5 subunit Forms exist in which mutation affects ⍺3 or ⍺4 subunit Typically progressive, renal failure in middle age Often have deafness, ocular disease

Answer 1132

IgA Nephropathy Commonest glomerulonephritis IgA predominant mesangial immune complex deposition Aetiology not well understood in primary form Secondary forms observed in liver, bowel and skin disease Can be seen with small-vessel vasculitis (Henoch-Schönlein Purpura) 30% develop end stage renal failure Oxford Classification (MEST-C)

Answer 1133

IgA Nephropathy

Answer 1134

REMEMBER 90/60/30/15 ``` 1 Kidney injury with normal or elevated GFR >90 2.0-3.0 2 Mild reduction in GFR 60-89 3.0 3 Moderate reduction in GFR 30-59 4.0-8.0 4 Severe reduction in GFR 15-29 0.2-0.4 5 End-Stage Renal Failure <15 0.2-0.3 ```

Answer 1135

``` Diabetes – 27.5% Glomerulonephritis – 14.1% Polycystic Kidney Disease – 7.4% Pyelonephritis – 6.5% Hypertension – 6.8% Renal Vascular Disease – 5.9% Other / Uncertain – 31.7% ```

Answer 1136

Hypertensive Nephropathy

Answer 1137

Arteriolar hyalinosis, arterial intimal thickening, ischaemic glomerular changes, segmental and global glomerulosclerosis

Answer 1138

hypertensive nephropathy

Answer 1139

The distal oesophageal squamo-columnar junction

Answer 1140

Fundus Body Pyloric antrum Pyloric canal

Answer 1141

Lamina propria

Answer 1142

gastric pits lie in the lamina pro-Tia

Answer 1143

Reflux of acidic gastric contents Commonest cause of oesophagitis

Answer 1144

``` Complications haemorrhage perforation stricture Barrett’s oesophagus ```

Answer 1145

Re-epithelialisation by metaplastic columnar epithelium usually with goblet cells (intestinal type epithelium) AKA columnar lined oesophagus (CLO)

Answer 1146

Adenocarcinoma of the oesophagus

Answer 1147

Squamous Cell Carcinomaof the oesophagus

Answer 1148

inflammation of the gastric mucosa Acute gastritis - acute insult Chronic gastritis - chronic / persistent insult

Answer 1149

``` Chemical aspirin/NSAIDs alcohol corrosives Infection e.g. Helicobacter pylori ```

Answer 1150

H. pylori associated Chemical (NSAIDs, bile reflux; antrum ) Autoimmune (body, auto-antibodies e.g. antiparietal) Lymphocytes +/- Neutrophils Mucosal Associated Lymphoid Tissue (MALT)induction

Answer 1151

CLO-IM-Dysplasia, Adenocarcinoma Lymphoma (MALToma)

Answer 1152

Helicobacter infection is associated with an 8x increased risk of (non-cardia) gastric cancer cag-A-positive H.pylori have a needle like appendage that injects toxin into intercellular junctions allowing the bacteria to attach more easily. This strain is associated with more chronic inflammation. Treatment of the infection with antibiotics drastically reduces the risk of cancer.

Answer 1153

Bleeding - Anaemia - Shock (massive haemorrhage) Perforation - Peritonitis

Answer 1154

Gastric Cancer

Answer 1155

Gastric Cancer

Answer 1156

Intestinal - well differentiated Diffuse – poorly differentiated (Linitis plastica), includes signet ring cell carcinoma

Answer 1157

``` The remaining 5% is made up of: Squamous cell carcinoma Lymphoma (MALToma) Gastrointestinal stromal tumour (GIST) Neuroendocrine tumours ```

Answer 1158

Gastric MALToma / Lymphoma

Answer 1159

Duodenitis and formation of a duodenal ulcer H.Pylori infection

Answer 1160

``` Immunosuppressed CMV Cryptosporidiosis Giardia lamblia infection Whipple’s disease -Tropheryma whippelii. ```

Answer 1161

Villous atrophy Crypt hyperplasia Increased Intraepithelial lymphocytes (normal range less than 20 lymphocytes /100 enterocytes)

Answer 1162

normal range less than 20 lymphocytes per 100 enterocytes

Answer 1163

Diagnosis requires: Endomysial antibodies and tissue transglutaminase antibodies Duodenal biopsies: On gluten rich diet showing villous atrophy Off gluten showing normal villi There are other causes of malabsorption with similar histology e.g. tropical sprue

Answer 1164

MALToma associated with Coeliac is in the duodenum | T-cell origin Enteropathy Associated T-cell Lymphoma

Answer 1165

Urine microscopy

Answer 1166

``` pH 4.5 to 8.0 Specific gravity 1.003 to 1.035 (Bowmans space 1.007 to 1.010) Protein Sensitive to albumin, not BJPs Zero, Trace, 1+ to 4+ Blood Leucocyte esterase Negative result is significant Nitrite Detects bacteria, esp. Gm negatives Ketones Glucose ```

Answer 1167

- Vascular calcification | - Uraemic cardiomyopathy

Answer 1168

Three phases: Left ventricle (LV) hypertrophy LV dilatation LV dysfunction

Answer 1169

``` Vesiculobullous Spongiotic Psoriasiform Lichenoid Vasculitic Granulomatous ```

Answer 1170

Crystal aggregates that form in the renal collecting ducts | May be deposited anywhere in the urinary tract

Answer 1171

Lifetime incidence 15% Males three times more likely to be affected than females

Answer 1172

Males three times more likely to be affected than females

Answer 1173

Calcium Oxalate (Weddellite) – 75% Magnesium Ammonium Phosphate (Struvite) – 15% Uric Acid – 5%

Answer 1174

Calcium oxalate stones are related to hypercalciuria Absorptive hypercalciuria – excessive calcium absorption from gut Renal hypercalciuria – impaired absorption of calcium in proximal renal tubule Hypercalcaemia – primary hyperparathyroidism Rare

Answer 1175

Magnesium ammonium phosphate stones are also known as ”triple stones” aka struvite

Answer 1176

Form as a consequence of infection with urease-producing organisms Proteus sp. Ammonia alkalinises urine – precipitation of magnesium ammonium phosphate salts follows

Answer 1177

Triple stones

Answer 1178

Uric acid stones may form in patients with hyperuricaemia: Gout Rapid cell turnover N.B: Most patients do not actually have hyperuricaemia or increased uric acid excretion in urine Believed to be due to tendency to produce slightly acidic urine

Answer 1179

Papillary Adenoma

Answer 1180

Papillary Adenoma

Answer 1181

Renal Oncocytoma

Answer 1182

Renal Oncocytoma

Answer 1183

Angiomyolipoma

Answer 1184

Angiomyolipoma

Answer 1185

Angiomyolipoma Papillary Adenoma Renal Oncocytoma

Answer 1186

Renal cell carcinoma

Answer 1187

``` Risk factors include: Smoking Hypertension Obesity Long-Term Dialysis Genetic Syndromes – von Hippel Lindau ```

Answer 1188

Half of cases present with painless haematuria Most of the remaining cases are detected incidentally on imaging Small proportion present with metastatic disease

Answer 1189

Clear Cell Renal Cell Carcinoma (70%) Papillary Renal Cell Carcinoma (15%) Chromophobe Renal Cell Carcinoma (5%) Remaining 10% are various rare subtypes

Answer 1190

Clear Cell Renal Cell Carcinoma

Answer 1191

Clear Cell Renal Cell Carcinoma

Answer 1192

Papillary Renal Cell Carcinoma

Answer 1193

Papillary Renal Cell Carcinoma

Answer 1194

Chromophobe Renal Cell Carcinoma

Answer 1195

Five year survival across all tumour types is 60%

Answer 1196

``` Also known as Wilm’s Tumour Malignant triphasic kidney tumour of childhood Blastema (small round blue cells) Epithelial Stromal ``` Typically presents as an abdominal mass in children aged 2-5 years old 1 in 8,000 – second most common childhood malignancy 95% of cases show favourable histological features with excellent prognosis

Answer 1197

Typically presents as an abdominal mass in children aged 2-5 years old 1 in 8,000 – second most common childhood malignancy 95% of cases show favourable histological features with excellent prognosis

Answer 1198

Group of malignant epithelial neoplasms arising in urothelial tract Bladder Renal Pelvis Ureters

Answer 1199

Smoking | Aromatic amines

Answer 1200

Painless haematuria

Answer 1201

Non-Invasive Papillary Urothelial Carcinoma Infiltrating Urothelial Carcinoma Flat Urothelial Carcinoma in-situ

Answer 1202

Non-Invasive Papillary Urothelial Carcinoma Divided into low grade and high grade (WHO 2004) based on nuclear atypia Low grade tumours have a low risk of progression to invasive disease (<5%) High grade tumours carry a higher risk of progression to invasive disease Unstable, carry a number of genetic aberrations including in RB and TP53

Answer 1203

Flat Urothelial Carcinoma In-Situ Flat urothelial lesion with unequivocal high grade features High risk of progression

Answer 1204

Benign Prostatic Hyperplasia

Answer 1205

Very common – symptomatic in 25% of men by age 80 | Histologically present in 90% of men by age 80

Answer 1206

Increased oestrogen levels in blood, which rises with age, may induce androgen receptors and stimulate hyperplasia Treatment based on alpha blockers and 5⍺-reductase inhibitors as well as transurethral resection

Answer 1207

``` Presents with “Lower Urinary Tract Symptoms” Frequency Nocturia Urgency Hesitancy Poor flow Terminal Dribbling ``` May also present with urinary tract infection, acute urinary retention or renal failure

Answer 1208

Prostatic Adenocarcinoma

Answer 1209

Arises from Prostatic Intraepithelial Neoplasia

Answer 1210

Mutations in PTEN, AMACR, GST-pi, p27 and more

Answer 1211

Usually asymptomatic; usually diagnosed on biopsy following raised serum prostate-specific antigen or digital rectal examination May have lower urinary tract symptoms Rarely may present with metastatic disease Pathological fracture

Answer 1212

Most powerful prognostic indicator is the Gleason score | Influences treatment decisions

Answer 1213

Testicular Germ Cell Tumours

Answer 1214

Testicular Germ Cell Tumours

Answer 1215

Typically arise in men aged 20-45

Answer 1216

Risk factors include Undescended testis (3-5x increased risk) Low birth weight / small for gestational age

Answer 1217

Testicular Germ Cell Tumours

Answer 1218

Present as painless lump 10% present with symptoms related to metastasis Back pain Cough Dyspnoea Five histological subtypes Single tumour may be purely one subtype or contain a mixture of multiple subtypes

Answer 1219

Highly sensitive to platinum-based chemotherapy regimes Prognosis excellent Five year survival is 98% in most countries

Answer 1220

Testicular Lymphoma

Answer 1221

Leydig Cell Tumour

Answer 1222

Sertoli Cell Tumour

Answer 1223

Epididymitis

Answer 1224

Varicocele

Answer 1225

Fluid between layers of tunica vaginalis

Answer 1226

Adenomatoid Tumour

Answer 1227

Small tubules lined by mesothelial cells

Answer 1228

Lichen Sclerosus / Balanitis Xerotica Obliterans

Answer 1229

Zoon’s balanitis

Answer 1230

HPV 6 and 11

Answer 1231

Peyronie’s Disease

Answer 1232

Penile carcinoma

Answer 1233

N. gonorrhoeae, C. trachomatis

Answer 1234

Prostatic Urethral Polyp

Answer 1235

Urethral Caruncle

Answer 1236

Urethral Carcinoma

Answer 1237

Scrotal Calcinosis

Answer 1238

Angiokeratomas

Answer 1239

Necrotising fasciitis; mortality of 15-20%

Answer 1240

Necrotising fasciitis; mortality of 15-20%

Answer 1241

Atresia is a condition in which an orifice or passage in the body is (usually abnormally) closed or absent.

Answer 1242

Absence of ganglion cells in myenteric plexus, Distal colon fails to dilate 80% male Constipation, abdominal distension, vomiting, ‘overflow’ diarrhoea Associated with Down’s syndrome (2%) RET proto-oncogene Cr10 + others

Answer 1243

Absence of ganglion cells in myenteric plexus, Distal colon fails to dilate 80% male Constipation, abdominal distension, vomiting, ‘overflow’ diarrhoea Associated with Down’s syndrome (2%) RET proto-oncogene Cr10 + others

Answer 1244

Absence of ganglion cells in myenteric plexus, Distal colon fails to dilate 80% male Constipation, abdominal distension, vomiting, ‘overflow’ diarrhoea Associated with Down’s syndrome (2%) RET proto-oncogene Cr10 + others

Answer 1245

Hirschsprung’s disease

Answer 1246

clinical impression biopsy of affected segment. hypertrophied nerve fibers but no ganglia.

Answer 1247

Treatment: resection of affected (constricted) segment. (frozen section)

Answer 1248

Adhesions Herniation Extrinsic mass Volvulus

Answer 1249

``` Complete twisting of a loop of bowel at mesenteric base, around vascular pedicle intestinal obstruction +/- infarction small bowel (infants) sigmoid colon (elderly) ```

Answer 1250

``` small bowel (infants) sigmoid colon (elderly) ```

Answer 1251

``` High incidence in West Low fibre diet High intraluminal pressure ‘Weak points’ in wall of bowel 90% occur in left colon ```

Answer 1252

``` Pain Diverticulitis Gross perforation Fistula (bowel, bladder, vagina) Obstruction ```

Answer 1253

Infection (bacterial, viral, protozoal etc.) Drug/toxin (esp.antibiotic) Chemotherapy Radiation

Answer 1254

Crohn’s Ulcerative colitis TB

Answer 1255

Antibiotic associated colitis Acute colitis with pseudomembrane formation Caused by protein exotoxins of C.difficile

Answer 1256

Laboratory: C. difficile toxin stool assay

Answer 1257

Therapy: Metronidazole or Vancomycin

Answer 1258

Ischaemic Colitis/ Infarction

Answer 1259

Usually occurs in segments in “watershed” zones, e.g. splenic flexure (SMA and IMA) and the rectosigmoid (IMA and internal iliac artery)

Answer 1260

Arterial Occlusion: atheroma, thrombosis, embolism Venous Occlusion: thrombus, hypercoagulable states Small Vessel Disease: DM, cholesterol emboli, vasculitis Low Flow States: CCF, haemorrhage, shock Obstruction: hernia, intussusception, volvulus, adhesions

Answer 1261

``` Diarrhoea +/- blood Fever Abdominal pain Acute abdomen Anaemia Weight loss Extra-intestinal manifestations ```

Answer 1262

``` Arthritis Uveitis Stomatitis/cheilitis Skin lesions Pyoderma gangrenosum Erythema multiforme Erythema nodosum ```

Answer 1263

UC slightly more common than Crohn’s

Answer 1264

Ulcerative colitis

Answer 1265

Severe haemorrhage Toxic megacolon Adenocarcinoma (20-30 x risk)

Answer 1266

``` Arthritis Myositis Uveitis/iritis Erythema nodosum, pyoderma gangrenosum Primary Sclerosing Cholangitis (5.5% in pancolitis) ```

Answer 1267

(Hyperplastic) Inflammatory (“pseudo-polyps”) Hamartomatous (juvenile, Peutz Jeghers)

Answer 1268

Tubular adenoma Tubulovillous adenoma Villous adenoma

Answer 1269

20-30% prevalence before age 40 | 40-50% prev. after age 60

Answer 1270

Size of polyp (> 4 cm approx 45% have invasive malignancy) Proportion of villous component Degree of dysplastic change within polyp

Answer 1271

Usually none | Bleeding/anaemia

Answer 1272

``` (Peutz Jeghers) Familial adenomatous polyposis Gardner’s Turcot Hereditary non polyposis colon cancer ```

Answer 1273

Autosomal dominant - average onset is 25 years old Adenomatous polyps, mostly colorectal Minimum 100 polyps, average ~1,000 polyps chromosome 5q21, APC tumour suppressor gene virtually 100% will develop cancer within 10 to 15 years; 5% periampullary Ca

Answer 1274

chromosome 5q21, APC tumour suppressor gene | virtually 100% will develop cancer within 10 to 15 years; 5% periampullary Ca

Answer 1275

Same clinical, pathological, and etiologic features as FAP, with high Ca risk BUT distinctive extra-intestinal manifestations: multiple osteomas of skull & mandible epidermoid cysts desmoid tumors dental caries, unerrupted supernumery teeth post-surgical mesenteric fibromatoses

Answer 1276

Distinctive extra-intestinal manifestations: multiple osteomas of skull & mandible epidermoid cysts desmoid tumors dental caries, unerrupted supernumery teeth post-surgical mesenteric fibromatoses

Answer 1277

Uncommon autosomal dominant disease 3-5% of all colorectal cancers 1 of 4 DNA mismatch repair genes involved (mutation) Numerous DNA replication errors (RER) Onset of colorectal cancer at an early age High frequency of carcinomas proximal to splenic flexure Poorly differentiated and mucinous carcinoma more frequent Multiple synchronous cancers Presence of extracolonic cancers (endometrium, prostate, breast, stomach)

Answer 1278

Uncommon autosomal dominant disease 3-5% of all colorectal cancers 1 of 4 DNA mismatch repair genes involved (mutation) Numerous DNA replication errors (RER) Onset of colorectal cancer at an early age High frequency of carcinomas proximal to splenic flexure Poorly differentiated and mucinous carcinoma more frequent Multiple synchronous cancers Presence of extracolonic cancers (endometrium, prostate, breast, stomach)

Answer 1279

Uncommon autosomal dominant disease 3-5% of all colorectal cancers 1 of 4 DNA mismatch repair genes involved (mutation) Numerous DNA replication errors (RER) Onset of colorectal cancer at an early age High frequency of carcinomas proximal to splenic flexure Poorly differentiated and mucinous carcinoma more frequent Multiple synchronous cancers Presence of extracolonic cancers (endometrium, prostate, breast, stomach)

Answer 1280

Colorectal carcinoma

Answer 1281

Diet (low fibre, high fat etc) Lack of exercise Obesity Familial Chronic Inflammatory bowel disease

Answer 1282

``` Bleeding Change of bowel habit Anaemia Weight loss Pain Fistula ```

Answer 1283

``` Grade = level of differentiation Dukes’ staging A = confined to wall of bowel B = through wall of bowel C = lymph node metastases D = distant metastases TNM (tumour, nodes, metastases) ```

Answer 1284

``` Grade = level of differentiation Dukes’ staging A = confined to wall of bowel B = through wall of bowel C = lymph node metastases D = distant metastases TNM (tumour, nodes, metastases) ```

Answer 1285

The study of cell morphology to establish underlying disease processes

Answer 1286

Women between the ages of 25 – 65 years are invited for screening Repeated every 3-5 years

Answer 1287

Cervical sample collected into fluid filled bottle, Liquid Based Cytology (LBC) Sample viewed microscopically looking for precancer and cancer cells HR-HPV triage and test of cure testing Future will be primary HR-HPV testing

Answer 1288

The risk of developing cancer is related to the grade of CIN. Most cases of CIN1 will go back to normal without any treatment. CIN2 and CIN3 may develop into cancer in some cases, if left untreated

Answer 1289

This is the pre-cancerous change involving the inner glandular cells of the cervix. Treatment of cGIN is usually the same as CIN.

Answer 1290

If HR-HPV negative – routine recall

Answer 1291

If HR-HPV positive – refer to colposcopy

Answer 1292

High grade abnormalities refer to colposcopy – no HR-HPV test

Answer 1293

Types 6 and 11 – cause about 90 percent of genital warts

Answer 1294

Types 16 and 18 cause about 70% of cervical cancers.

Answer 1295

2008 For girls aged 12 to 13 with a catch up for girls up to 18 in the following 3 years

Answer 1296

Exfoliative - Bronchial washings and brushings, serous cavity effusions such as pleural effusions, ascitic fluid, peritoneal fluid, urine Fine needle aspirations

Answer 1297

``` Breast lesions Lung Thyroid Lymph nodes Head and neck lesions Pancreas Deep seated lymph nodes ```

Answer 1298

lung adenocarcinoma

Answer 1299

Breast cancer

Answer 1300

Colon cancer

Answer 1301

``` Accurate Quick Acceptable to patient Rapid turnaround time Organised into fast access clinics run by cytopathologists for aspiration of palpable swellings Cheap Triage material for ancillary tests On-site diagnosis allows immediate patient management ```

Answer 1302

calcium hydroxyapatite (10Ca 6PO4 OH2) Cells and protein matrix

Answer 1303

Periosteum

Answer 1304

Cortical vs cancellous

Answer 1305

Cortical - longbones | Cancellous - vertebrae + pelvis

Answer 1306

Cortical - mechanical and protective mainly | Cancellous - metabolic

Answer 1307

cortical - 90% | cancellous - 15-25%

Answer 1308

build bone by laying down osteoid

Answer 1309

multinucleate cells of macrophage family resorb or chew bone

Answer 1310

osteoblast like cells which sit in lacunae

Answer 1311

Binding of RANKL to RANK | M-CSF costimulates

Answer 1312

Histology requires bone biopsy from iliac crest, | processed un-decalcified for histomorphometry

Answer 1313

‘Static’ parameters include cortical thickness & porosity trabecular bone volume thickness, number & separation of trabeculae Bone mineralisation is studied using osteoid parameters ‘Histodynamic parameters’ are obtained from fluorescent tetracycline labelling

Answer 1314

‘High turnover’ OP results from ↑ bone resorption ‘Low turnover’ OP results from ↓ bone formation Fracture Pathogenesis – low initial bone mass or accelerated bone loss can reduce bone mass below the fracture threshold

Answer 1315

90% cases due to insufficient Ca intake and post-menopausal oestrogen deficiency

Answer 1316

``` Advanced age Female sex Smoking XS Alcohol Early menopause Long-term immobility Low body mass index Poor diet ↓vit D, ↓Ca2+ Malabsorption Thyroid disease Low testosterone Chronic renal disease Steroids ```

Answer 1317

Osteoporosis RFs

Answer 1318

Patients commonly present with back pain and # wrist (Colles’), hip (NOF and intertrochanteric) & pelvis may be the first sign of disease > 60% vertebral # are asymptomatic Compression # usually in T11-L2 distribution

Answer 1319

Lab investigations: Serum calcium, phosphorous & alk phos (usually N) Urinary calcium Collagen breakdown products Imaging Bone Densitometry T score between 1 & 2.5 SD below normal peak bone mass= T score >2.5 SD below normal peak bone mass = osteoporosis

Answer 1320

Defective bone mineralisation

Answer 1321

1. Deficiency of vitamin D | 2. Deficiency of PO4

Answer 1322

bone pain/tenderness fracture proximal weakness bone deformity

Answer 1323

Osteomalacia

Answer 1324

Hyperparathyroidism

Answer 1325

``` parathyroid adenoma (85-90%) chief cell hyperplasia ```

Answer 1326

chronic renal deficiency vit D deficiency malabsorption

Answer 1327

Symptoms Mnemonic Stones (Ca oxalate renal stones) Bones (osteitis fibrosa cystica, bone resorption) Abdominal groans (acute pancreatitis) Psychic moans (psychosis & depression)

Answer 1328

Comprises all the skeletal changes of chronic renal disease:- Increased bone resorption (osteitis fibrosa cystica) Osteomalacia Osteosclerosis Growth retardation Osteoporosis

Answer 1329

Disorder of bone turnover 1. Osteolytic 2. Osteolytic-osteosclerotic 3. Quiescent osteosclerotic

Answer 1330

5q35 Aetiology is unknown Familial cases show autosomal pattern of inheritance with incomplete penetrance (mutation 5q35-qter - sequestosome 1 gene) Parvomyxovirus type particles have been seen on EM in Pagetic bone

Answer 1331

Clinical Presentation pain microfractures nerve compression (incl. Spinal N and cord) skull changes may put medulla at risk +/- haemodynamic changes, cardiac failure Development of sarcoma in area of involvement 1%

Answer 1332

1. Organisation of haematoma at # site (pro-callus) 2. Formation of fibrocartilaginous callus 3. Mineralisation of fibrocartilaginous callus 4. Remodelling of bone along weight-bearing lines

Answer 1333

``` Type of fracture Presence of infection Pre-existing systemic condition :- Neoplasm Metabolic disorder Drugs Vitamin deficiency ```

Answer 1334

Vertebrae Jaw (2º to dental abscess) Toe (2º to diabetic skin ulcer) (>3mm) Long bones (usually metaphysis)

Answer 1335

Clinical features General - malaise, fever , chills , leucocytosis Local - pain, swelling and redness 60% positive blood cultures X-ray - mixed picture; eventually lytic

Answer 1336

60% positive blood cultures X-ray - mixed picture; eventually lytic

Answer 1337

Almost always bacterial Rarely fungal Routes of infection- a) haematogenous (blood borne) b) direct extension c) traumatic (inc surgery)

Answer 1338

``` Staph Aureus(90%) E. Coli Klebsiella Salmonella (associated with sickle cell disease) Pseudomonas (IVDA) ``` Neonates Haemophilus influenzae Group B Streptococcus Occasionally enterobacter

Answer 1339

Usually appear 10 days or so post onset Mottled rarefaction and lifting of periosteum >1week - irregular sub-periosteal new bone formation called involucrum Later - irregular lytic destruction (takes 10-14days) Some areas of necrotic cortex may become detached called sequestra (takes 3-6 weeks)

Answer 1340

Pott's disease ``` Affects immunocompromised patients More destructive and resistant to control Spinal disease (50% cases) may result in psoas abscess and severe skeletal deformity (Pott’s disease) Systemic amyloidosis may result in protracted cases ```

Answer 1341

Inflammatory arthropathy as part of a complex multisystem illness resulting from tick bite. It is the most prevalent vector bone disease in temperate Northern hemisphere

Answer 1342

Borrelia burgdorferi

Answer 1343

Tick species vector of B.burgdorferi

Answer 1344

Lyme Disease

Answer 1345

Early localised Characterised by rash (90%) usually within 7-10 days and between 1 & 50cm diameter. Often thigh, groin, axilla (earlobe in children) Early Disseminated Affects many organs, musculoskeletal, heart, nervous system. Late, persistent Dominated by arthritis.

Answer 1346

Degenerative joint disease Primary - age related Secondary - any age previously damaged or congenitally abnormal joint

Answer 1347

``` Result in :- cartilage degeneration fissuring abnormal matrix calcification osteophytes ```

Answer 1348

Main sites vertebrae hips and knees +/-DIPJ PIPJ of the hand +/- carpometacarpal and metatarsophalangeal joints

Answer 1349

Rheumatoid Arthritis

Answer 1350

Aetiology most likely autoimmune genetic predisposition (risk alleles TNFA1P3, STAT4) Increased incidence amongst first degree relatives Associated with HLA DR4 & DR1 (Chr 6p21)

Answer 1351

``` Clinical Features Mild anaemia Raised ESR RF+ve(80%) +/- rheumatoid nodules (25%) ``` *can be multisystem disease

Answer 1352

Sites:- Small joints, hands and feet, sparing DIPJ Wrists elbows ankles and knees ``` Characteristic deformities include:- Radial deviation of wrist Ulnar deviation of fingers ‘Swan neck’ & ‘Boutonniere’ deformity of fingers ‘Z’ shaped thumb ```

Answer 1353

Proliferative synovitis with 1. Thickening of synovial membranes ( villous) 2. Hyperplasia of surface synoviocytes 3. Intense inflammatory cell infiltrate 4. Fibrin deposition and necrosis Pannus formation with exuberant inflamed synovium overlying the articular surface

Answer 1354

Usual age > 50y Crystals of Calcium pyrophosphate - mainly knees or Calcium phosphates (hydroxyapatite) - knees and shoulders

Answer 1355

Pseudogout

Answer 1356

a) Sporadic (8% pts <75; 22%>85 ?F>M) b) Metabolic (haemochromatosis, primary HPT, hypoMg; low PO4) c) Hereditary (autosomal dominant) (ANKH mutn – transmembrane glygoprotein. Chr 8q, 5p, younger age 18% OA knee; 10% hip) d) Traumatic

Answer 1357

``` Adults Breast Prostate Lung Kidney Thyroid ``` ``` Children Neuroblastoma Wilm’s tumour Osteosarcoma Ewings Rhabdomyosarcoma ```

Answer 1358

Osteosarcoma Chondrosarcoma Ewing’s sarcoma/PNET (primitive peripheral neuroectodermal tumour)

Answer 1359

Osteosarcoma

Answer 1360

Age: peak in adolescence (75% patients are <20y) Site: 60% occur around the knee X-ray: usually metaphyseal, lytic, permeative, elevated periosteum (Codman’s Triangle) Histo: malignant mesenchymal cells +/- bone and cartilage formation Prognosis: poor- 60% 5 year survival. Treatment is usually chemo and limb salvage surgery

Answer 1361

Age: peak in adolescence (75% patients are <20y) Site: 60% occur around the knee X-ray: usually metaphyseal, lytic, permeative, elevated periosteum (Codman’s Triangle) Histo: malignant mesenchymal cells +/- bone and cartilage formation Prognosis: poor- 60% 5 year survival. Treatment is usually chemo and limb salvage surgery

Answer 1362

Chrondroarcoma

Answer 1363

Malignant cartilage producing tumour Age: 40y and over Site: pelvis, axial skeleton, prox femur, prox tibia X-ray: lytic with fluffy calcification Histo: malignant chondrocytes +/- chondroid matrix may dedifferentiate to high grade sarcoma Prognosis: 70% 5y survival (depends on grade & size

Answer 1364

Malignant cartilage producing tumour Age: 40y and over Site: pelvis, axial skeleton, prox femur, prox tibia X-ray: lytic with fluffy calcification Histo: malignant chondrocytes +/- chondroid matrix may dedifferentiate to high grade sarcoma Prognosis: 70% 5y survival (depends on grade & size

Answer 1365

Ewing’s Sarcoma/PPNET

Answer 1366

Highly malignant small round cell tumour Age: usually < 20y (80%) Site: diaphysis/metaphysis of long bones, pelvis X-ray: onion skinning of periosteum, lytic +/- sclerosis Histo: sheets of small round cells Prognosis : - 75% 5y survival 50% longterm Specific chromosome translocation 11:22 (EWS/Fli1)

Answer 1367

Highly malignant small round cell tumour Age: usually < 20y (80%) Site: diaphysis/metaphysis of long bones, pelvis X-ray: onion skinning of periosteum, lytic +/- sclerosis Histo: sheets of small round cells Prognosis : - 75% 5y survival 50% longterm Specific chromosome translocation 11:22 (EWS/Fli1)

Answer 1368

Excess accumulation of fluid in the brain parenchyma Two main types: Vasogenic – disruption of the blood brain barrier Cytotoxic – secondary to cellular injury e.g. hypoxia/ischaemia Result is raised intracranial pressure

Answer 1369

Excess accumulation of fluid in the brain parenchyma Two main types: Vasogenic – disruption of the blood brain barrier Cytotoxic – secondary to cellular injury e.g. hypoxia/ischaemia Result is raised intracranial pressure

Answer 1370

Accumulation of CSF in the brain. Non-communicating involves obstruction of flow of CSF Communicating involves no obstruction but problems with reabsorption of CSF into venous sinuses

Answer 1371

Accumulation of CSF in the brain. Non-communicating involves obstruction of flow of CSF Communicating involves no obstruction but problems with reabsorption of CSF into venous sinuses

Answer 1372

ICP is measured in mmHg and, at rest, is normally 7–15mmHg for a supine adult Enclosed bony box- pressure can increase because of localised (space occupying) lesions, oedema or both Increased pressure forces brain against unyielding bony wall of skull This results in herniation of brain structures where space is available

Answer 1373

Subfalcine Transtentorial herniation Tonsillar herniation

Answer 1374

A stroke is a clinical syndrome characterised by rapidly developing clinical symptoms and/or signs of focal, and at times global loss of cerebral function, with symptoms lasting more than 24 hours or leading to death, with no apparent cause other than that of vascular origin (Hatano, 1976)

Answer 1375

TIA is caused by a clot; the blockage is temporary Most TIAs last less than five minutes; the average is about a minute. Unlike a stroke, when a TIA is over, there is usually no permanent injury to the brain 1/3 of those with TIA get significant infarct within 5 years REMEMBER: TIA important predictor of future infarct

Answer 1376

Haemorrhage into the substance of the brain - rupture of a small intraparenchymal vessel Most common in basal ganglia Hypertension > 50% of bleeds Presentation with severe headache, vomiting, rapid loss of consciousness, focal neurological signs

Answer 1377

Hypertension > 50% of bleeds Presentation with severe headache, vomiting, rapid loss of consciousness, focal neurological signs Haemorrhage into the substance of the brain - rupture of a small intraparenchymal vessel Most common in basal ganglia

Answer 1378

Occur anywhere in the CNS Become symptomatic between 2nd and 5th decade (mean age 31.2 years) Present with haemorrhage, seizures, headache, focal neurological deficits High pressure – MASSIVE BLEEDING!!! Seen on angiography Morbidity after rupture 53-81% - high in eloquent areas Mortality 10-17.6% Treatment: surgery, embolization, radiosurgery

Answer 1379

Occur anywhere in the CNS Become symptomatic between 2nd and 5th decade (mean age 31.2 years) Present with haemorrhage, seizures, headache, focal neurological deficits High pressure – MASSIVE BLEEDING!!! Seen on angiography Morbidity after rupture 53-81% - high in eloquent areas Mortality 10-17.6% Treatment: surgery, embolization, radiosurgery

Answer 1380

Occur anywhere in the CNS Become symptomatic between 2nd and 5th decade (mean age 31.2 years) Present with haemorrhage, seizures, headache, focal neurological deficits High pressure – MASSIVE BLEEDING!!! Seen on angiography Morbidity after rupture 53-81% - high in eloquent areas Mortality 10-17.6% Treatment: surgery, embolization, radiosurgery

Answer 1381

“Well-defined malformative lesion composed of closely packed vessels with no parenchyma interposed between vascular spaces” Can be found anywhere in the CNS, usually symptomatic after age 50 Pathogenesis unknown Present with headache, seizures, focal deficits, haemorrhage Low pressure – recurrent bleeds Treatment: surgery

Answer 1382

“Well-defined malformative lesion composed of closely packed vessels with no parenchyma interposed between vascular spaces” Can be found anywhere in the CNS, usually symptomatic after age 50 Pathogenesis unknown Present with headache, seizures, focal deficits, haemorrhage Low pressure – recurrent bleeds Treatment: surgery

Answer 1383

Rupture of a berry aneurysm; present in 1% of general population 80 % - internal carotid artery bifurcation, 20% occur within the vertebro-basilar circulation 30% of patients have multiple aneurysms Greatest risk of rupture when 6-10mm diameter Present with sudden onset of severe headache, vomiting, loss of consciousness

Answer 1384

Rupture of a berry aneurysm; present in 1% of general population 80 % - internal carotid artery bifurcation, 20% occur within the vertebro-basilar circulation 30% of patients have multiple aneurysms Greatest risk of rupture when 6-10mm diameter Present with sudden onset of severe headache, vomiting, loss of consciousness

Answer 1385

Tissue death due to ischaemia Commonest form of cerebrovascular disease 70-80% of strokes Cerebral atherosclerosis most common cause hypertension, diabetes, smoking are major risks factors

Answer 1386

Worst atherosclerosis in larger vessels (extracerebral arteries) – thrombosis Often near carotid bifurcation or in basilar artery Other cause - emboli (intracerebral arteries) Usually from heart or atherosclerotic plaques Embolic occlusion usually in middle cerebral artery branches

Answer 1387

Lateral area - MCA Posterior area - PCA Medial anterior-to-posterior - ACA

Answer 1388

``` Trauma single largest cause of death in people under 45 9 deaths from head injury per 100,000 Account for 25% of all trauma deaths High morbidity: 19% vegetative or severely disabled 31% good recovery ```

Answer 1389

``` Non-missile and missile Non-missile acceleration/deceleration rotation RTA, falls and assaults Focal or diffuse ```

Answer 1390

Fissure fractures often extend into base of skull May pass through middle ear or anterior cranial fossa Otorrhea or rhinorrhea Infection risk Blood pooling at mastoid process Eye lid swelling

Answer 1391

Brain in collision with skull Surface “bruising” If pia mater torn then becomes laceration Lateral surfaces of hemispheres, inferior surfaces of frontal and temporal lobes Coup or contrecoup

Answer 1392

Diffuse axonal injury Occurs at moment of injury Shear & tensile forces affecting axons Midline structures particularly affected e.g. corpus callosum, rostral brainstem and septum pellucidum

Answer 1393

Tumours that originated within the CNS Primary CNS tumours are rare in adults (1-2%) Second most common cancer in children (25%)

Answer 1394

(Metastases): 10x more frequent than primary tumours in adults (30% of patients with systemic cancer)

Answer 1395

Tumours of bone, cranial soft tissue, meninges, nerves, metastatic deposits

Answer 1396

Derived from the normal cell populations of the CNS glia, neurons, vessels, connective tissue.. Derived from other cells types metastases, lymphomas, germ cell tumours

Answer 1397

Mainly unknown Radiation to head and neck: meningiomas, rarely gliomas Neurocarcinogens? Genetic predisposition <5% of primary brain tumours Familiarity Familial syndromes

Answer 1398

``` Neurofibromatosis 1 (17q11) AD ``` NF1: NEUROFIBROMA, PILOCYTIC ASTROCYTOMA

Answer 1399

``` Neurofibromatosis 2 (22q12) AD ``` NF2: SCHWANNOMA, MENINGIOMA

Answer 1400

``` Neurofibromatosis 1 (17q11) AD ``` NF1: NEUROFIBROMA, PILOCYTIC ASTROCYTOMA

Answer 1401

``` Neurofibromatosis 2 (22q12) AD ``` NF2: SCHWANNOMA, MENINGIOMA

Answer 1402

Von Hippel Lindau (3q25) | HEMANGIOBLASTOMA

Answer 1403

Headache, vomiting Change in mental status Supratentorial Focal neurological deficit Seizures Personality changes Headache, vomiting Change in mental status Supratentorial Focal neurological deficit Seizures Personality changes Signs and symptoms can be subtle in slowly growing tumours Short history in aggressive tumours Non-neoplastic lesions can mimic CNS cancer!

Answer 1404

A. SURGERY Maximal safe resection aims to obtain an extensive excision with minimal damage to the patient Age and performance status Resectability: location, size, number of lesions B. RADIOTHERAPY Low and high-grade gliomas, metastases External fractionated RT, stereotactic radiosurgery, whole brain C. CHEMOTHERAPY Mainly for high-grade gliomas (temozolomide) Biological agents (EGFR inhibitors, PD-1 inhibitors etc)

Answer 1405

Craniotomy for debulking –subtotal and complete resections (as much tissue as possible) Open biopsy – inoperable but approachable tumours (about 1cm) – more accurate Stereotactic biopsy – inoperable tumours (about 0.5cm tissue) – tissue may not be representative

Answer 1406

Tumour type: putative cell of origin Tumour differentiation: grading note: metastases are not graded Tumours defined by genetic profile: INTEGRATED DIAGNOSIS ``` No staging (like TNM) exception: medulloblastoma ```

Answer 1407

Grade I - benign - long-term survival Grade II - cause death in more than 5 yrs Grade III - cause death within 5 yrs Grade IV - cause death within 1yr

Answer 1408

``` Diffuse infiltration - grades ≥ II - adults - malignant progression Astrocytomas (grades II-IV) Oligodendrogliomas (grades II-III) ```

Answer 1409

Glial tumours

Answer 1410

Circumscribed gliomas - grades I-II - children - rare malignant transformation Pilocytic astrocytoma (grade I) Pleomorphic xanthoastrocytoma (grade II) Subependymal giant cell astrocytoma (grade I)

Answer 1411

DIFFUSE GLIOMAS IDH1/2 mutations Positive prognostic factor

Answer 1412

MAPK mutations (BRAF)

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