VERTICAL MODULES

NRTI (e.g. AZT): Competitive analogues of nucleosides. AZT behaves as a thymidine analogues and prevents DNA extension. When incorporated into DNA, it causes chain termination due to lack of 3' -OH. NNRTI: Non-competitive. Bind to hydrophobic pocket near the catalytic site of HIV-1 RT.

Reverse Transcriptase Inhibitors (MoA)

Drug binds reversibly. Competes with agonist binding. Produces a *rightward shift*. The effect is surmountable.

Reversible Competitive Antagonism

Classical pathway Alternate pathway Lectin pathway

Revise COMPLEMENT (watch YT video)

Destruction / dissolution of striated muscle.

Rhabdomyolysis

an antigen on surface of red blood cells of Rh+ individuals.

Rhesus Factor (Rh)

· >65 years · Antimicrobial use (within the last three months) · Hospitalisation · Pregnant women Patients with the infection should be kept in isolation.

Risk Factors for C. difficile Infection

Age (>50) Inflammatory bowel disease Personal or family Hx Genetic syndromes (FAP, HNPCC) Lifestyle (lack of physical activity, low vegetable intake, low-fibre and high-fat diet, alcohol consumption).

Risk Factors for Colorectal Cancer

(1) Smoking cigarettes (2) Radon (a radioactive gas found in soil). (3) Exposure to radiation → such as repetitive imaging (e.g. X-ray). (4) Asbestos (5) Environmental tobacco exposure (6) Genetics (7) Other lung diseases

Risk Factors for Lung Cancer

Damage to ciliated epithelium Underlying disease Immunocompromised Drugs (e.g. proton pump inhibitors)

Risk Factors for Pneumonia

Immunosuppression Age (infant, adolescent, elderly) Trauma Infection Asplenia

Risk Factors: Meningitis

Immunosuppression PVD IDU Chronic joint disease Recent surgery Recent trauma

Risk Factors: Osteomyelitis

Migrants from Africa, Asia, Pacific. Immunosuppressed (HIV, AIDS).

Risk Groups for TB Infection

Centric fusion translocation. The long arms of two *acrocentric chromosomes* become joined to a common centromere, resulting in a chromosome with two long arms and usually another chromosome with two short arms.

Robertsonian Translocation

Controls the GI tract motility.

Role of Myenteric Plexus

These neurons transmit APs which generate contraction in muscles. They release ACh at their terminals, which acts on nicotinic receptors present in the muscle cell membrane.

Role of Somatomotor NS

Controls absorption and mucous secretion.

Role of Submucosal Plexus

Short-term process that occurs in response to tissue injury. Usually appears within mins / hours. Delivers WBCs and plasma proteins to site of injury. The WBCss clear the invaders and remove necrotic tissue.

Role of acute inflammation

Search, ingest and destroy bacteria. Usually occurs in tissues (not bloodstream).

Role of neutrophils.

Vasodilator (relaxes vascular SM). Inhibits platelet aggregation. Inhibits leukocyte endothelial interactions (hence, anti-inflammatory).

Roles of NO

Haematogenous spread (through blood). Direct inoculation into CNS (trauma or iatrogenic). Contiguous spread (local infection → dental / ear). PNS into CNS (viral spread).

Routes of Infection: Meningitis

*Haematogenous* - Monomicrobial - Staph. aureus *Exogenous* - Direct or Contiguous - Polymicrobial. - Staph. aureus

Routes of Infection: Osteomyelitis

Local spread (mucosa then submucosa then muscular then serosa, then adjacent structures). Perineural (growth up nerves) Lymphatic spread Haematogenous spread Trans-coelomic spread (body cavity)

Routes of Neoplastic Spread

Enteral Parenteral

Routes of drug administration

Redness

Rubor

Shigatoxin- / Verotoxin- producing E. coli

STEC / VTEC

*Organism*: Strep. pyogenes Follows pharyngitis. *Risk Groups*: Children (5-15yrs) *Treatment*: Penicillin (macrolides if penicillin allergy).

Scarlet Fever: → Organisms → Risk Groups → Treatment

Bias introduced when screening detects a disease earlier and thus lengthens the time from diagnosis to death. Hence, for screening to be effective if must extend life beyond the lead time.

Screening Biases: Lead Time Bias

Fast-growing tumours progress rapidly, so screening is less likely to detect these. Screening at infrequent intervals thus detects more slow growing tumours with a good prognosis.

Screening Biases: Length Bias

Screening may detect abnormalities of questionable malignancy that wouldn't have been diagnosed in the absence of screening.

Screening Biases: Over-diagnosis Bias

People who take up screening may differ in their underlying risk of disease and / or mortality so that their prognosis would have differed from non-participants, even in the absence of screening.

Screening Biases: Selection Bias

1st / 2nd trimester ultrasound: maternal serum markers (result is LOW or INCREASED risk). Then, amniocentesis is performed. New Technology: Non-invasive prenatal screening (NIPS).

Screening Programmes for Down Syndrome (Describe the current vs. new technology).

*AUDIT-C:* This is another questionnaire that looks at the patterns of alcohol use. · How often · How many standard drinks · How often >6 drinks on one occasion

Screening for Alcoholism: AUDIT-C

*CAGE:* This is a questionnaire that patients fill out. It asks them about the following: · Considered Cutting down drinking? · Have people Annoyed you by criticising your drinking? · Have you ever felt Guilty about your drinking? · Have you ever had a drink first thing in the morning? (Eye opener)

Screening for Alcoholism: CAGE

Statins Aspirin BP management in people with established CVD

Secondary Prevention: Ischaemic Heart Disease

Healing by secondary intention. - Edges of wound are not closed. - Vulnerable to infection. - Wound has an ulcer base. - More inflammation, granulation tissue, etc. - Wound contraction via myofibroblasts.

Secondary Union

Proportion of people with disease who test positive. a/(a+c)

Sensitivity

(1) Inflammation (2) Suppuration (3) Sequestrum (4) Involucrum (5) Resolution OR Complications

Sequences of Events: Pathogenesis of Osteomyelitis

Ceasing smoking for ~24 hours

Serious Quit Attempt (smoking)

Thalassemia major Thalassemia intermedia Thalassemia minor

Severities of Thalassemia

*Common Species*: Shigella sonnei *Transmission*: Faecal-oral *Location*: Occurs in small and large bowel. *Clinical Presentation*: Diarrhoea (dysentery → mucous, blood in stools).

Shigella → Common spp. → Transmission → Location → Clinical presentation

Offer molecular genetic testing to the adult siblings of a proband homozygous for Cys282Tyr to allow early diagnosis and surveillance.

Should siblings of an HFE-HH patient be screened?

Immunosuppressant: Increased risk of infection. Osteoporosis: Activates osteoclasts and reduces the body's ability to absorb calcium. Cushingoid Effects: due to high concentrations of steroids. Hypertension: Overstimulation of a receptor which causes sodium retention in kidney → body retains fluid → extra fluid in circulation → increased BP. Interfere with Tissue Regeneration: Decreases fibroblast function = decreased collagen production = prolonged healing.

Side Effects: Corticosteroids [Rheumatoid Arthritis]

Since it inhibits COX-1, there are side effects such as gastric ulcers (due to blocking of mucosal secretions). Detail: internal bleeding and anaemia can result from these stomach ulcers. *Celebrex* specifically inhibits COX-2, such that there are less gastric side effects, BUT increases risk of a CV event.

Side Effects: NSAIDs [Rheumatoid Arthritis]

Slurred speech Change in mood / personality Amnesia N & V Respiratory depression ...etc...

Signs of High Alcohol Intake

No effect.

Silent mutation

Block interaction with cellular receptor (prevents attachment). Fusion inhibitors (prevents pentration). Inhibitors of uncoating. Integrase inhibitors. Inhibitors of nucleic acid synthesis (& therefore viral genome replication). Protease inhibitors (HCV: polyprotein processing; HIV: maturation) → impairs assembly. Neuraminidase inhibitors → impair viral release and maturation.

Sites of Antiviral Drug Action

Context: HIV CCR5 inhibitors (e.g., Maraviroc) · Prevents binding of gp120 to co-receptor

Sites of Antiviral Drug Action: Blocking interaction with cellular receptor

Context: HIV e.g., Enfuvirtide → Peptide analogue of fusion domain of gp41 inhibits fusion.

Sites of Antiviral Drug Action: Fusion inhibitors

Context: HSV-1, HSV-2, VZV · Acyclovir is converted to its triphosphate form (viral thymidine kinase is required for activation). Its activated (ACV-TP) inhibitors nucleic acid synthesis. Context: CMV (cytomegalovirus) · Ganciclovir also requires activation by phosphorylation (via ganciclovir) in order to carry out its effects. Hence, mutation of ganciclovir can lead to resistance.

Sites of Antiviral Drug Action: Inhibitors of nucleic acid synthesis

Context: Influenza A Amantadine binds influence A M2 protein, inhibiting uncoating. A mutation in the M2 protein can result in resistance.

Sites of Antiviral Drug Action: Inhibitors of uncoating

Context: Influenza Virus These prevent the reason of influenza virus (A and B). They are good for severe infections.

Sites of Antiviral Drug Action: Neuroaminidase inhibitors

Context: Hep C Hep C is transmitted via bodily fluids (hence common in IDUs). It can be cleared acutely or progress to a chronic infection → cirrhosis of liver → liver failure / liver carcinoma. It infects hepatocytes by binding to surface receptor, entering cell and then undergoing transcription and translation. The translation and polymerisation can be targeted via protease inhibitors and polymerase inhibitors, respectively. The NS5A replication complex can also be targeted. · Protease Inhibitors (NS3B inhibitors). · Polymerase Inhibitors (NS5B inhibitors). · NS5A Inhibitors These are used in combination to prevent resistance.

Sites of Antiviral Drug Action: Protease inhibitors

Destruction of exocrine glands. Dry eyes & dry mouth. Type 2 sensitivity.

Sjögren's Syndrome

...likelihood of quitting

Smokers overestimate their...

• Loss of life and life quality • Loss of output due to temporary incapacitation • Medical costs • Legal costs • Vehicle damage costs

Social costs of a road crash / injury include...

the medicalisation of the patient's problem by both the patient and physician

Somatic fixation

Occur in somatic cells during life of the individual (incl. embryo stage). Only cells derived from initial mutated cell will have obtained the mutation. Cannot be inherited / transmitted to offspring. Depends on what cell the mutation occurs on & whether it will express the mutated gene.

Somatic mutations

Bodily symptoms in relation to psychosocial distress.

Somatisation

*Immune cells* (granulocytes → mast cells & basophils) produce histamine and store it within granules. Fast release when they degranulate. *Neuroendocrine production* of histamine is slower (since its not stored in histaminergic neurons or ECL cells).

Sources of Histamine

Proportion of people without the disease who test negative. d/(b+d)

Specificity

*Type of Drug*: K+ sparing diuretic / MR-inhibitor. *Site of Action*: Distal tubules and collecting ducts. Binds on basolateral side. *MoA*: Aldosterone antagonists which competitively bind to and prevent translocation of MR receptor (hence, preventing nuclear transport of aldosterone). *Effects*: Conserves potassium. *Dependent On*: Aldosterone concentration (high aldosterone level = greater diuretic effect). *Pharmacokinetics*: Oral delivery with 70% adsorption in GI tract. First pass metabolism. Extensively protein bound. *Toxicity*: Hyperkalemia, Androgen-modulating effects, Gynaecomastia (male femininity) and GI disturbances.

Spironolactone → Type of Drug → Site of Action → Mechanism of Action → Effect → Dependent on... → Pharmacokinetics → Toxicity

Cells which have a low level of replication, but can regenerate upon stimulus. EXAMPLE: Liver hepatocytes (stimulated by excessive alcohol consumption).

Stable cells

Normal cell Pyknosis Karyorrhexis Karyolysis Cellular releases of contents → infarction.

Stages of Necrosis

10g alcohol

Standard Drink

*Organism*: Staph. aureus *Risk Groups*: Babies & young children. *Treatment*: Flucloxacillin (if MRSA, Vancomycin).

Staphylococcal scalded skin syndrome: → Organisms → Risk Groups → Treatment

Gram-positive cocci in clusters. Facultative anaerobe. Opportunistic pathogen. Catalase positive. Antimicrobial resistant. Often results in localised infections.

Staphylococcus auerus: → Gram-stain → Appearance → Respiration → Type of pathogen → Catalase (+) or (-) → Resistance → Type of infection

accumulations of fat (lipid droplets) in cytoplasm. Example: alcoholism leads to steatosis in liver cells.

Steatosis

(1) Define and measure problem. (2) Describe causes. (3) Develop & evaluate interventions. (4) Disseminating effective policy & practice. (5) Monitoring!

Steps for Prevention of Disease

Formulate clinical question. Search for studies. Select studies. Assess quality of studies. Extract data. Meta-analysis.

Steps of Systematic Review

(1) *Define and measure the problem*: young people (15-24 y/o). (2) *Describe causes*: we are interested in modifiable causes. (3) *Develop and evaluate interventions* (4) *Disseminate effective policy and practice* (then continual monitoring)

Steps to applying the public health model to young driver crashes

UAA, UAG, UGA (Does not code for an amino acid; it is recognised by the enzyme which completes transcription).

Stop codons

See information sheet. [Page 5, Vertical Answers #4]

Strengths & Limitations of Biomedical and Biopsychosocial Models

• Rare outcome • Transient exposures • Multiple exposures • Temporal sequencing • Quick & inexpensive

Strengths of Case-Control Studies

· Temporal sequencing · Can examine multiple outcomes · Can calculate incidence · Can study rare exposures.

Strengths of Cohort Studies

Alpha-haemolytic

Strep. viridans will appear GREEN on blood agar because it is...

Gram-positive cocci in chains. Facultative anaerobe. Opportunistic pathogen. Catalase negative. Not very resistant. Often results in spreading infections.

Streptococcus pyogenes: → Gram-stain → Appearance → Respiration → Type of pathogen

Page 51 (Vertical Answers #2)

Structure of viral vector for gene transfer

AKA generalisability. Can the results be applied outside of the study? Depends on who was included in study, definitions of expose and outcome, etc.

Study Appraisal: *External Validity*

Are the results valid within the study? Consider: chance, bias, confounding.

Study Appraisal: *Internal Validity*

Assess using Bradford-Hill criteria.

Study Appraisal: Evidence for *Cause-Effect* Relationship

Change in a chunk of chromosome. Deletion / duplication / inversion / insertion / translocation. Severe gene dosage consequence. Natural abortion.

Sub-chromosomal Mutations

Localised OM that presents with few clinical signs. Little / no pain. May persist for years.

Subacute Osteomyelitis

Environment (diet) factors Menstruation

Suggest a reason by haemochromatosis penetrance is less common in females.

A variable that provides an indirect measurement of effect in situations where direct measurement of clinical effect is not feasible or practical. In other words: A variable that can be measured (or is easy to measure) that is used in place of one that cannot be measured (or is difficult to measure).

Surrogate variable

Depolarising NMB. Indication: Rapid intubation. Administration: IV injection. • Fasciculations (twitching) within 1 min followed by relaxation. Common SEs: Bradychardia at low doses (parasympathetic activation). Tachycardia at high doses (sympathetic action at ganglia). Muscle pain due to excessive contraction. Hyperkalemia due to excessive contraction. Intercranial tension (neck muscle contraction).

Suxamethonium → What is it? → Indications → Administration → Side Effects

HIV-infected person on effective ART cannot transmit HIV through sexual contact. This was supported by a number of studies that followed which showed that condomless sex acts between couples where one partner was infected with HIV (and on ARTs) resulted in, effectively, no transmissions.

Swiss Statement (2008)

Triad (Fever, Stiff neck, Headache). Altered mental state Skin rash Vomiting Diarrhoea Photophobia Muscle pain Papilloedema Seizure

Symptoms: Meningitis

Acute joint inflammation & swelling Arthralgia Pseudo paralysis Systemic signs (fever)

Symptoms: Septic Arthritis

Triad of Symptoms: • Urethritis / Cervicitis • Conjunctivitis / Uveitis • Arthritis of large joints/ sacroiliac joint. Essentially: Eye, Joint and GUT inflammation.

Symptoms: Reactive Arthritis

Focus on answering a research question by critically appraising a number of studies, summarising the results and drawing conclusions.

Systematic Reviews

Effective treatments Serious harms of treatments Ineffective treatments

Systematic reviews enable timely identification of:

Fatigue Loss of appetite Weight loss Fever Night sweats Chills Aches & pains

Systemic signs of acute inflammation

important fibroblast growth factor, but also inhibits inflammation

TGF-beta

macrophages

TGF-beta is produced by...

"to follow the right path" The name given to Māori ethical principles.

Te Ara Tika

ACh needs to be degraded fast (removed from cleft) via the enzyme AChE. This enzyme hydrolyses the ester bond, allowing for the release of acetate and inactive choline.

Termination of the action potential involves...

Somatisation Functional illness MUS (medically unexplained symptoms) BDS (bodily stress syndrome)

Terms Used for Persistent Symptoms

Cardiac rehabilitation programmes

Tertiary Prevention: Ischaemic Heart Disease

Tezacaftor is also a corrector.

Tezacaftor-Ivacaftor (Symdeko)

Reduced but variable amount of alpha / beta product.

Thalassemia intermedia

No alpha / beta product. [α0 or β0] Clinical Findings: anaemia, splenomegaly, abnormal bone development, iron overload. Life expectancy is < 5 yrs if untreated, and 30+ yrs if treated.

Thalassemia major → What is it? → Clinical Findings → Life Expectancy

Carriers. Unaffected or mildly affected. [α+ or β+]

Thalassemia minor

Env (envelope glycoproteins). Gag (nucleocapsid proteins). Pol (enzymes for nuclear replication). Accessory proteins.

The HIV genome encodes for what types of proteins?

· Inflammatory cell activation (COX, NF-κB) → note: NF-κB is Nuclear Factor Kappa B · Immune cell proliferation (nucleotide synthesis) · Cytokine signalling (TNF, IL-12, IL-23) · Microbiota

The IBD drug targets are:

rheumatic fever.

The M-protein enables Strep. pyogenes to induce what condition?

(1) Whānau rooms and taoka (2) Karakia (3) Whānau support (4) Information and support (5) Body parts, tissues, and substances (6) Food, linen, and bed pans (7) Pending and following death [see document / reading]

The Tikanga Best Practice Guidelines include...

Sensitivity

The ability of the test to correctly identify those with the disease.

Specificity

The ability of the test to correctly identify those without the disease.

transient or permanent.

The chemical modifications to DNA are either...

3.6% [see Page 92, Vertical Answers #3]

The incidence of CF in NZ is ~1/3000 newborns. Calculate the approximate carrier frequency in NZ.

volume of distribution

The more compartments a drug gets into, the greater the...

O157:H7

The most common E. coli strain is:

Negative predictive value

The probability that a person with a negative test does not have the disease.

Positive predictive value

The probability that a person with a positive test is a true positive.

80%

The second X chromosome is ____% inactive.

Avoidance. Block mast cell triggering. Corticosteroids. Immunotherapy.

Therapy Options for Asthma

allelic heterogeneity

There are 600 mutations can result in Haemophilia A, which displays...

level of Hb in the blood. (i.e. a low level of haemoglobin is correlated with high bilirubin).

There is a strong correlation between bilirubin in amniotic fluid and the...

Unstable angina & MI DVT Pulmonary embolism Transient ischemic attacks & stroke

Thromboembolic diseases can *lead to* conditions such as...

Atherosclerotic plaque rupture CAD Atrial fibrillation Hypokinetic ventricles

Thromboembolic diseases can *result from conditions* such as...

To act in accordance with tikanga is to *behave in a way that is culturally proper or appropriate.*

Tikanga

Early: depletion of CD4 cells from intestine. Widespread dissemination of HIV to lymphoid tissues. Non-specific symptoms. 2-12 Years: Decline in viral load (to viral "set point"), which corresponds with CD8 T cell response. Asymptomatic phase.

Timeline of events following primary HIV infection

*Enterobacteriaceae* (E. coli) can cause sepsis, abscesses and peritonitis. If perforates bowel, it can contaminate at distant site (e.g. diabetic foot ulcer). Anaerobes (especially *Bacteroides fragilis*) → cause tissue infections such as polymicrobial abscesses. Facultative anaerobes use up O2, enabling anaerobes to grow. *Clostridium perfringens* can cause gas gangrene. It possesses enzymes which breakdown host tissue into nutrient sources for the bacteria, leading to gas production and rapid tissue necrosis. Normally, other commensals prevent its proliferation so is usually harmless.

Tissue Infections → E. coli → Anaerobes → Clostridium perfringens [opportunistic organisms of gut]

rt-PA = recombinant t-PA MoA: Increase cleavage of plasminogen to release plasmin → plasmin digests fibrin, fibrinogen and other proteins → thus enhancing the breakdown of *already-formed thrombi*. Optimal Outcome: Increase survival post-MI and stroke. Administration: IV within 6 hours post-MI.

Tissue Plasminogen Activator (tPA) → MoA → Optimal Outcome → Administration

IgG avidity

To determine if the infection occurred recently, we could measure...

a) Lung, larynx, kidney, pancreas, bladder. b) Oral cavity, oesophagus.

Tobacco consumption... a) causes what types of cancer? b) with alcohol consumption, causes what types of cancer?

Raw (unpasteurised) milk Airborne spread → cough, sneeze, spit.

Transmission Pathways of Mycobacterium Tuberculosis

Faecal-oral

Transmission: Hepatitis A Virus (HAV)

Blood Sexual

Transmission: Hepatitis B Virus (HBV)

Blood

Transmission: Hepatitis C Virus (HCV)

Blood Sexual

Transmission: Hepatitis D Virus (HDV)

Faecal-oral

Transmission: Hepatitis E Virus (HEV)

Treating *single factors* in isolation may not be as effect as targeting treatment to individuals who have a *high baseline risk*.

Treating __________ in isolation may not be as effect as targeting treatment to individuals who have a ___________.

· Acute detox (in hospital or community) · Psychoeducation · Community Alcohol and Drug Service (CADS) and peer support networks (e.g., AA). · Brief intervention · Drug treatment

Treatment Options for Alcoholism

Testosterone replacement. Fertility treatment options.

Treatment Options for Klinefelter Syndrome

Prophylaxis: PPIs, mucosal strengthener, or H2 receptor antagonists. If ulcer is present, discontinue NSAIDs and use PPI, H2 antagonist or misoprostol. If ulcer present, but cannot discontinue NSAIDs, switch to more selective COX-2 inhibitor and use PPI. Once healed, continue PPI or switch to misoprostol.

Treatment for NSAID-associated peptic ulcers

(1) Lifestyle changes (decrease alcohol, fewer aggravating foods, smaller volume meals, do not eat before bed). (2) Antacids (tablet / liquid).

Treatment for mild GORD (<1 attack weekly)

(1) PPI If ineffective... (2) H2 receptor antagonist If ineffective... (3) Consider H. pylori. Once confirmed, treat with antibiotics.

Treatment for severe GORD (2+ days / week)

Supportive care (hydration, nutrition, thiamine supplements, monitor for other illnesses such as encephalopathy). Medication only if serious (benzodiazepaines, 10mg/hr → they act as GABA receptor and inhibit sympathetic arousal).

Treatment of Alcohol Withdrawal

Cessation of the inducing antimicrobial therapy + Oral administration of either metronidazole or vancomycin

Treatment of C. difficile Infection

Start treatment with LABA and/or LAMA without ICS.

Treatment of COPD

(1) Removal of biofilm-infected objects. (2) Antimicrobial treatment. → Early aggressive treatment to avoid maturation of biofilm. → Chronic treatment should be suppressive (post-biofilm). → Future: antimicrobials + QS inhibitors.

Treatment of Clinical Biofilms

Omeprazole (20mg) + two of the antibiotic drugs. Treatment should occur over 14 days. ANTIBIOTICS: Amoxicillin Metronidazole Clarithromycin

Treatment of H. pylori Infection

Multi-drug resistant. Therapy is problematic & requires combinations of antimicrobials or broad-spectrum antimicrobials. Treatment: anti-pseudomonal penicillin + aminoglycoside OR anti-pseudomonal penicillin + beta-lactamase

Treatment of P. aeruginosa

Multidrug regimen for >6 months (if extrapulmonary TB, treatment for up to 1 year). · Rifampicin and isoniazid for 6 months. · ALSO, pyrazinamide and streptomycin for first 2 months. Healthcare provider / other responsible person should observe digestion of the medication.

Treatment of TB

Empiric treatment at first. 4-6 weeks IV + additional 2-4 weeks oral. Oral administration for kids. Staph. aureus (MRSA) → *Flucloxacillin* Consider surgical debridement (not for children).

Treatment: Osteomyelitis

Symptomatic Treatments: NSAIDs, DMARDs

Treatment: Reactive Arthritis

Core of bone marrow tissue is removed

Trephine Biopsy

Fever Stiff neck Headache (Present 20-66% pts).

Triad of Symptoms: Meningitis

More lipid-soluble glucocorticoid. When delivered into joints, decreases systemic exposure to drug and thus SEs.

Triamcinolone Acetonide

Toxins Food poisoning Electrolyte imbalance GIT disorders Infection Motion Pregnancy hormones Chemotherapy & radiation Medications Anaesthesia Migraine Anxiety

Triggers for Nausea and Vomiting

Functions as a non-depolarising NMB. It is a competitive antagonist of nicotinic receptors. Effect: Causes motor paralysis. Indications: Surgery. Administration: IV (since oral absorption is minimal). Antidote: AChE inhibitor (e.g. neostigmine).

Tubocurarine → What is it? → Effect → Indications → Administration → Antidote

A chromosomal disorder in females. *Clinical Signs*: Neonatal oedema, Webbed neck, Coarctation of aorta, Growth delay, Primary amenorrhoea. • *45,X karyotype* (lack of an X-chromosome). or; • Structural abnormality of one X-chromosome.

Turner Syndrome → Karyotype → Clinical Signs

(1) Non-competitive (2) Competitive

Two Types of Enzyme Inhibition

Interferes with active site of enzyme such that substrate cannot bind.

Two Types of Enzyme Inhibition: (1) Competitive enzyme inhibition

Binds allosterically and change shapes of enzyme upon binding so that it cannot bind its usual substrate.

Two Types of Enzyme Inhibition: (1) Non-competitive enzyme inhibition

Primary union Secondary union

Two Types of Skin Wounds

Vascular component Cellular component

Two components of acute inflammation

*IgE mediated hypersensitivity* Stimulated by Helper T-cells, which produce cytokines. The Helper T-cells interact with B cells, which produce IgE antibody in response to this. IgE binds to mast cells, causing their degranulation. Upon second exposure, allergen binds to IgE (which is already located on FceR receptor of mast cells) → cross-linking of IgE & FceR → degranulation of mast cell → release of mediators (e.g., histamine). OTHER EXPLANATION: Antigen / allergen binds to Fc receptors on the surface of mast cells. IgE recognises the antigen, leading to degranulation of the mast cells → histamine release from granules → vasodilation, erythema, oedema, etc. *Antibody-mediated*

Type 1 hypersensitivity

Antibodies (IgG or IgM) are directed against cellular antigens (i.e. self-antigens present on cell surfaces), with the resultant cellular destruction, functional loss, or damage to tissues. • Cells opsonised by IgG. • IgG / IgM on surface of cells induces complement activation, and hence deposition of products on cells - these are later recognised by phagocytes. *Antibody-mediated*

Type 2 hypersensitivity

Formation of antigen-antibody aggregates (immune complexes) → deposition in vessel walls → neutrophil influx & complement activation → frustrated phagocytosis → neutrophil degranulation → damage due to complement-mediated inflammation. *Antibody mediated*

Type 3 hypersensitivity

Delayed Type: Cytokine-mediated inflammation, Direct cell toxicity / cytolysis is mediated by CD8 cells. DCs (APCs) displays antigen peptide in lymph node → T cells recognise antigen on MHC-1 or MHC-2 → T-cell activation → migration to tissues → cytokine release → inflammatory reaction. *Cell-mediated*

Type 4 hypersensitivity

*FIRST EXPOSURE:* (1) Allergen picked up by tissue-resident immune cells (APCs). (2) APC migrates to lymph node. (3) APC presents antigen to naïve T-helper cells. (4) Differentiation into TH2 cells in response to IL-4, IL-5, IL-10. (Primed T-helper cell) (5) TH2 releases IL-4, causing class-switching of B-cells (such that they produce IgE). (6) Allergen-specific IgE antibodies have high affinity for FcƐR on mast cells, so IgE binds to the mast cells. (7) Sensitisation has occurred. *SECOND EXPOSURE:* (1) Mast cell binds to antigen. (2) Cross-linking of IgE antibodies. (3) Degranulation and release of pro-inflammatory mediators.

Type I Sensitivity [Sequence of Events]

Induced by a tightly regulated suicide programme. Activation of intrinsic enzymes that degrade the cell's genomic DNA and nuclear & cytoplasmic proteins.

Type of Cell Death: Apoptosis

Consequence of severe injury. Denaturation of cellular proteins. Leakage of cellular contents through demaged cell membranes. Local inflammation. Enzymatic digestion of the lethally injured cell.

Type of Cell Death: Necrosis

Paroxysmal (short term). Persistent (responsive to treatment). Permanent, long-standing.

Types of AF

(1) Dihydropyridines (2) Phenylalyklamines (3) Benzothiazepines

Types of CCBs

Selectivity: Has both cardiac depressant and vasodilator actions. Example: Diltiazem MoA: Inhibits calcium influx during membrane depolarisation of cardiac and vascular SM. Indications: *primarily used in AF as a rate controller*. Pharmacokinetics: Highly absorbed. First pass metabolism.

Types of CCBs: Benzothiazepine

Selectivity: Vaso-selective (for arterial smooth muscle). Example: Amlodipine Indications: Hypertension (the drugs reduce systemic vascular resistance and arterial pressure). MoA: Binds to and stabilises inactivated LTCCs, preventing calcium entry. Effect: Dilates peripheral arterioles, thus reducing TPR (after load) and cardiac O2 consumption. Warning: Do not use in angina as excessive peripheral dilation will lead to hypotension → reflex cardiac stimulation → tachycardia and increase ionotropy → increased myocardial ox. demand. Pharmacokinetics: Complete absorption from GIT. Slow onset of action. Hepatic metabolism, and excretion as inactive metabolites in urine. CYP3A4 interactions.

Types of CCBs: Dihydropyridines → Selectivity → Example → MoA → Effect → Warning → Pharmacokinetics

Selectivity: Cardio-selective Example: Verapamil Indications: Angina; Arrythmias. MoA: Binds to *open* LTCCs. Interferes with calcium binding and promotes inactive channel conformation. Slows channel recovery from inactivation, increasing refractory period of the drug-bound channel. Channel inhibition increases as heart rate increases. Effect: Suppresses cardiac contractility, reducing work and ox. consumption. Warning: *Do not administer* to HF patients in conjunction with beta-blockers. Pharmacokinetics: Rapid & complete oral absorption. First pass metabolism. Substrate from CYP3A4 metabolism.

Types of CCBs: Phenylalyklamines → Selectivity → Example → Indications → MoA → Effect → Warning → Pharmacokinetics

Necrosis Apoptosis

Types of Cell Death

SFA = saturated fatty acids (animal fats, palm oil, coconut oil). TFA = trans-fatty acids (vegetable oils, processed foods). MUFA = mono-unsaturated fatty acids (olive, avo, peanut oils). PUFA = poly-unsaturated fatty acids (sunflower oil, fish oil, etc.)

Types of Fats (and the food products they are found in...)

A B C E Delta

Types of Hepatitis Viruses

Four types: A, B, C, D.

Types of Influenza Viruses

Host-material embedded (CF wounds, etc.) Surface attached (impacts, catheters, etc.)

Types of Mature Biofilms (locations)

Acute bacterial meningitis. Viral meningitis. Chronic meningitis.

Types of Meningitis

PAGE 37 Vertical Answers #3

Types of Pneumonia [table]

Ligand-gated ion channels GPCRs Kinase-linked receptors Nuclear receptors

Types of Receptors

(1) Superiority RQ = evaluates if new treatment is superior to existing treatment or no treatment. (2) Non-inferiority RQ = evaluate if new treatment is no worse than an existing treatment.

Types of Research Questions

Modifiable Non-modifiable (we can also group risk factors as upstream vs. downstream).

Types of Risk Factors

salmonella enterica

Typhi and paratyphi serotypes of...

Undetectable = Untransmittable

U = U

*Anticoagulant* (Note: not used as regularly anymore?) MoA: Reduces the formation of fibrin by increasing the action of AT III (antithrombin III) binding with both Factor Xa and thrombin (Factor IIa). Administration: IV infusion (T1/2 = 0.5 - 1 hour). Risks: Haemorrhage; HIT.

UFH (Unfractioned Heparin) → MoA → Administration → Risk

Confirm that organism is susceptible to antimicrobial used. Allows clinician to switch pt. to cheaper / less toxic alternative. Can indicate resistance. Quantitative tests can assist clinician to optimise dosing regime.

Usefulness of Antimicrobial Susceptibility Tests

This is one way in which you can help Māori patients toward hauora and guides the clinician about what information they should obtain when taking a history.

Usefulness of Meihana Model

• The practitioner • Family or friends • Time available • Undue threats or incentives

VOLUNTARINESS What sort of factors may affect the voluntariness of a decision?

Classified on ability to block specific ionic currents & Beta-adrenergic receptor action. Class I Class II Class III Class IV

VW Classification of Anti-arrythmics

Antibody levels decline after vaccination. Memory B & T cells persist, but response may be too slow. Booster vaccination increases antibody levels so that protective.

Vaccination Boosting

Hep A and B

Vaccination is available for which hepatitis viruses?

Conjugate vaccine

Vaccine For: H. influenzae (Type B)

Capsule polysaccharide vaccine

Vaccine For: N. meningitidis

Pneumococcal capsular polysaccharide vaccine Conjugate vaccine

Vaccine For: S. pneumoniae

(1) Brief arteriolar constriction. (2) Vasodilation → warmth and redness. (3) Increased vascular permeability → leaky capillaries. Allows protein-rich exudate to leave circulation. (4) ↑ concentration of red cellss in flowing blood = ↑viscosity = slows circulation (*stasis*). (5) Slowed WBCs begin to accumulate along endothelial wall.

Vascular component of acute inflammation

Cause arteriolar smooth muscle to vasodilate, thus affecting the *afterload*. MoA: Inhibit calcium influx through LTCCs in *arteriolar smooth muscle*. This enables vasodilation (through relaxation in vascular tone in coronary arteries and peripheral arterioles). No effect on veins = do NOT affect the preload.

Vaso-Selective Effect of CCBs (General Mechanism)

Half-life

Vd and Cl can be used to determine...

Observe change in body (e.g. HR) → perceive a threat to health → ANS activation → more symptoms → further cognitions → cycle... Often occurs at rest / asleep BECAUSE: Attention turns to themselves → increases likelihood of awareness of possible physiological change in body → leading to vicious cycle.

Vicious Cycle of Panic Attack

Adhesion proteins for attachment to endothelial cells. Porins (assist translocation across epithelia into BS). Capsule (immune evasion). LOS (pro-inflammatory).

Virulence Factors of N. meningitidis

Different stains = different virulence factors. Produce PVL (leucocidin toxin). Produce *coagulase*. Produce *catalase*. Adhesins, enzymes, capsule, etc.

Virulence Factors of S. aureus

Anti-phagocytic capsules. Ability to inhibit leukocyte activity. Degradation of immunoglobulins. Motility.

Virulent bacteria must resist host defences & multiply. What factors aid their ability to do so?

Volume into which a drug appears to be distributed with a concentration equal to that of plasma. Vd = (amount of drug in the body) / (plasma drug concentration)

Volume of Distribution

an approach that improves the quality of life of patients and their families facing the problems associated with life-threatening illness via early identification and impeccable assessment and treatment.

WHO Definition of Palliative Care

*Anticoagulant* MoA: Prevents Vit K from activating Factors 10, 9, 7, 2 and Protein S & C. Administration: Oral. Takes 24-48 hrs to build effects, but weeks to stabilise. Interactions: Metabolised by CYPs, with adverse interactions via CYP2C9. Interacts with many drugs! Monitoring: INR. In the event of ADR: Withdraw therapy or Reversal of Therapy (Vit K administration - slow acting; Prothrombinex-VF - fast acting; Fresh frozen plasma containing Vit K-dependent factors).

Warfarin → MoA → Administration → Interactions → Monitoring → In the event of ADR

Can induce arrhythmias. [There is a small difference between therapeutic and toxic doses].

Warning: Antiarrythmic Use

5%

What % of population are carriers of haemoglobinpathies?

30% (nasal carriage)

What % pop. carries Staph. aureus?

5-15% (pharyngeal locations)

What % pop. carries Strep. pyogenes?

• Raise minimum licensing age from 15 to 16 • Reduce blood and breath alcohol limits to zero • Discontinue time discount in restricted licence phase

What *were* the proposed changes for GDLs?

Verapamil Diltiazem

What CCB is indicated for the following condition? *Angina*

Diltiazem

What CCB is indicated for the following condition? *Arrythmia*

Dihydropyridines

What CCB is indicated for the following condition? *Hypertension*

· Submucosal enteric nerve cells produce ACh. · ECL cells produce histamine in response to gastrin and ACh. · G cells produce gastrin in response to gastric contents / distention. *Gastrin*, *ACh* and *histamine* act on parietal cells to activate proton pumps. They do so by binding to their respective receptors. This activates a second messenger system (cAMP or calcium), which in turn activates the *hydrogen-potassium proton pump* (H+/K+ ATPase). This promotes acid secretion.

What NTs promote acid secretion? How (specifically) do they do this?

Protein A

What Staphylococcus aureus protein inhibits phagocytosis?

Cytotoxic agents. Affect dividing cells of the marrow. Have more targeted effects on the immune system. Reduce the activity of the immune system. Slow onset.

What are DMARDs?

*Electronic Nicotine Delivery Systems* e.g., vaping Higher rates of 1-year smoking abstinence (compared to NRT).

What are ENDS?

No previous exposure to FVIII. Body raises antibodies against FVIII protein. Therefore, need to slowly build up FVIII exposure in low, repeated doses to develop immune tolerance. Incidence of this is similar in both forms of treatment. EXPENSIVE: $400,000 per person / year.

What are FVIII inhibitors?

PRRs = pattern recognition receptors. They recognise PAMPs, thus stimulating the pro-inflammatory response (innate immunity). Example: TLRs

What are PRRs?

Tobacco Control Treaty Standardised packaging Increased price (but could lead to financial insecurity, so need to funnel $$ back into community). Tobacco smuggling prevention Eliminate tobacco advertising Age restriction of movies Social media (unregulated forum → need to change this somehow).

What are actions that have been / could be taken to reduce smoking prevalence?

Tablet / Liquid form Antacids are salt compounds, often aluminium or magnesium. They do not have much evidence in terms of efficacy but do have SEs. They are generally taken 4x daily, especially before bed.

What are antacids? How and when are they taken?

Ligands that allow docking of lipoproteins to tissues. Examples: ApoB48, B100, A1.

What are apolipoproteins?

Experiments in patients used to evaluate the benefits and risks of treatment. Regulated by regulatory authorities, ethnical and clinical guidelines groups.

What are clinical trials?

Example: SMART (Symbicort single use Maintenance And Reliever Therapy). Symbicort = Budesonide (ICS) + Formoterol (LABA) Benefits: - <1-3 minute onset. - Better outcomes in combination than when taken seperately. - Allows steroid dose to be reduced (minimises ADRs).

What are combination inhalers? Provide an example.

(1) Sequence the genes. (2) Look for small scale dels & dups. (3) Look for larger dels & dups that encompass the relevant genes (via chromosomal microarray).

What are different methods to assay for deletions and duplications of different sizes in the genome?

Short sequences of DNA located upstream (before promoter region). Bind *activator TFs* in order to enhance transcription. DNA bends and enables the interaction of the enhancers with TFs and the promoter region.

What are enhancers?

Granulocytes (phagocytic). Have a role in immune defence against parasites (and allergy). Release cytotoxic granules (against parasites); in allergy, these contribute to skin itching and bronchial irritability.

What are eosinophils? Role in allergy?

The chemical covalent modifications of DNA that result in changes to the regulation of genes (w/o altering the DNA sequence).

What are epigenetics / epigenomics concerned with?

Twitching

What are fasciculations?

Eukaryotes (similar to human cells → poses a treatment difficulty). Fungi have ergosterol in their lipid membrane (rather than cholesterol). Grow as yeast or mould.

What are fungi and how do they grow?

Corticosteroid hormone. Effect: Reduce inflammation and suppress immune system. Synthesised by adrenal cortex and act on nuclear receptors, altering gene transcription.

What are glucocorticoids? → Effect → Location of synthesis

Packaging proteins which enable the DNA to fold. There are 4 Types, which two of each type in each nucleosome. Thus, a nucleosome comprises 8 histones.

What are histones?

Different molecular forms of an enzyme which *catalyse the same reactions* and which have small differences in the AA sequence.

What are isoenzymes?

Microbe-mediated: Damage to the host tissues ensues through production of exotoxins, enzymes &/or host cell invasion. Host-mediated: The immune & inflammatory response against the pathogen also causes damage. Both contribute to pathology.

What are microbe-mediated and host-mediated pathogenesis?

Drugs which mimic the vasodilatory actions of endogenous NO. They release NO in plasma or form NO from within cells. Increase venous capacitance = less venous return = less pressure on cardiac walls. Less ox. consumed = ↓ subendocardial BF = improved myocardial perfusion in diastole. Examples: Sodium nitroprusside Organic nitrates (GTN)

What are nitrodilators?

Located in stomach or duodenum. Caused by either: (1) Imbalance in protective vs. damaging agents. (2) Infection of gastric mucosa with H. pylori

What are peptic ulcers?

Short sequences of DNA located upstream (before promoter region). Bind *inhibitor TFs* rather than activators, thus decreasing rate of transcription.

What are silencers?

Vaccination Antimicrobials Public health Education Stable government

What are some human interventions to control communicable disease?

*Medication:* prolonged NSAID use. Reduces mucous and mucosal blood flow, damages epithelium, and impairs healing and immunity. *Zoolinger-Ellison Syndrome:* Excess acid secretion by tumours. It is treated to control acid, or via chemotherapy. *Stress:* Cortisol increase following traumatic injury / brain injury e.g., stroke or burns.

What are some non-infectious causes of peptic ulcers?

Physical examination X-rays Isotope bone scan CT scan MRI scan PET scan Tumour markers

What are some techniques used for staging tumours?

HMG-CoA reductase inhibitors. They are sstructural analogues of HMG-CoA reductase's substrate (which is HMG). Example: Atorvastatin

What are statins? Provide an example.

· Land appropriation · Transfer of resources → fisheries, farms, etc. · Transfer of politic power · Cultural subjugation → example: suppression of Te Reo Māori language in schools; suppression of Māori metaphysics to be replaced by Christianity; white supremacy.

What are the "elements" to colonisation?

Allergen + Serum factor (IgE) + Tissue factor (mast cells)

What are the "three components" of allergy?

(1) What was going on in your life when the symptom(s) started? (2) Are there times when the symptoms are less likely to be present? (3) Are there times when the symptoms are more likely to be / always present? (4) Is your symptom ever related to stuff on your plate, pressure, responsibility, or relationship challenges, etc.?

What are the *four key questions* would you ask a patient whom you suspect to have a functional illness? [*important*]

· Building and maintaining trust · Increasing access · Enhanced communication and information sharing · Patients not leaving identity (or being Māori) "at the door" · Reputation and positive future engagement · Greater patient satisfaction · Increased adherence with medical and management · Greater sense of partnership · Increased quality of care · Better consultation and health outcomes

What are the benefits of cultural safety?

Benefits growth. Prevents malnutrition (which would otherwise affect cognitive function). Pulmonary benefits.

What are the benefits of newborn screening for CF (via heel-prick test)?

Iron supplementation Blood transfusion Acute infection HFE mutation

What are the causes of high ferritin levels (other than HFE-HH)?

(1) Abnormality of growth (a syndrome). (2) Intellectual disability. (3) Recurrent miscarriages. (4) Cancer investigation.

What are the clinical indications for assessing chromosomal structure?

Lymph nodes, liver, lungs, bone, skin, brain. Less likely are ovaries, kidney, muscle, and heart.

What are the common sites of cancer spread?

(1) Condition suitable for screening (2) Suitable test (3) Effective & accessible treatment / intervention (4) High-quality evidence (such as RCT) that screening programme will reduce mortality (5) Potential benefits outweigh potential harms (6) Health sector capable of supporting diagnosis, follow-up and programme evaluation (7) Consideration of social & ethical issues (8) Consideration of cost-benefit issues

What are the criteria for assessing screening programmes?

The donated blood undergoes purification, but only enveloped viruses are removed / inactivated. So viruses without envelopes, such as Hep A, may not be effectively inactivated.

What are the dangers of use Factor 8 concentrates from plasma?

Potentially teratogenic. Inhibits cholesterol formation and can affect developmental genes.

What are the dangers of using statins in pregnancy?

Fungi are eukaryotes (similar to human cells), however they have a cell wall and different cell membrane composition (which *can* be targeted). Many drugs that inhibit / kill fungi are quite toxic for humans (i.e., there is a low therapeutic index).

What are the difficulties with antifungal drugs?

CF shows allelic heterogeneity. Most common: F508 del mutation. There are different functional consequences depending on the type of mutation.

What are the genetic mutations that lead to a defective chloride channel?

Histamine acts through GCPRs: H1, H2, H3, H4. · H1 = low affinity receptors. Role in *allergic inflammation*. Bind of histamine modulates endothelium and vascular permeability. · H2 = low affinity receptor. Has a role in gastric acid secretion. · H3 = high affinity receptor. Has a role in neurotransmission. · H4 = high affinity receptor. Has a role in immunomodulation (affects immune cells).

What are the histamine receptors? For each, state its role.

5% hospital admitted patients will develop pneumonia, and 25% of those artificially ventilated. Onset ~48hrs following admission. *VAP = Ventilator Associated Pneumonia* Causative Organism: typical & atypical. Gram-neg rods cause most causes. Often a polymicrobial infxn so requires drug combinations. High mortality! *Aspiration Pneumonia* Secretions from URT / GIT are breathed into lungs. Risk factors include intubation and mechanical ventilation.

What are the hospital acquired pneumonias?

Arrythmias

What are the indications for antiarrhythmic drugs?

It is important to know that: · Fungi, unlike human cells, have a cell wall. · Fungi have ergosterol in their lipid membrane (rather than cholesterol).

What are the key targets for antifungal drugs?

Bronchial obstruction · Collapse · Endogenous lipoid pneumonia · Infection / Abscess · Bronchiectasis Pleural involvement Direct invasion to chest wall, nerves, mediastinum (SVC, pericardium) and intrapulmonary lymph nodes.

What are the local effects of lung cancer?

(1) Natural selection: The antibiotic establishes a selective pressure. Only bacteria which survive proliferate. (2) Horizontal gene transfer: Resistant bacteria pass genes to susceptible bacteria. Note: it is easier to acquire resistance genes from another bacterium than to rely on mutation.

What are the mechanisms that allow antibiotic resistance to spread?

Virulent microbe + Susceptible host = Infection

What are the necessary events that should happen / components in order for an infection to occur?

De nono mutation Mistaken paternity Very low penetrance

What are the possible causes of an abnormal phenotype, but with no family history?

SNS arousal Seizures Appear at 12 hours, and peak at 48 hours. With increased severity of consumption, there is increased severity of withdrawal symptoms (higher risk of seizure).

What are the signs and symptoms of alcohol withdrawal? Describe the timeframe.

· Antenatal screening · Newborn Metabolic Screening Programme · Universal Newborn Hearing Screening Programme · Cervical screening · Breast screening · Bowel screening

What are the six organised screening programmes overseen by New Zealand's National Screening Unit?

- Risk is predominantly determined before age 25 and lasts a lifetime. - May be influenced to a small degree later in life. - Reduction in risk is greater for cancer of the colon than rectum. - Unknown factor influencing trends took effect sometime between WW2 and 1966... - More school milk associated with decreased risk of colon cancer.

What are the theories of causation for the reduction in colon cancer mortality rates from 1975 to 200?

(1) Patient *makes links* between life and symptoms (self-awareness). (2) Patient can be *coached* towards making links between life and symptoms (increasing flexibility of thinking). (3) Patient has *fixed beliefs* about the bodily causes of their symptoms. They have less self-awareness and flexibility.

What are the three main "patient categories" for those with a functional illness?

*Type 1 Alcoholic:* tends to be anxious and shy and consumes alcohol as a way to self-medicate and managed emotions. *Type 2 Alcoholic:* tends to be more impulsive and likely started excessive alcohol consumption at an earlier age. Associated with polysubstance abuse.

What are the two types of alcoholics?

Multiple ear infxn Several sinus infxn Prolonged oral abx required >2 episodes pneumonia in 1yr Failure to gain weight / grow Recurrent abscesses Persistent thrush Family history

What are the warning signs that alert a clinician to an underlying congenital immune deficiency?

conditions involving the partial or complete obstruction of a blood vessel

What are thromboembolic disorders?

(1) Diagnostic test accuracy (2) Aetiology (3) Interventions

What can you do a systematic review of?

"It's not your fault that you cannot diagnose them! The problem is neither you nor the patient but rather the medical model that you are working under."

What can you tell a doctor who is feeling frustrated and confused about their patient's presentation, which may be a functional illness?

"It's not your fault. You have a real illness; it's just not well recognised in modern medicine and there are treatments available now."

What can you tell a patient who is feeling frustrated about their functional illness?

Antibody crosslinking of granulocytes. Somatostatin / gastrin bind to ECL cells. Activation of receptors on histaminergic neurons.

What causes release of histamine?

Killed by virus. Killed by CD8 cells. Decreased production.

What causes the depletion of CD4+ cells?

Amino acid disorders (9 disorders, including PKU and MSUD) Fatty acid oxidation disorders (8 disorders) Congenital hypothyroidism (CH) Cystic fibrosis (CF) Congenital adrenal hyperplasia (CAH) Galactosaemia Biotinidase deficiency Severe combined immune deficiency (SCID). These screens are not obligatory.

What classes of metabolic disorders are currently screened for in newborns in NZ?

Xyntha ($1.00 per unit).

What company currently supplies recombinant FVIII?

COPD --> since there is a major reversible cholinergic component to COPD. [or LAMA for severe asthma due to increased vagal stimulation at night].

What condition indicates the use of SAMAs and LAMAs?

Rhabdomyolysis

What condition is characterised by the destruction of muscle?

· Acute bacterial infection · Leukaemia · Tissue death / necrosis - as in burns or gangrene.

What conditions are associated with an increase in neutrophils (neutrophilia)?

Diabetes, Alcoholism → impair phagocytosis & killing. Renal Failure → impairs phagocytosis. Steroid medication → neutrophilia via demargination (less adherence & migration into tissues).

What conditions impair the function of neutrophils?

Reactivation can be due to immunosuppression, alcoholism, TNFa inhibitors, poor nutrition, HIV, etc. The increased replication causes the granuloma to become necrotic, such that it then breaks down into *caseous granuloma* and ruptures into the airway.

What contributes to reactivation of TB? What is the effect of reactivation?

Efficacy Tissue properties (A drug may therefore appear to be a partial agonist in one tissue, and a full agonist in another).

What determines the maximum response of a tissue to a drug?

HFE-associated hereditary hemochromatosis (HFE-HH)

What disorder is characterised by inappropriately high absorption of iron by GI mucosa?

· Small bowel = watery diarrhoea. · Large bowel = frequent stools, fever, blood / mucous.

What do are the symptoms of small bowel vs. large bowel infections.

*PREDICT equation* (incorporates multiple risk factors to calculate *5-year CV risk*). Only for primary prevention (since people who have already had a CV event are already assumed to be at high risk).

What does NZ use to calculate the combined CVD risk?

Supernatural creatures; they were said to hide in the ocean, rivers, lakes, or caves. Some taniwhas would eat and kill people or kidnap women.

What does a Taniwha represent?

AUC corresponds to the fraction of doses administered that reaches the systemic circulation (i.e. body exposure). Units: mg*hr/L Dependent of rate of drug elimination and the doses that is administered.

What does the AUC represent? What units are used?

· Understand Māori indigenous rights · Respond to Treaty-based requirement to deliver effective, equitable health care · Incorporate Māori models of health · Identify and address structures and processes that limit Māori health development · Support a strong Māori health workforce

What does the Medical Council of NZ require from doctors in order to achieve Māori health equity?

Type of mutation Location in gene Location in 3D protein structure / ncRNA sequenec

What does the effect of a mutation depend on?

Secrete enzymes, including pepsinogen and gastric lipase (enzyme for TAG hydrolysis).

What does the following cell secrete? *Chief Cells*

Secrete somatostatin.

What does the following cell secrete? *D Cells*

Secrete histamine (which is important for acid production). ECL = Enterochromaffin-Like

What does the following cell secrete? *ECL Cells*

Secrete serotonin (produces ACh, which stimulates parietal cells) and ANP (regulates somatostatin from D cells).

What does the following cell secrete? *Enterochromaffin Cells*

Secrete gastrin and regulate enzyme and acid release.

What does the following cell secrete? *Enteroendocrine / G Cells*

Secrete alkaline substance (bicarbonate) and mucous.

What does the following cell secrete? *Mucous Neck Cells*

Secrete HCl- (a.k.a parietal cells)

What does the following cell secrete? *Oxyntic Cells*

· Aminosalicylates (limit inflammatory signalling) · Glucocorticoids (limit inflammatory signalling) · Immunomodulators (suppress immune cell proliferation) · Biologics (target inflammatory cytokines) · Antibiotics (target gut microbiota)

What drug classes are used to treat IBD?

LABA + LAMA These have synergistic effect for symptomatic relief in COPD. If not controlled, use ICS + LABA + LAMA. Beware: ICS use ONLY if necessary since immunosuppression puts patient at risk of pneumonia.

What drug combination(s) should be used for COPD?

Osmotic laxatives (such as *macrogols*). Stimulant laxatives (such as *sennoside B* which acts on D2 receptors in GIT).

What drugs are indicated for chronic or recalcitrant constipation?

Bulk laxatives Stool softeners

What drugs are indicated for mild constipation?

Anticholinergics (scopolamine / hycosine). Opioids (loperamide).

What drugs are indicated for severe or persistent diarrhoea?

Antacids PPIs H2 receptor antagonists Mucosal stregntheners Antibiotics

What drugs are used to treat GIT acid disorders?

Anti-histamines (such as *cyclizine* and *promethazine*).

What drugs used for emesis and motion sickness act on H1 receptors in the CNS?

Anticholinergics (scopolamine / hyoscine).

What drugs used for emesis and motion sickness act on M receptors in the GIT and CTZ?

5HT-3 antagonists (*ondansetron*)

What drugs used for postoperative N&V act on serotonin receptors in GIT, CTZ and higher cortex?

Post-translational modifications of AAs in the histone tails. In other words, acetylation and methylation.

What enables the switch between euchromatin and heterochromatin?

HMG CoA reductase

What enzyme catalyses the rate-limiting step in cholesterol metabolism?

Choline acetyltransferase

What enzyme is responsible for the *production of ACh* from Acetyl CoA and Choline?

Cytochrome P450 enzymes (CYPs). Reduce / alter pharmacological activity of many drugs, and facilitate their elimination. Have substrate specificity - they often oxidise a particular region of a drug molecule.

What enzymes are often responsible for Phase 1 of drug metabolism?

*UGTs*: Adds glucuronic acid to the FGs, forming glycosides. *SULTs*: Adds sulphate groups derived from PAPs to -OH or -NH2 groups. Examples: SULT1A1 (liver) and SULT1B1 (intestine). *GSTs*: Adds GSH to electrophilic molecules.

What enzymes are often responsible for Phase 2 of drug metabolism?

*Conventional Mouse:* given 106 salmonella enteritides → dies. If given any less, it survives. *Conventional Mouse:* given antibiotics (Streptomycin) AND only 10 salmonella enteritides → dies. *Germ-free Mouse:* given only 10 salmonella enteritides → dies.

What evidence is there that shows the human microflora as having a protective role against pathogen invasion?

· Amount of alcohol consumed · Rate at which alcohol is consumed ("sculling" or slowly) · Body weight, gender, food, age, alcoholic content, drug interactions

What factors affect BAC?

Lack of natural immunity within pandemic. Infectious before symptoms. Transmission. Virulence. Lack / failure of local control.

What factors contribute to a pandemic?

(1) Microbial factors → virulence + virulence factors. (2) Host factors → susceptibility. (3) Environmental factors → transmission, route of entry, pH, temperature.

What factors determine likelihood of infection?

Environment factors (family and friends, previous experience, etc.) Host factors (genetics, personality traits, etc.) Drug factors (availability, affordability, route of administration, pharmacokinetics, etc.)

What factors may determine one's susceptibility to substance dependence?

Treatment worthwhile? Patient's thoughts. Patient's concerns.

What factors should doctors take into account when deciding whether or not to offer, or continue providing, a curative treatment?

Paramyxovirus Common cause of RTIs in infants and young children.

What family do the following viruses belong to? • RSV • Mumps • Measles

Glycoprotein (proteins are required to induce T-cell response). Enzymatically active. Low dose. Low molecular weight. Highly soluble. Stable.

What features of allergens promote the priming of T-helper cells?

1/5

What fraction of patients in NZ hospitals have palliative care needs?

ERBB2

What gene is used to interpret Her2 status?

Prednisone

What glucocorticoid is used to treat RA?

gp120

What glycoprotein in the HIV virus attaches to CD4?

gp41

What glycoprotein in the HIV virus is used for fusion?

Broken down in spleen and Hb is released.

What happens as RBCs reach end of their lifespan?

If the screening test detects any abnormalities, then theses patients are directed to a clinic for *diagnostic testing* to confirm the diagnosis.

What happens if someone has a positive screening test?

Cartilage is lain down.

What happens if there is not enough oxygen available for bone healing?

Droplet nuclei inhaled → phagocytosed by alveolar macrophages → phagosome fuses with lysosome → formation of phagolysosome. This provides a hostile environment for the bacterium . However, mycobacterium tuberculosis can survive since it has protective mechanisms against each of these hostile factors. Macrophages activate T cells via antigen presentation. DCs take up apoptotic bodies with mycobacterial peptides from infected macrophages or are directly infected. DCs prime T cells in the lymph node.

What happens once mycobacterium tuberculosis is inhaled into the alveoli?

Becomes modified. Activates macrophages. GFs and cytokines are released. Cell proliferation, and recruitment and internalisation of monocytes (→ macrophages). Ultimately leads to the degradation of the cell matrix, thickening of the intimate and decreased diameter of vessel lumen.

What happens once the LDL enters the intimate of the blood vessel?

MRI

What imaging technique can be used to distinguish between non-infectious (brain bleeds) and infectious (abscesses) causes in the CNS?

x4 increase

What increase in antibody is considered significant?

· Sweat test · Faeces test → pancreatic enzymes · Genetic analysis for mutations in CFTR alleles

What investigations can be carried out to confirm the diagnosis of CF?

Use NSAIDs/glucocorticoids to treat the patient until the effects of DMARDs appear.

What is "bridging therapy" in RA?

F = 1.00 (since it is delivered directly into circulation)

What is *F* for an IV drug?

Epstein Barr Virus a.k.a *Glandular Fever*. Infects B cells. Blood film will show large, atypical lymphocytes (reactive T cells). Common in young adults. Symptoms: fever, enlargement of neck lymph nodes, sore throat, enlarged spleen, etc.

What is EBV?

EPS = Extracellular Polymeric Substance. It is a glycocalyx that helps cells in a biofilm attach to their target environment and to each other.

What is EPS?

Used to produce a visible karyotype by staining condensed chromosomes with Giemsa.

What is G-banding?

Gastro-Oesophageal Reflux Disease Acidic contents of stomach rise into oesophagus and oral cavity, causing burning sensation in chest. Can induce damage to mouth and inflammation of oesophagus. Can lead to: oral lesions, severe erosive oesophagitis, Barrett's metaplasia.

What is GORD? What can it lead to?

A cellular antioxidant that exists as either GSH (reduced) or GSSG (oxidised). Protects cell from oxidative damage. Its depletion may result in cellular oxidation. Drugs metabolised via this pathway may become toxic.

What is GSH?

HIT = Heparin Induced Thrombocytopenia. Platelet destruction that arises secondary to heparin therapy.

What is HIT? [Clinical Pharmacology]

LAMP: Loop Mediated Isothermal Amplification A nucleic acid amplification technique that is different from PCR. It is isothermal (occurs at a constant temperature). There are multiple short primers in LAMP, which are highly specific. It uses a BST polymerase which has *strand-displacement activity* → it can form a loop which speeds up the amplification process. There is visible formation of a product → if amplification occurred, the sample appears turbid). In this case, we are looking for the TcdB toxin (which must be present for there to be disease) → if positive for TcdB gene, the sample will appear cloudy / turbid.

What is LAMP? [Context = C. difficile detection]

Lipooligosaccharide (a.k.a Endotoxin).

What is LOS?

*Nitrate Oxide* A gaseous mediator / free radical that binds to many things.

What is NO?

*Nicotine Replacement Therapy* A form of medicine that delivers small amounts of nicotine to the body to help a person quit using tobacco.

What is NRT?

Post-exposure prophylaxis A medication given to people who may have been exposed to HIV. If taken within 72 hours of being exposed to HIV, it is likely to reduce the chances of contracting HIV.

What is PEP?

PG12 (prostacyclin): inhibitor of platelet aggregation prevents thrombus formation.

What is PG12?

Pre-exposure prophylaxis An HIV medication (for uninfected) taken to reduce the risk of acquiring HIV by up to 99%. Give to those who participate in riskier sexual activities.

What is PrEP?

*Reproduction number* The number of secondary infections that result from a single infected individual entering a population of entirely susceptible individuals. If R0 = 2.5, then someone coming in with the virus is likely to affect ~2.5 people. This leads to an exponential growth in the number of cases.

What is R-naught?

*Respiratory Syncytial Virus* Major cause of LRTI in infants. Most children have had by 2yrs. Bronchiolitis associated with RSV. Increases risk of wheezing and childhood asthma. Types A and B. Infect epithelial cells and cause cells to fuse together, thus making multinucleate cells. No vaccine. Monoclonal ab therapy.

What is RSV?

Granulation tissue containing bone or cartilage.

What is a callus?

unidirectional block

What is a common cause of tachyarrythmias?

Polysaccharide is conjugated to a familiar carrier protein. The T cell can recognise this and thus provide help to B cells. Has IgG involvement, hence there is effective memory development.

What is a conjugated vaccine?

Nitrate tolerance - thus, decreased efficacy. Solution: provide nitrate free intervals (e.g., once-daily dosing regimens).

What is a consequence of frequent dosing with nitrates?

Four types. Linear, ssRNA genome. Largest among RNA viruses. Spike protein enables interaction of virus with cell surface receptor on host cells, then entry into cell. No vaccine.

What is a coronavirus?

Two groups: A and B Cause herpangina (a severe febrile pharyngitis).

What is a coxsackievirus?

High efficacy. Produces a full response while occupying a relatively low proportion of receptors.

What is a full agonist?

A sequence of DNA that specifies the production of a functional product.

What is a gene?

Aggregation of macrophages that forms in response to chronic inflammation. Immune system attempts to isolate foreign substances which it is unable to eliminate.

What is a granuloma?

Lower efficacy. Cannot produce maximal response, even at 100% receptor occupancy.

What is a partial agonist?

Decreased risk of malaria.

What is a potential benefit of carrier status (beta thalassemia)?

*Common cold virus.* Exacerbates asthma. >100 types. No vaccine due to continuous evolution. Generally cause mild URTI.

What is a rhinovirus?

A localised collection of pus in a fibrin-lined cavity.

What is an abscess?

Long follow-ups allow studies to assess long-term positives and negatives.

What is an ideal duration of follow-up? Why?

Occurs in response to... (1) Prolonged exposure to toxics. (2) Autoimmune reactions. (3) Persistent infections. Continued inflammation, tissue injury and healing by fibrosis occur simultaneously.

What is chronic inflammation?

Culture is shared and expressed in individuals (members); it influences via the psychologies of individuals. Culture consists of shared un-observables (beliefs, purposes, aims) and shared observables (behaviours, attitudes, practices). Members get 'culture' from others who already have that culture.

What is culture?

*Gene:* Single mutation in CFTR gene. Common mutation is F508 del. *Age of onset:* From birth. *Inheritance:* Autosomal recessive. *Penetrance*: High clinical penetrance. *Effects*: Causes defective function or production of the CFTR regulatory protein (which normally creates a channel in the membrane for Cl- transport). Ducts in the lungs become block with thick mucus, so higher risk of infxn. *Treatment:* Kalydeco potentiates function of defective channels (only works for some mutations). *Epidemiology:* 4% of Caucasians are carriers.

What is cystic fibrosis? [CF] → Gene → Age of onset → Inheritance → Penetrance → Effects → Treatment → Epidemiology

Drugs which act to alter the epigenetic markers. E.g. DNA methylation inhibitors can be used against some cancers / psychiatric diseases.

What is epigenetic therapy?

Investigates the complex relationship between *genotype* and *phenotype*. Technology is used to investigate the function of genes & gene products, and the impact of genetic variation on an organism's biology.

What is genomics good for in the clinic?

Blood clotting disorder. Type A: Factor 8 deficiency. Type B: Factor 9 deficiency.

What is haemophilia? What are the types of haemophilia?

Begins early after a necrosis-inducing injury. Overlaps with inflammation. Involves: *regeneration* and *scarring*.

What is healing (tissue repair)?

A biogenic amine that initiates allergic and inflammatory responses, and aids digestion. Shares a similar structure to neurotransmitters (incl. dopamines, serotonin, noradrenaline).

What is histamine involved in?

Deficiency of oxygen. - ↓aerobic oxidative respiration causes cell injury.

What is hypoxia?

Occurs one antimicrobial induces resistance to a second antimicrobial, which may belong to the same or a different family. Can lead to unexpected treatment failure. Laboratory Methods: Double disc diffusion test (qualitative).

What is inducible antimicrobial resistance? How can it be assessed?

Reduced blood flow (or loss of blood supply) due to impeded arterial supply.

What is ischemia?

Harm-reduction via non-IV opioids (less likely to contract virus from shared IV needles, or to engage in illicit practices). Once stabilised, patient is unlikely to escalate dose. Methadone (20-80mg per day), Suboxone, EU (heroin).

What is long-term opioid substitution?

PAPs are required for SULT function, but PAP has low intracellular conc. (energy is required for its formation). Low PAP → SULTs have low metabolic activity. Hence, drugs cannot be metabolised via this pathway. The drug undergoes *metabolic shunting* through other pathways (such as UGT or GSH pathways). This often occurs: (1) As drug doses increases, or; (2) Due to co-administration with other drugs competing for PAPs stores (e.g., alcohol metabolism involves sulfation).

What is metabolic shunting? Describe in the context of SULT & PAP.

Depletion of GSH means that GSH-conjugation cannot occur, so a different conjugation takes place → production of a toxic product → liver cell death.

What is metabolic shunting? Describe in the context paracetamol metabolism.

Inflammation of bone and bone marrow.

What is osteomyelitis?

An approach to disease treatment that accounts for individual's genetic background. Requires molecular testing to establish genetic background & metabolic responses.

What is precision medicine?

A system of structuring opportunity and assigning value based on social interpretation of how one looks (i.e., ethnicity / race). It... · Unfairly disadvantages some individuals and communities. · Unfairly advantages some individuals and communities. · Saps the strength of the whole society through the waste of human resources.

What is racism?

Autoimmune inflammatory joint disease

What is reactive arthritis?

Measure of efficacy (tangible to patient → length of survival, QoL). Measures of safety. Surrogate variables.

What is required for measurement of treatment effects?

Invasion of joint by infectious agent which produces arthritis.

What is septic arthritis?

Inherited defect in ability to produce haemoglobin.

What is thalassemia?

Accumulated strength of multiple affinities. (Whereas affinity describes the single interaction between epitope and antigen-binding site).

What is the *avidity*?

→ Diffusibility of antimicrobial → Susceptibility of the bacteria → Concentration of antimicrobial in the disc → Others: Solubility of antimicrobial; Agar thickness; Inoculum size.

What is the *size of the Zone of Inhibition* dependent on?

Minimum concentration of an antibacterial agent that results in bacterial *death*. More accurate method. This test is usually done is the pt. is immunocompromised, or in cases such as IE.

What is the MBC (Minimum Bactericidal Concentration)?

The lowest concentration of an antibiotic that prevents visible growth of the organism. Most infections are treated on this basis.

What is the MIC (Minimum Inhibitory Concentration)?

Our health system is changing, and part of these reforms are the creation of a new MHA. The role of the MHA is to: - Support the Ministry of Health in shaping system policy and strategy to ensure performance for Māori. - Work in partnership with Health NZ to commission care across Aotearoa. - Ensure the needs and expectations of Māori communities are centred in design and delivery.

What is the Māori Health Authority?

Doctors must meet the cultural safety standards outlined below: - Cultural safety requires doctors to reflect on how their own views and biases impact on their clinical interactions and the case they provide to patients. - Cultural safety benefits all patients and communities. - This may include communities based on Indigenous status, age or generations, gender, sexual orientation, socioeconomic status, ethnicity, religious or spiritual belief and disability.

What is the NZ Medical Council's requirements for cultural safety?

Within the GI epithelium, P-gp pumps toxins/drugs back into the lumen, thus decreasing their absorption and ultimately bioavailability. Drugs that inhibit P-gp, such as verapamil, increase the bioavailability of susceptible drugs, whereas drugs which induce the transporter (e.g. rifampicin) can reduce the bioavailability of some drugs.

What is the P-gp transporter? How can its action be altered?

The whole population is mixing randomly.

What is the assumption in the R-naught calculation?

Deaths per 100,000 vehicles. Deaths per 100 million km travelled. → Better than 'death per 100,000 population' which treats the whole population as if equally at risk.

What is the best way in which to report the injury burden of MVTC?

*Absorption* from gut lumen. *First pass metabolism* (which is dependent on: metabolic enzymes that break down drug, and gastric pH & motility, hepatic perfusion).

What is the bioavailability dependent on?

Often considered a medically unexplained symptom, although ~half of cases have a psychiatric disorder, and in a significant proportion some organic cause is eventually found (e.g. GI or MSK).

What is the cause of NCCP?

Surgery: IV. Artificial intervention due to effects on lungs. Following surgery --> can be reverse by AChE inhibitor (e.g. Neostigmine). Order of Administration: Anaesthetic → Analgesic → NMB.

What is the clinical application of a non-depolarising NMB?

Lower potency = higher dose is required = more likely to act at more than one target. Hence, results in a wider range of adverse effects.

What is the consequence of low-potency drugs?

Deficient virus, so only ever co-infects with Hep B. Hence, if vaccinated against B, you are also vaccinated against Delta.

What is the distinguishing feature of the Delta hepatitis virus (HDV)?

ACh released from parasympathetic neurons acts through muscarinic receptors (M2 and M3) present in airway SM to induce bronchoconstriction. *M2 receptor activation* = counteracts bronchodilation (relaxation) induced by Beta-2 receptors. *M3 receptor activation* = causes contraction of SM (bronchoconstriction).

What is the effect of M2 and M3 receptor activation, respectively?

It effects EP3 receptor and inhibits acid secretion (inhibits activation of cAMP). It also activates mucous neck cells. Note: NSAIDs inhibit PG synthesis, so could lead to excess acid secretion.

What is the effect of PGE2 on parietal cells?

Neuromuscular blocks cause *motor paralysis*, but do NOT affect consciousness.

What is the effect of a neuromuscular block?

inhibition or activation

What is the effect of chemical modification of histone proteins on gene expression?

Certain organs which are predominantly composed of cells from the mutated cell line are more at risk of physical consequences.

What is the effect of mosaicism in Turner Syndrome?

Has a negative charge, so repels phagocytes. Also makes it difficult for complement activation. Limited cross-protection due to antigenic variation. Enables Strep. pyogenes to induce rheumatic fever.

What is the function of the M-protein of Streptococcus pyogenes?

Dose-rate (dose per unit time) required to maintain a steady plasma concentration. Applies to drugs with first-order kinetics.

What is the importance of the parameter drug clearance?

Chronic inflammation following cytokine release (from prime T cells) leads to *granuloma formation* (which is dependent upon IFNy and TNFa). The granuloma restricts spread of M. tuberculosis. It provides a hostile environment (hypoxic condition and lack of nutrients), which forces the bacteria into dormancy such that it ceases replication or only persists at a low rate.

What is the inflammatory consequence of cytokine release from T cells?

Carcinoma of lung

What is the leading cause of cancer-related death?

RTIs

What is the leading cause of death for 15-29-year-olds?

Avoids confounding.

What is the major advantage of RCTs?

Produces the catalase enzyme and can protect itself from oxidative damage by ROS (reactive ox. species).

What is the meaning of *catalase positive*?

F508del

What is the most common CFTR mutation?

Cause: Antimicrobials that inhibit the growth of normal gut microbiota. Leads to C. difficile diarrhoea. Overgrowth of C. difficile causes it to produce toxins (tcdA, tcdB) which damage gut mucosa. In mild cases, this may resolve spontaneously, but can progress in more severe cases and lead to following diseases: · Antimicrobial associated (pseudomembranous) colitis · Toxic megacolon

What is the most common cause (and complications) of a C. difficile infection?

Lung cancer

What is the most common cause of cancer-related mortality?

IgA deficiency (1:100 to 1:1000)

What is the most common primary immune deficiency?

Campylobacter, of which C. jejuni is most common species. (Second most common species is C. coli).

What is the most notifiable disease in NZ?

Haemoglobinpathies - Abnormal or structural variants (e.g., HbS). - Thalassemia

What is the name given to conditions which affects the haemoglobin component of blood?

The pH at which 50% of the drug is ionised.

What is the pKa of a drug?

Pulmonary disease

What is the primary cause of morbidity and mortality in CF patients?

· Problem: a mouse antibody is recognised as 'foreign' to human cells. · Solution: *Emicizumab molecule* → this is a "humanised" antibody. The constant region of the antibody is human derived whereas the variable regions are mouse AND rat derived.

What is the problem with obtaining recombinant antibodies from mouse WBCs? What is the solution?

*Benzyl penicillin*: Neisseria meningitidis *Ceftriaxone*: most effective against current strains (most organisms!). If Strep. pneumoniae → vancomycin + cephalosporin (e.g. ceftriaxone). If L. monocytogenes → amoxicillin.

What is the recommended empiric antibiotic therapy for suspected bacterial meningitis on hospital admission?

Drug / substance abuse can lead to alterations in epigenetic markers → increased reliance & more difficult to quit.

What is the relationship between epigenetic markers and addiction?

Amount smoked per day. Duration of smoking. Depth of inhalation. Relative risk for cancer in smokers is 20 compared to non-smokers, and 1.2 for passive smoking. Risk decreases after stopping.

What is the risk of lung cancer determined by?

Understand: - the burden - injuries are no accident - there are multiple causes - many ways to intervene Provide non-judgemental, evidence-based advice. Advocate for a healthier public policy.

What is the role of doctors in injury prevention?

Health is not strictly conceptualised as the absence of disease and infirmity but a state of social, mental, physical, and spiritual wellbeing. Spirituality and faith are important aspects of Pacific health.

What is the understanding health, sickness, and wellness in the Pacific context?

Trephine Biopsy

What is this instrument used for?

In the lungs, neutrophils produce enzymes which destroy bacteria. These enzymes can cause damage to elastin present in alveoli, and cause emphysema. Alpha-1-antitrypsin prevents this from occurring via inhibition of the elastase (protease) enzymes.

What leads to emphysema in the lungs? How is this prevented in normal individuals?

q

What letter represents the long arm of a chromosome?

p (petite)

What letter represents the short arm of a chromosome?

Optimal therapeutic range

What lies between MTC and MEC?

Comparable groups. Adherence. Unbias assessment of outcome. Good randomisation process.

What makes a good RCT?

Pain free. Fitting death (fits life & reflects values). Goodbyes & reconciliations. Dignified. Timely.

What makes a good death?

CCBs may have greater affinity for *open* LTCCs or *inactivated* LTCCs. The LTCCs spend a greater period of time in their open state, hence CCBs with greater affinity for open LTCCs tend to be cardio-selective. Peripheral vessels experience contraction less frequently, and therefore have a greater proportion of receptors in the inactivated state than cardiac cells. Vaso-selective drugs are those which bind to this inactivated state.

What makes certain CCBs cardio-selective or vaso-selective?

Adherence to intervention & control. Adherence to protocol. Low / no loss-to-follow-up. Complete data. Accurate capture of data.

What methods minimise bias during the trial? [RCT]

Intention to treat analysis Limited no. of statistical analyses (multiplicity can increase chance of false-pos result / overestimation of positive effect). Publication of trial protocol. Pre-specification of appropriate statistical analyses.

What methods minimise bias in the analysis and reporting phase? [RCT]

Randomisation (method of allocation). Blinding (conceal allocation). Assessment methods that minimise bias (blinding).

What methods minimise bias in the study design? [RCT]

Talk to patient and express concern; provide feedback about their drinking and the effects on their health; educate them about driving limits; offer advice to cut down / abstain; follow up 2-4 weeks later. Refer to speciality addiction services if required!

What might a 'brief intervention' with an alcoholic involve?

1%

What percent of the human genome is variable?

Hydrophilic / lipophilic nature Molecular weight Weak acids / bases are non-ionised Strong acids / bases are ionised

What physiochemical properties of a drug affect bioavailability?

Glycan shield of the virus

What prevents antibody binding to gp120?

(1) Detection of antibody response to HIV. (2) Detection of HIV itself.

What principals are used in the diagnosis of HIV?

Allele frequency = 0.7242 Homozygous frequency = (0.7242)2 = 0.5245

What proportion would be homozygous for F508 del mutation? [European; See Abbott test information]

p24

What protein of the HIV virus does ELISA detect to determine whether a patient is HIV positive?

*PG12* inhibits platelet aggregation and secretion. *AT* inhibits coagulation. *Thrombomodulin* and *Protein C* are antithrombotic proteins expressed on endothelial cells. They bind and inactivate CFs.

What proteins normally stop us from forming thrombi?

Medicinal iron Mineral supplements Excess Vit C Uncooked seafood Alcohol

What should HFE-HH patients avoid?

(1) *Host Factors:* genetics, age, gender, behaviours, height, weight. (2) *Agent Factors:* examples → virulence of organism, serotype, antibiotic resistance, cigarettes, type of glass in car windscreen. (3) *Environmental Factors:* home overcrowding, air composition, food, radiation, workplace hygiene, weather, food contamination, animal / human contact, asbestos.

What should be considered when determining the causes of diseases?

The doctor needs to engage and respect pt, ask the 4 key questions, look for clinical signs / symptoms in general history and examination. Skills: → Empathy → Make clear & firm diagnosis → Explain > investigate (else there is the risk of somatic fixation). → Pre-emptive strike re-coping ("...this does not necessarily mean you are not coping"). → Normalisation ("everyone can get symptoms if there is something on their plate").

What should the doctors do, and what skills are required, when dealing with a patient who may have functional illness?

Parents typically make decision for children. Welfare Guardian appointed by court. Patients may appoint an EPA (enduring power of attorney). Advance directives. If no person is entitled to consent on behalf of pt, the *doctor* may provide the service where: (i) it is in the best interest of pt and; (ii) reasonable steps have been taken to ascertain the views of the actual pt (not just the family's views!).

What should you do if a patient is not competent to make a decision?

(1) Environmental agents / Lifestyle factors e.g., tobacco, alcohol, aflatoxins. (2) Biological agents e.g., infectious agents. (3) Ionizing radiation e.g., radon. (4) Industrial processes / occupational exposures. (5) Chemicals (6) Medicinal drugs

What substances and types of exposure are classified as Group 1 (carcinogenic to humans)?

ICD-10 Classified according to: - Underlying intent - Mechanism of injury - Area of injury - Purpose of the activity - Setting of the event

What system is used to classify injuries?

Chromosomal microarray

What technology is used to assess chromosomal imbalances?

Aneuploidy

What term describes an abnormal number of chromosomes?

Acrocentric Metacentric

What terms describe centromere position?

*Skin Prick Test* = rapid; introduce antigen into dermis, mast cells bind and degranulate if antibody is present → observable response. *Wheel and Flare*

What tests are used to measure Type 1 Hypersensitivity?

*Patch Testing* = allergen applied to skin → cells recruited it allergic. *Tuberculin Skin Test* = bacterial proteins injected into dermis. Previous exposure to tuberculosis bacterium will lead to a response (raised skin). *IGRAs* = monocytes present peptide chunks to T cells; if previous exposure to antigen, there will be T cell activation and release of cytokines (e.g. IFN-gamma). IFN-gamma can be measured via ELISA.

What tests are used to measure Type 4 Hypersensitivity?

Microcytic anaemia

What type of anaemia does thalassemia present as?

*Reciprocal translocation* Carriers of balanced reciprocal translocations have increased risk of gametes with unbalanced chromosome translocations, leading to infertility, miscarriage, or children with severe phenotypical consequences.

What type of chromosomal abnormality is associated with recurrent miscarriage?

an environment in which individuals believe that their culture is valued and respected

What type of environment does cultural safety promote?

alpha haemolysis = green zone. beta haemolysis = clear zone.

What type of haemolysis produces a clear zone vs green zone?

*Type 1 sensitivity*, but it associated with a *Type IV late phase reaction*.

What type of hypersensitivity is allergy?

Organisms that cause atypical pneumonia will not respond to penicillin (due to their intracellular nature or lack of peptidoglycan cell wall). More common causes of atypical pneumonia (legionella, chlamydia, mycoplasma) respond to *macrolides* (erythromycin). Less common causes (such as M. tuberculosis) do not respond to macrolides.

What type of pneumonia is associated with TB, and what does this mean for treatment?

inotropic receptor

What type of receptor is the nicotinic ACh receptor (nACh)?

Primary union

What type of skin wound is shown?

Secondary union

What type of skin wound is shown?

*Retrovirus*: Uses RNA as its genetic material. It is also a *Lentivirus*: Causes chronic disease characterised by long incubation period.

What type of virus is HIV?

Religious / transcendent Behavioural / humanist / secular Contemporary / inclusive Other

What types of definitions are there around *spirituality*?

*LOCALISED INFECTIONS* Infections of skin & wounds, osteomyelitis, abscesses, meningitis, ~sepsis.

What types of infections does Staphylococcus aureus cause?

*SPREADING INFECTIONS* Pneumonia Skin infections Scarlet fever ...etc...

What types of infections does Streptococcus pyogenes cause?

i. Adenovirus (only short-term use due to immune response). ii. AAV2 (small virus). iii. Retrovirus → lentivirus (provides long-term expression due to integration into junk DNA).

What types of viral vectors are used for gene therapy?

(1) Polysaccharide vaccine (2) Conjugate vaccines

What vaccines that are available to protect against infection with bacteria that cause meningitis?

Adenoviruses Coronaviruses Orthomyxoviruses Paramyxoviruses + Others

What viruses cause respiratory infection in humans?

Dopamine antagonists (such as *metoclopramide*). Acts on D2 receptors in CTZ and GIT.

What was the original first-line treatment for emesis? Where does this drug act?

(1) No. of people who would benefit (2) Cost (3) Efficacy

What would be PHARMAC's considerations for Kalydeco prior to funding it?

α-/α- is the carrier status.

What would be the alleles for a 'carrier' alpha gene?

There are two identical copes of the alpha gene so normal αα/αα.

What would be the alleles for a 'normal' alpha gene?

Decreased pH = more H+ ions available to protonate amino acid side chains. Vice versa.

What would happen to proteins if you altered pH of the buffer?

Most lung cancers arise centrally or peripherally. Disease presents late and often with metastatic disease.

When and where do lung cancers arise?

If you want to be sure that someone *doesn't* have the disease. RULE OUT But: High rate of false alarms. Many false positives.

When are high sensitivity tests beneficial?

If you want to be sure that someone *does* have the disease. RULE IN But: High false reassurance rate. Many false negatives.

When are high specificity tests beneficial?

Activation of complement factors at the pathogen surface → cleave other factors → generates *classical C3 convertase* → converts C3 to C3a & C3b. C3a is released as a signalling molecules. C3b binds to the surface of the pathogen.

When complement is activated at the surface of the pathogen (in Classical and Lectin pathway), what events follow?

(1) *Genetic:* typically stable in incidence, and there will be clusters within the family. (2) *Environmental:* the incidence will vary rapidly overtime, or between genetically similar populations.

When determining if the disease is mainly genetic or environmental, what should be considered? (i.e., what are the clues?)

Important for follow-up of treated cancers. Not useful for diagnosis since not specific to cancer, not sensitive enough to detect early cancers [hence, not good for screening]. A high marker level at diagnosis = worse prognosis.

When do we measure serum tumour markers?

Occurs with the second and subsequent exposures to antigen.

When does hypersensitivity occur?

Acute sample Convalescent sample (2-3 weeks later; allows us to monitor for seroconversion).

When measuring a patient's antibodies, it is recommended to take two samples. What are these? Why?

Only test if very sick (hospitalised), has severe symptoms, or has had symptoms for prolonged time (>7 days). Obtain stool sample and perform test.

When should we test for diarrhoeagenic infections?

Different conc. reach target tissue. *pharmacokinetics* Tissues from different individuals response differently to equal drug conc. *pharmacodynamics*

When taking a specific type of drug, why is there variability in the ADME factors across individuals?

No answer. Doesn't fit what expect. Missing something "real". Patient is making it up.

When the patient presents with unexplained symptoms, describe the experience for the: *Doctor*

Doesn't feel believed. Ongoing frustration with disabling symptoms. Fear that something has been missed. Feel blamed. No hope. "Going mad". Too many referrals.

When the patient presents with unexplained symptoms, describe the experience for the: *Patient*

treat with bronchodilators alone.

When treating asthma, we should never...

Debated over 4th to 6th February 1840; signed on the *6th February 1840*.

When was the Treaty of Waitangi debated and signed?

For disease caused by overactivity of the receptor. Example: Precocious puberty.

When would an inverse agonist be advantageous over an antagonist?

Supraventricular arrhythmia (atria / AV node). Ventricular arrhythmia.

Where do arrhythmias originate?

Hospital (2nd = Rest Home)

Where do most people in NZ die?

Auckland (~half of diagnoses).

Where is HIV most concentrated in NZ?

Produced by hepatocytes.

Where is alpha-1-antitrypsin produced?

Between the TATA box and ATG (start codon).

Where is the 5' UTR located?

X-chromosome near the telomere (Xq28). Large (186kb), and comprises 26 axons and 9kb of cDNA.

Where is the gene for Factor 8 located?

CpG (cytosine-guanine) dinucleotides. Inactive genes have methylated CpG islands in their promoters.

Which DNA cytosine bases are methylated?

Trisomy 13, 18, 21

Which aneuploidies are viable?

HBeAg HBsAg

Which antigens are present in active hepatitis B?

HBsAg Anti-HBe IgG

Which antigens are present in chronic hepatitis B?

Carcinoma / sarcoma of *kidney, breast, bowl*.

Which cancers commonly metastasise *to* the lung?

Asian African Mediterranean

Which ethnicites have the highest rates of beta thalassemia carriers?

*histamine*, *chemotactic factors*, neutral proteases, acid hydrolases, heparin.

Which mediators in asthma are pre-formed prior to mast cell stimulation, then released during allergic or inflammatory reactions?

Arachidonic acid and metabolites, including leukotrienes and prostanoids (or PGs), are released from activated inflammatory cells (e.g., neutrophils, macrophages) through PLA2 (phospholipase A2) action.

Which mediators in asthma are synthesised at time of mast cell stimulation?

Non-Depolarising Block

Which neuromuscular block can be overcome with ACh esterase inhibitors?

RCTs (with mortality as the outcome measure)

Which study is not affected by the screening biases?

Alcohol

Which substance poses the greatest risk of harm to self and others?

Types A, B, C

Which types of influenza infect humans?

Henry Williams and his son Edward Williams

Who translated the Treaty into Māori?

They alter the progression of the disease!!!

Why are DMARDs effective treatments for RA?

As a biofilm forms, fast-growing susceptible bacteria become slow-growing tolerant bacteria. The bacteria can trade virulence factors and the physical barrier (due to the biofilm) makes it difficult for the immune system to access.

Why are biofilms highly resistant to antibiotics?

Characteristics of biofilms: Hard to culture. Hard to treat → resistant against host defences and antibiotics. Chronic & relapsing.

Why are biofilms medically important?

They house repetitive, duplicated DNA, so are not essential. (There is no important DNA in the p-arm).

Why are the short arms of acrocentric chromsomes "dispensible"?

Receptive anal intercourse → there is mucosal trauma, so easier transmission.

Why are there greater rates of HIV transmission for MSM?

Sovereignty is either claimed by: · Discovery of uninhabited land · Conflict / warfare · *Treaty* → in NZ's case. The purpose of the Treaty was to enable the British settlers and the Māori people to live together in New Zealand under a common set of laws or agreements. The Treaty aimed to protect the rights of Māori to keep their land, forests, fisheries and treasures while handing over sovereignty to the English.

Why did the British need a Treaty to establish a colony in NZ?

Single drug places a significant selection pressure on the virus, and the already-resistant, mutated versions may survive. Hence, the use of three drugs is more likely to eliminate any initial mutants / resistant strains, resulting in complete viral suppression.

Why do HIV patients take three drugs rather than one?

Psychological effect Develop dependence Social benefits Psychosocial benefits We need to focus on each of these aspects / barriers in order to help patients with smoking cessation.

Why do people smoke?

To strengthen repair! Occurs in response to GFs, cytokines & mechanical stress.

Why does scar tissue undergo remodelling?

Inappropriate use of antibiotics, puts selective pressure & enables genetic plasticity of bacteria. Increased spread (crowding, poor sanitation, international travel). Increased susceptibility to infection and antibiotic usage (poor nutrition, immunosuppression, invasive procedures).

Why is antibiotic resistance so high?

Hyperuricaemia (uric acid retention) → since the diuretics are excreted into the proximal tubule in by OATs in competition with uric acid.

Why is hyperuricaemia a potential side effect of Frusemide?

Respects autonomy. Prevents harm. Builds trust. Legal requirement.

Why is informed consent important?

Colonises alveolar sacs, so IV antibiotics must diffuse through tissue and biofilm. Nebuliser antibiotic only needs to diffuse through biofilm. Virulence factors such as efflux pumps.

Why is it difficult to treat P. aeruginosa infection?

Most palliative care is provided by non-specialists (those w/o intesive palliative care training). Junior doctors will encounter ~40 patients who will die.

Why is it important for medical students and general doctors to know how to provide palliative care?

Difficult because of contamination by microorganisms residing in the upper respiratory tract. Assessment of sputum quality shows whether a sample is truly sputum or saliva. A true sputum sample should have *<10 squamous epithelial cells* and *>25 polymorphonuclear leukocytes* per low power microscope field (10x objective). More invasive techniques can be used to obtain samples without contamination.

Why is laboratory examination of lower respiratory exudate (sputum) which is expectorated (coughed up) difficult? What is a true sputum sample?

Haematogenous spread via vascular stasis as growth plate → easier for pathogen to enter bone tissue.

Why is osteomyelitis common in children?

Latently infected CD4 cells do not express antigen = invisible to immune system. Virus is transcriptionally silent. HIV replicates when the infected T cells become activated. Also, macrophages and DCs can be infected by HIV without being killed.

Why is there a 'cellular reservoir' of HIV infection.

*Glycosylation not identical* to human cells → deemed foreign to immune system. OR *Factor VIII inhibitors*

Why may there be an autoimmune response to FVIII treatment?

Zoonotic infections (can live in humans + other species). Hence, faeces of animal can contaminate water supplies, leading to outbreak.

Why might infectious gastroenteritis become endemic?

Drugs bind to plasma albumin, eliciting no effect. Only the unbound drug has a physiological consequence.

Why will a patient with high albumin levels require an altered drug dosage?

Period following initial transmission during which there is local amplification and spreading of the virus to lymph nodes - at this stage, the virus has not reached the blood and cannot be detected.

Window period of HIV

Lipophilic drug (enters more compartments as it can cross membranes readily).

Would a hydrophilic or lipophilic drug have a greater Vd?

*Transmission*: Food-borne pathogen *Location*: Infects in ileum, so is often mistaken for appendicitis (since pain in LRQ). *Complications*: Arthritis, Bacteraemia / Septicaemia, Erythema nodosum. *Symptoms*: Diarrhoea, abdominal pain, headache, fever. It is a zoonotic infection Age-related disease (and self-limiting / mild in children).

Y. enterocolitica → Transmission → Location → Complications → Symptoms (Y = Yersinia)

B. Test with high specificity. Explanation: We want to make sure they don't have an infection prior to going ahead with the surgery.

You think that your patient has a condition that needs surgery but they are frail and surgery could be dangerous. What investigations would convince you to go ahead with surgery? Which would be better? A. Test with high sensitivity. B. Test with high specificity.

A. Test with high sensitivity. Explanation: We really want to know if they do have the disease so that we don't accidentally skip the diagnosis and send them home with a fatal condition.

Your patient wants to go home, but you are concerned that they might have a potentially fatal condition. You do some investigations to make sure that it is safe to discharge them. Which would be better? A. Test with high sensitivity. B. Test with high specificity.

The general spirit of the time. (The general intellectual, moral and cultural climate of an era).

Zeitgeist

Region around a chemical saturated disc, where bacteria are unable to grow due to adverse effects of the compound in the disc.

Zone of Inhibition

50-80%

_______% of infections are associated with biofilms.

Formation of granulation tissue Following angiogenesis, fibroblasts migrate to site of injury, proliferate and lay down ECM (especially collagen). TGF-beta drives this!

growth of new capillaries, rebuild collagen fibers

Non-coding RNA: a form of RNA that does not encode for protein but has a *regulatory role in gene expression*. Examples: tRNA, mRNA, etc.

ncRNA

hydrogen ion concentration

pH is a measure of...

World Wars → Normalisation and desensitisation of death. Medicalisation of death. Denial. Perception that death = failure to cure. Trivialisation of death (entertainment). Fear around death.

"The Death of Death"

Homologous chromosomes

(A)

Albumin

(F)

Infection & Immunity: Lecture 10, Allergy & Hypersensitivity (VERTICAL ANS #3)

***DO ASSESSMENT QUESTIONS***

Attaches to the intestinal epithelium. Invades host (either tricks the host to uptake the bacteria via a vacuole; or undergoes translocation). Synthesises toxins (cyto-lethal distending toxin). S-layer enables its evasion of the immune system. · Enterocytes damaged by cytokines. · Lysis of RBCs also occurs.

*Campylobacter* Outline the pathogenesis.

- Reactive arthritis - Guillain-Barré syndrome (rare; due to similarity between bacterial surface antigens and host myelin sheath → therefore causing nerve demyelination). - IBS (10-15%) ~ Bacteraemia (but usually only in elderly / immunocompromised).

*Campylobacter* What are the complications of infection?

C. jejuni

*Campylobacter* What is the most common spp.?

Invades small bowel epithelium and later spreads to large bowel.

*Campylobacter* Where does it infect?

Transmission: Faecal-oral. Food-borne (possibly water too). Host: Many species. Commonly in chicken intestines (since ideal temp.). Length: 6 days.

*Campylobacter* → Transmission → Host → Length of infection

(EPEC): Adheres to intestinal epithelium, then releases corrosive chemicals which wears away epithelium. The lack of epithelium = reduced absorption. (STEC): Shiga toxin binds GB3, which terminates protein synthesis, causing cell death (apoptosis). The host's sensitivity to shiga toxin depends on the if they have (and if so, how many) GB3 receptors. There are many in kidneys, CNS, and are also expressed more in children so more sensitive.

*E. coli* Pathogenesis (EPEC and STEC)

Children Infants Travellers

*E. coli* Risk groups for EPEC infection.

Genome encodes for virulence traits → this depends on the type of E. coli and thus determines if it is considered commensal or pathogenic. · Toxins · Adhesion factors · Invasion factors

*E. coli* Virulence Traits

Page 67, Vertical Answers #3

*ESSENTIAL* Exam Question Genetics Calculation Page 67, Vertical Answers #3

*Inhibition of co-stimulation* Inhibit co-stimulatory interaction between CD80/86 and CD28. In other words, they bind to CD28 and prevent the normal signalling of CTL3 via CD28.

*Immunosuppressive Drugs* CTLA-4 fusion protein immunoglobin (e.g., belatacept, abatacept)

*Inhibition of TCR signalling* Block the NFAT signalling pathway and block IL-2 production. Calcineurin normally activates NFAT, so the presence of inhibitors prevents activation of NFAT (which is required in gene transcription). T cell proliferation is IL-2 dependent, so these drugs (which block IL-2 production) lead to a diminished T cell population. These effects are very targeted, affecting mostly T cells (minimal effect on B cells and myeloid cells).

*Immunosuppressive Drugs* Calcineurin inhibitors (e.g., cyclosporin, tacrolimus)

Inhibit TFs (AP-1 and NF-κB) necessary for gene transcription, thereby reducing expression of IL-2 and other cytokines.

*Immunosuppressive Drugs* Steroids

*Inhibition of Proliferation* Inhibition of cytokine signalling. mTOR inhibitor drugs (e.g., sirolimus, everolimus) block the downstream signalling of the IL-2 receptor. Alternatively, purine analogues (such as azathioprine) inhibit purine synthesis. Since purines are require for nucleic acid synthesis (and thus DNA), cellular proliferation is inhibited.

*Immunosuppressive Drugs* mTOR inhibitor drugs

I. What are the major defences of the intestinal tract? II. What are the beneficial effects of the gut microbiota? III. What is antibiotic-associated colitis? IV. What types of tissue/blood infections are associated with the gut microbiota? V. Which diseases are attributed to H. pylori colonisation of the stomach? VI. What are the main virulence factors in H. pylori? VII. How would you diagnose and treat a patient with symptoms of H. pylori infection?

*Lecture Questions:* I & I (Lecture 17, pg. 12, Vertical #4) ALSO, see worksheet at start of lecture.

1. What are the major symptoms of viral hepatitis? 2. Describe how the pathogenesis of hepatitis due to HAV and HEV differs from HBV and HCV. 3. What are the main routes of transmission for HAV/HEV, HBV and HCV? 4. What are the main consequences of infection with HAV, HBV, HCV and HEV? 5. How can viral hepatitis be prevented? 6. What type of laboratory tests are used for diagnosing hepatitis virus infections? 7. What are the main antivirals for treating chronic viral hepatitis?

*Lecture Questions:* I & I (Lecture 18, pg. 15, Vertical #4) ALSO, see worksheet at start of lecture.

*What is it?* A middle ear infection that involves inflammation and effusion in the middle ear. *Causative Organisms*: Strep. pneumoniae, Haemophilus, Moraxella. They result in an acute infection. *Epidemiology*: Childhood infection [~2y/o] since children have short Eustachian tube so more difficult for mucous drainage, organisms have easier passage into middle ear; Malformation of ET; Socioeconomic; Winter. *Clinical Presentation*: Acute OM = pain, purulent discharge, worse at night due to collapse of ET, fever. OM with Effusion = No evidence of infxn in middle ear space (MES). Follows AOM, whereby recurrent episodes lead to "glue ear" (thickened effusion). Relief with grommet. Failure to treat → learning difficulties due to issues with sound conductivity. *Pathogenesis*: Viral URTI then inflammation, causing swelling and blockage of ET. Creates vacuum in MES → filled with an effusion → colonisation by bacteria from nasopharynx. *Diagnosis*: Clinical & microbial (culture). *Treatment*: Abs not required in most cases; treat symptoms. ~Can give amoxicillin.

*Otitis Media* o What is it? o Causative organism(s) o Epidemiology (risk factors) o Clinical Presentation o Pathogenesis o Diagnosis o Complications o Treatment

*What is it?* Infection of the lung parenchyma with consolidation. *Epidemiology*: Affects all age groups (esp. <5 or >65); M > F; Māori and Pasifika. *Routes of Infection*: - Inhalation (Atypical) - Aspiration (Typical) - Haematogenous *Signs / Symptoms*: Productive cough, Fever, Chest Pain, Dyspnoea + others. *Bacterial Virulence*: Capsules are common in typical causes of pneumonia. ~ Toxins in serious causes. Types of Pneumonia: Community acquired (Typical and Atypical); Hospital acquired (VAP and Aspiration).

*Pneumonia* o What is it? o Epidemiology o Routes of Infection o Signs / Symptoms (typical) o Bacterial Virulence o Types of Pneumonia o Diagnosis

This is the classic 'food-poisoning' kind of salmonella infection. Patient will have GI symptoms of gastroenteritis. Bacteraemia is rare (usually only in young / elderly / immunocompromised). Patients with sickle cell anaemia are more vulnerable.

*Salmonella* Clinical consequence of infection with the gastroenteritis salmonella varieties.

They cause enteric fever (paratyphoid / typhoid fever). *Enteric Fever*: Occurs when there is bacteraemia of Salmonella bacteria, leading to septicaemia (blood poisoning). Hence, patient may present with fever or rose spots. GI symptoms may develop (but ~not with initial infection). Causative organisms are salmonella typhi bacteria.

*Salmonella* Clinical consequence of paratyphi / typhi infection.

Bind to small intestinal epithelium then are taken up via a vacuole. They are then taken into a macrophage and proliferate here. The macrophages usually do not travel to the LNs; rather, the macrophages multiply in the intestine and remain local → causing local GI symptoms (such as cAMP-mediated diarrhoea). The infection will resolve. RARE: Bacteraemia and may travel to LNs.

*Salmonella* Pathogenesis of food-borne (animal origin) infections.

Do not (initially) cause diarrhoea / GI symptoms. The infected macrophages travel to the lymph nodes and cause septicaemia then cause typhoid / paratyphoid fever. May travel to other organs - if it reaches GI organs GI symptoms. Patient may recover, by there will be chronic carriage of the organism in lymphoid tissue / organs.

*Salmonella* Pathogenesis of salmonella typhi / paratyphi (human-origin).

Typhi/Paratyphi = SEPTICAEMIA. Typimurium = DIARRHOEA. Enteridis = DIARRHOEA. Cholerasuis = SEPTICAEMIA.

*Salmonella* What are the common serogroups (of the subspecies enterica)?

All (except typhi/paratyphi). They cause food-poisoning (which has a quicker resolution than infectious causes).

*Salmonella* What are the food-borne salmonella organisms?

Typhi / paratyphi serotypes

*Salmonella* What are the human-origin salmonella organisms?

See Table on Page 40 (Vertical #4)

*Screening Methods:* Cervical cancer Breast cancer Colorectal cancer Prostate cancer

Not acceptable. Leukocytes → should be >25 per LPF. Epithelia cells → should be <10 per LPF.

*Sputum Sample:* Leukocytes (mainly neutrophils) = 5 per LPF. Epithelia cells = 18 per LPF. Is this sputum sample acceptable?

*Causative Organism*: Strep. pyogenes (GAS) *Risk Groups*: Children (5-15y), Māori & Pasifika. *Transmission:* Respiratory droplets (overcrowding, damp home, cold temp). Often occurs secondary to viral URTI. *Symptoms*: Acute onset sore throat, dysphagia, enlarged lymph nodes, exudate, petechiae, tonsil-pharyngeal erythema. *Diagnosis:* Clinical features, Risks, Culture & Gram-stain to confirm GAS. *Complications: * - Suppurative [invasion of surrounding tissues]. - Non-suppurative [systemic autoimmune disease → RF / RHD]. *Treatment*: Short course of oral penicillin.

*Streptococcal Pharyngitis* o Causative organism(s) o Risk groups o Transmission o Symptoms o Diagnosis o Complications o Treatment

ADP binds to P2Y receptors on platelet membrane → inhibits cAMP formation → ↓PKA (protein-kinase) formation → induces more platelet activation. Thrombin and ADP also bind to promote PLC activation, also resulting in increased platelet activation.

1. Describe the purinergic receptors significance in PKA inhibition and PLC-mediated platelet activation.

*LOW* since less drug if required to produce the effect.

1. Will a drug of relatively high potency have a LOW / HIGH value for EC50?

A Māori committee occupied Takaparawhā (Bastion Point reserve). They claimed the land had been unjustly taken from them and were angered by plans to subdivide it for a private housing development. The government offered to return some land if the iwi paid $200,000 in development costs. The occupiers stayed put. 506 days after they had arrived a large force of police moved in to evict them, arresting 222 protesters and demolishing buildings.

1978: Bastion Point

Ihumātoa is Auckland's oldest settlement. The land also has significance as an unsettled land dispute. The SOUL the campaign group attests that Ihumātao is land that was confiscated by the State in 1863, as punishment for local iwi refusing to swear allegiance to the Crown.

2019: Ihumātoa

(1) Institutional racism (2) Personally mediated racism (3) Internalised racism

3 Levels of Racism

Refers to differential access to the goods, services, and opportunities of society by race. It manifests itself both in material conditions and in access to power. o Health services are less accessible for Māori. o Health services are not providing the same benefits for Māori. o Poor recruitment and retention of Māori health professionals. o Health services that are not culturally safe for Māori.

3 Levels of Racism: Institutional Racism

Acceptance by stigmatised races of negative messages about their own abilities and intrinsic worth. Example: "Everyone in my family gets diabetes, so there is no point trying to prevent it." ...or... "I'm Māori, we don't feel pain, so we don't need medical help."

3 Levels of Racism: Internalised Racism

Defined as prejudice and discrimination. It refers to different assumptions about the abilities, motives and intentions of others based on their race. Includes: discrimination, marginalisation, stereotyping, victim blaming. It occurs between individuals!

3 Levels of Racism: Personally Mediated Racism

T cells (majority) B cells NK cells

3 Types of Lymphocytes

Receptors Enzymes Transport / carrier molecules Ion channels

4 Main Drug Targets

Heat Redness Swelling Pain Loss of function

5 Clinical Signs of Inflammation

(1) Raise price → increase tax; minimum price per standard drink (so cheap drinks are more expensive). (2) Raise purchase age (3) Reduce accessibility (4) Reduce marketing and advertising (5) Increase drink-driving counter measures + Increase treatment opportunities for heavy drinking.

5 Solutions for Reducing Alcohol Consumption & Harm

chromosomal abnormalities

50% of spontaneous abortions are due to...

40% of a cure is due to antimicrobial. 60% is due to immune system. Thus, in patients with immune deficiency, infections may be more difficult to treat.

60/40 Rule

LMICs (low-medium income countries)

90% of road fatalities occur in...

Felodipine is a calcium channel blocker that regulates BP. It undergoes first pass metabolism, which is catalysed by CYP3A4 enzyme. The drug does not build up the same effective plasma conc. in patients with increased CYP3A4 activity.

A patient with increased CYP3A4 activity has recently been put on Felodipine for their high BP. How will their increased CYP3A4 activity affect the metabolism of this drug?

B cell (esp. plasma cells) make immunoglobins including IgM. IgM doesn't have the Fc region which enables recognition by phagocytes. Therefore, IgM is a poor opsoniser. In multiple myeloma, all other white cells are suppressed since more IgM is being made, and there is suppression of IgG. We need IgE for opsonisation and phagocytosis of bacteria.

A patient with multiple myeloma has recently acquired an infection. The causative respiratory pathogen is capsulated. In multiple myeloma IgM is overproduced but there is little IgG. Why is this patient susceptible to infection with capsulated bacteria?

they see themselves at risk of disintegration.

A person suffers when...

Forms either a *Lymphoid* or *Myeloid* stem cell.

A pluripotent stem cell differentiates into one of two lineages:

Ischemia MI Cardiac myocyte injury

A re-entrant circuit is often caused by...

A spore stain for C. difficile infection is not diagnostic. The endospores are classified as either terminal, sub-terminal or central.

A spore stain for C. difficile infection is not __________. The endospores are classified as either __________, __________ or __________.

The microbiota of the mouth has been cultured, as well as the infectious organism.

A sputum sample was performed and cultured. Upon analysis, there was more than one type of bacterium present. Why?

Too little / none / too much gene product. Decreased / abnormal function of gene product. Gene product expressed in wrong cell type or at wrong time. Possible Consequence: *genetic disorders*

ABNORMAL Gene Expression

Ester bond & N+ (four bonds, hence positive charge on nitrogen)

ACh

Absorption Distribution Metabolism Elimination

ADME

administered amount of drug in body

Abbreviation: Ab

fraction of drug which is bioavailable

Abbreviation: F

rate constant of drug elimination

Abbreviation: K

before food

Abbreviation: a.c.

intramuscular

Abbreviation: i.m.

intravenous

Abbreviation: i.v.

after food

Abbreviation: p.c.

orally

Abbreviation: p.o.

rectal

Abbreviation: p.r.

as required

Abbreviation: p.r.n

subcutaneous

Abbreviation: s.c.

*Inadequate scar formation*: → Wound dehiscence: rupture. → Ulceration: inadequate vascularisation. *Hypertrophic scar* (overgrowth of scar tissue → keloid). *Contracture deformities*

Aberrations of Inflammation and Repair

q = 1/14 q2 = 1/196

About 1/7 Europeans are carriers of one copy of the HFE C282Y mutation (q = 1/14). What proportion of this population would be homozygous and thus at risk of developing HHC?

To accept death means at some point *ceasing to provide curative or life-extending treatments*. Palliative care affirms life and regards dying as a normal process. Neither hastens nor postpones death.

Acceptance of Death

Resistance acquired through gene acquisition or mutation. Ex: Vancomycin-resistant enterococci; MRSA.

Acquired Resistance

centromere close to end

Acrocentric

(1) Low nicotine cigarettes. (2) Decrease prevalence of cigarettes in retail stores. (3) Smokefree generation (increase legal age each year).

Action Plan for Reducing Smoking Prevalence

Person is required to do something. E.g. Put on a seatbelt.

Active Intervention

Acute = viral (Chronic = bacteria exacerbation)

Acute and chronic causes of bronchitis and bronchiolitis.

innate immune system

Acute inflammation is associated with which arm of the immune system?

A response of innate immunity that occurs soon after the start of an infection and involves the synthesis of acute-phase proteins by the liver and their secretion into the blood.

Acute phase response

*Advantages*: Easy Inexpensive ~Rapid absorption (depends) *Disadvantages*: Slow onset Not possible if unconscious (unless rectal). Harsh GI environment First pass metabolism Irritation of mucosa

Advantages & Disadvantages of *Enteral* Administration

*Advantages*: Rapid delivery Avoids first pass metabolism. Good for drugs which are not well absorbed in GI tract. Easy delivery *Disadvantages*: Difficult to reverses Risk of infection Requires skill Risk of bleeding

Advantages & Disadvantages of *Parenteral* Administration

Do not induce bronchoconstriction. Do not adversely affect lipid profiles.

Advantages of CCBs

Flushing Headache Reflex tachycardia Palpitations Avoid abrupt nitrate withdrawal after prolonged use. (mostly dose-related effects - due to vasodilation).

Adverse Effects of Nitrate Drugs

Alcohol is converted to acetaldehyde via ADH and CYP2E1, then to acetic acid via aldehyde dehydrogenase. This is a rate-limiting process (zero-order elimination).

Alcohol Metabolism

All staphylococci are catalase *positive* and all streptococci are catalase *negative*.

All staphylococci are catalase _____ and all streptococci are catalase _____.

More IgE molecules / mast cells. Genetic predisposition (80%). High affinity Fc receptors for IgE on mast cells & basophils.

Allergic individuals may have... (what features?)

The development of an allergy is by repetitive low-dose allergen stimulation. *Desensitisation* escalates allergen doses (delivery is subcutaneous). High dose antigen elicits a TH1 immune response (and antagonises TH2). B cells will be instructed to make IgG, which binds antigen and thus prevents IgE from binding. Since mast cells do not have high affinity FcR for IgG, degranulation will not occur.

Allergy Desensitisation

Drugs that bind to the target at a site that is distinct from the orthosteric ligand, and modify the action of the orthosteric ligand (either enhance or inhibit response.

Allosteric modulators

A site on an enzyme other than the active site to which a specific substance binds.

Allosteric site

Type of Drug: Weak diuretic (K+ sparing diuretic). MoA: Blocks ENaC channels. Inhibits sodium flux. Indications: Hypokalaemia, Hypertension.

Amiloride → Type of Drug → Mechanism of Action → Indications

The general name for complement fragments C3a and C5a, which are produced during complement activation. They induce inflammation, recruiting fluid and inflammatory cells to sites of antigen deposition.

Anaphylatoxin

Brain: impaired development, cravings, irritability, antisocially, depression, anxiety, impaired memory, ataxia. Liver: cirrhosis, hepatitis. Stomach: chronic gastritis. Pancreas: pancreatitis. Peripheral tissues: increased risk of Type 2 diabetes. See Page 45 (Vertical #4)

Anatomical Harms of Alcohol Consumption

Title Abstract Body of the Paper (IMRAD) - Intro - Methods - Results - And... - Discussion Acknowledgements Funding Sources / Conflicts of Interest References

Anatomy of a Research Paper

Interaction between 2+ drugs that have the opposite effects on the body. Drug antagonism may block or reduce the effectiveness of 1+ drugs.

Antibiotic Kinetics: Antagonism

When the antimicrobials are neither synergistic or antagonistic (i.e., do not influence each other's action).

Antibiotic Kinetics: Indifference

Interaction between 2+ drugs causes the total effect of the drugs to be greater than the sum of the individual effects of each drug.

Antibiotic Kinetics: Synergy

Erythromycin / Norfloxacin

Antibiotic for Campylobacter jejuni

Inhibits DNA synthesis. However, it first requires uptake into the fungal cells via cytosine permease and cytosine deaminase → mutation in either of those can lead to resistance. It is then converted to cytostatic 5-FC in the fungal cell, and inhibits thymidylate synthase and causes RNA miscoding.

Antifungal Drug: Flucytosine (5-FC)

Target 14α-demethylase, thereby preventing ergosterol synthesis → impairs membrane fluidity and leads to accumulation of toxic alternative sterols. Imidazole (topic). Triazole (fluconazole has activity against yeast; itraconazole has improved activity against moulds). Resistance to azoles can develop via mutation of 14α-demethylase (leading to cross-resistance) and overexpression of efflux pumps.

Antifungal Drug: Azoles

Binds β-1, 3-D-glucan synthase. β-1, 3-D-glucan polymers are key cross-linking structural components of the cell wall in some fungi. Echinocandins inhibit synthesis of these polymers. Glucan-depleted cell walls are susceptible to osmotic lysis.

Antifungal Drug: Echinocandins

Bind with high affinity to ergosterol, leading to formation of pores in fungal cell membrane.

Antifungal Drug: Polyenes

Inhibits ergosterol synthesis by inhibiting squalene monoxygenase. Leads to accumulation of toxic alternative sterols. Concentrates in the skin & nail beds and has low bloodstream concentration. Its use is thus restricted to treatment of onychomycosis and cutaneous fungal infection.

Antifungal Drug: Terbinafine (Allylamine)

A mechanism for variation in viruses that involves the accumulation of mutations within the genes that code for antibody-binding sites. *Minor change in influenza virus antigens due to gene mutation.* Example: Occurs in HA and NA, and both Type A & B influenza viruses. Main reason for recurring seasonal epidermis and the need for annual flu vaccination.

Antigenic Drift

The process by which two or more different strains of a virus, or strains of two or more different viruses, combine to form a new subtype having a mixture of the surface antigens of the two or more original strains. *Major change in influenza virus antigen due to gene reassortment.* Example: Occurs for Type A viruses (only) and usually results in a pandemic.

Antigenic Shift

Changes in surface antigens that occur in a microbial population. Ensures that previous immune memory functions less well because a new set of epitopes are presented to the host (e.g. Influenza A virus).

Antigenic Variation

*Characteristics:* Structure resembles histamine. Strong sedative. *Indications:* Allergic rhinitis; Conjunctivitis; Hay fever; Anaphylactic shock; Motion sickness; Urticaria [hives]. *MoA:* Competitive reversible antagonist. Blocks H1 receptors (and M1 receptors → anti-emetic). *Side Effects:* Wide range of SEs! Anticholinergic SEs (due to blocking of M1 receptors) → impacts secretory glands [possibly beneficial for common cold], heart, SM, pupil, ciliary muscle. Also blocks adrenal a1 receptor activation so can cause hypotension, flushing, tachycardia. Crosses BBB so can cause depressant effects (drowsiness, dizziness, fatigue). *Metabolism:* CYP2D6 & CYP3A4. Metabolism reduced by CYP3A4 inhibitors (e.g., grapefruit juice), which enhances drug effects.

Antihistamines: H1 Receptor Antagonists *1st Generation* → Characteristics → Indications → MoA → Effects → Side Effects → Metabolism

*Characteristics:* Structure resembles histamine. Nonsedative / mildly sedative. SAFER. *Indications:* Allergy; Urticaria [hives]. *MoA:* Non-competitive antagonist. Binds to different site, so does not compete with histamine, allowing it to remain bound longer. Prevents G-protein coupling. *Side Effects:* Does not mimic shape of other NTs, so does not bind to other receptors. Reduced crossing of BBB due to presence of aromatic groups = little / no fatigue. *Metabolism:* CYP2D6 and CYP3A4. The drug is cleared through the PgP secretory system (a drug efflux pump system).

Antihistamines: H1 Receptor Antagonists *2nd/3rd Generation* → Characteristics → Indications → MoA → Effects → Side Effects → Metabolism

'an organisational or healthcare system wide approach to promoting and monitoring judicious use of antimicrobials to preserve their future effectiveness'.

Antimicrobial Stewardship

See Lecture 10 (Public Health)

Apply the screening criteria to CF.

2

Appropriate autosomal gene dosage is...

Yes (but erased in the germline). Allow a cell to have its own methylation pattern such that a unique set of proteins are expressed to perform the functions specific to that cell type.

Are DNA methylation patterns passed onto daughter cells?

*YES* Excessive activation of HPA axis / SNS. Increased release of catecholamines → damage vascular endothelium → release of FAs. Anxiety → greater strain on heart by increasing HR, baroreflex dysfunction, variability in ventricular repolarisation. Altered CV autonomic control / decrease HRV. Inflammatory pathways. Poorer health behaviours. Sudden extreme emotional states → MI.

Are anxiety disorders associated with increased risk of developing heart disease? If so, what are the mechanisms?

-cidal drugs = kill. -static drugs = stop growth. Thus, -cidal drugs are preferred.

Are bactericidal / fungicidal or static agents preferred in patients with immune deficiency?

"True pathogens" shouldn't be routinely cultured from healthy people. However, there are some microorganisms which exist within a normal gut microbiome but can still cause disease (these are opportunistic infections → require specific conditions to cause infection). Escape of the gut microbiome into the blood or tissues may lead to life-threatening infections.

Are commensals and pathogens always different organisms?

No, only probabilistic.

Are copy number variants determinative of phenotype?

*Non-ionised drugs* This depends on drug pKa & gut pH. · Weak acids (aspirin) = less ionized in acidic (low pH) conditions. · Weak base (diazepam) = less ionized at basic (high pH).

Are ionised OR non-ionised drug more lipid soluble?

Men → 2x more likely.

Are men or women more at risk of death from RTIs?

Neutral (no effect) Advantageous (rare) Disadvantageous (pathogenic)

Are mutations always disadvantageous?

(1) High BMI (2) Low fruit and vegetable intake (3) Lack of physical exercise (4) Tobacco use → responsible for 22% cancer deaths. (5) Alcohol use

Around 1/3 of deaths from cancer are due to the 5 leading behavioural and dietary risks, which are...

surgical puncture of a joint

Arthrocentesis

(1) Immediate: SOS SABA + Oxygen (if arterial pO2 < 90mmHg) → not responding? Give Ipatropium (SAMA). → not responding? Give either oral or IV corticosteroid. → not responding? Give magnesium sulphate (IV). Ensure patient is in comfortable tripod position. (2) Continuing management - Prevent exhaustion. - Avoid retention of secretions (clear airway and suction out mucous). - Ensure not aspirating. - Frequent assessment of response to treatment. (3) Long-term - Investigate causative allergens / triggers - Avoid allergen - Ensure correct inhaler technique - Monitor with FEV1 / peak flows (peak flow meter). - Asthma 4-stage action plan - Address inflammatory process (short course oral steroids for ~5 days, then ICS). - Check patient knows signs of worsening asthma.

Asthma Exacerbation: (1) Immediate (2) Continuing management (3) Long-term

*Oral Corticosteroids:* Prednisone → Indications: Used early in acute asthma exacerbation. Short course for ~5 days. Inhaled *Corticosteroids (ICS):* Fluticasone → 1-2 puffs once/twice daily. → Minimal systemic exposure (minimises ADRs).

Asthma Treatment: Preventers What are the types of corticosteroids? Provide an example and indications for each.

*Drug Class:* Anti-inflammatory Drugs → Corticosteroids *Mechanism of Action:* The drug binds to intercellular receptor, and is transported into the nucleus where it alters gene transcription: - Upregulation of lipocortin-1 (an inhibitor of phospholipase). Hence, membrane phospholipids cannot undergo conversion to arachidonic acid. - Upregulation of anti-inflammatory IL-receptor antagonists. - Downregulation of pro inflammatory PLA2 (Phospholipase A2), iNOS and COX. They also inhibit the movement of inflammatory cells, and are therefore immunosuppressant. *Side Effects:* - Immunosuppression (local → candidiasis) - Suppression of HPA axis (reduced production of endogenous corticosteroids such as cortisol). - Fat gain - Muscle wastage - Osteoporosis (decreased calcium absorption and suppression of osteoblasts).

Asthma Treatment: Preventers → Drug Class → Mechanism of Action → Side Effects

Beta-2 agonists [Bronchodilators] (1) *SABAs*: Short acting beta-2 agonist Example: SalbutamolIndications: Acute asthma exacerbation (rapid relief, "rescuer"). MoA: Binds to beta-2 receptor → increase cAMP → activates PKA → phosphorylatory action increases conductance of calcium-sensitive potassium channels → hyperpolarisation and relaxation of smooth muscle within bronchioles. Also, there is increased ciliary beat frequency due to increase cAMP in epithelial cells. Side Effects: Skeletal muscle tremor, increased HR and force of contraction (high dosage = loss of receptor-selectivity), hypokalaemia. (2) *LABAs*: Long acting beta-2 agonist Example: Salmetrol Indications: Nocturnal asthma or exercise-induced asthma. Not used for rapid relief. MoA: Has a lipophilic side chain which increases its 1/2 life (~12 hours of bronchodilatory action). Side Effects: see above.

Asthma Treatment: Relievers For each, provide: - Example - Mechanism of Action - Indications - Side Effects

High cholesterol diet Smoking (more oxidised LDL) Deficiency in Apo B receptors (e.g., Familial hypercholesterolemia).

Atherosclerosis is associated with...

*Reversible inhibitor of hepatic HMG-CoA reductase enzyme*, ∴ inhibitor of hepatic de novo cholesterol biosynthesis. Thus, depletes sterol pools → activates production of HMG-CoA reductase & LDL receptor → greater uptake of IDL and LDL from plasma → decreases plasma LDL-cholesterol conc. (and TAGs). Also, slight increase plasma HDL-cholesterol. Pharmacokinetics: Poor bioavailability (14%) Highly protein bound (98%) Extensive hepatic metabolism to active products. Elimination via CYP3A4. Side Effects: Elevated liver enzymes. Myopathy. Rhabdomyolysis (rare but significant). Teratogenic (avoid in pregnancy).

Atorvastatin → MoA → Pharmacokinetics → Side Effects

The wasting away of a body organ or tissue. Occurs initially in response to decrease blood supply.

Atrophy

Pili Fimbriae Capsules Surface molecules (e.g.LPS)

Attachment of bacteria to host cells is through...

Influenza A virus. Endemic in poultry. Causes sporadic but deadly infection in humans. No human-to-human transmission.

Avian Influenza A (H5N1 and H7N9)

· Campylobacteria jejuni · Salmonella spp. · Shigella spp. · STEC / VTEC · Yersinia enterocolitica

Bacterial Causes of Gastroenteritis

Cells become simple columnar with goblet cells (normal is stratified squamous), and this increases risk of adenocarcinoma developing. Most common in Pakeha, overweight, older men. It is a potential consequence of GORD!

Barrett's Metaplasia

Lack of recognition that patient requires palliative care (late referrals). Culture of 'saving lives.' Unrealistic expectations. Disagreements about goals of care. Tempting fate. Patient 'not ready.' Fear of upsetting patient. Unsure of what is culturally appropriate. Lack of palliative care knowledge. CONSEQUENCE: Decreased QoL + unprepared for death.

Barriers to Palliative Care

Long treatment duration → poor adherence, loss to follow up. Complex regimens. Toxic effects in combination with ARVs. Drug resistant TB (MDR TB, XDR TB).

Barriers to Treatment Against TB

Drugs Speeding Thrill-seeking Tailgating Dangerous overtaking Misjudge speed / gap distance Over-estimate one's own ability

Behaviours which increase crash risk

*Type of Drug*: Thiazide diuretic (a mild-moderate diuretic). *Site of Action*: Distal tubules (this region only reabsorbs ~5% of filtered sodium). *Mechanism of Action*: Secreted in the proximal tubule via OAT, travel downstream, competitively bind to apical eNCC-1 sodium-chloride transporter. Transporter is unregulated by aldosterone. *Effect*: Modest increase in sodium and water excretion. Potassium loss. *Therapeutic Uses*: Hypertension (alongside ACE-i, ARBs, CCBs). *Adverse Effects*: Dehydration & postural hypertension, Electrolyte imbalances, Hyperglycemia (and impaired glucose tolerance).

Bendroflumethiazide → Type of Drug → Site of Action → Mechanism of Action → Effect → Therapeutic Uses → Adverse Effects

High-resolution technique which allows for diagnosis of genomic imbalances. Indicates duplications & deletions in genome. Measures size of dups & dels, so shows which genes are / are not affected. Chromosomes not required to be in metaphase. However, for infertility = microscopic analysis of chromosomes should be performed to assess rearrangements.

Benefits of Chromosomal Microarray

• Recognise injury is a process • Multi-disciplinary thinking • Creative solutions • Range of strategies for planning & resource allocation (primary & secondary prevention + active / passive interventions).

Benefits of Haddon Matrix

Improved QoL. Improved mood. Extended survival. Due to effective symptom management, support for family and open communication about goals of care, wishes and priorities.

Benefits of Palliative Care

· Improved prognosis → early detection · Less radical treatment (compared to that offered for later-stage disease) · Reassurance for those who receive negative test result

Benefits of Screening

- Decreased ADRs and other toxic effects. - Maximises therapeutic benefits.

Benefits of precision medicine

(1) Red blood cell breakdown (2) Liver damage

Bilirubin is formed either by...

Fraction of dose that reaches systemic circulation (following oral ingestion).

Bioavailability

Increased transferrin-iron saturation. Increased serum ferritin concentration.

Biochemical Presentation of HFE-HH

Attempts to apply biological and physiological principles to the medical care of individual patients. Based on understanding of cells, organs, physiology, etc. Linear process / logic. Assumes that a person's problems will be explained by known abnormalities within their organ systems. Based on biological plausibility. Most useful for *acute diseases and injury*. Less effective for *multi-morbidity and chronic illness*. Does not explain all observable clinical phenomena.

Biomedical Model of Health

Based on General Systems Theory, where the body's physiological state is an ongoing outcome of complex adaptive systems, each level of which attempts to respond to new inputs to maintain homeostasis. Can incorporate a range of inputs into a person's health & wellbeing (including personal ideas, family factors, work & social situations, etc.). Interactions between these complex systems. Non-linear. It can incorporate interpersonal, anthropological and sociological perspectives in the aetiology and management of chronic illness, without neglecting biological factors.

Biopsychosocial Model of Health

Page 96 (Vertical Answers #1)

Blood: Lab 1

Page 103 (Vertical Answers #1)

Blood: Lab 2

Page 110 (Vertical Answers #1)

Blood: Lab 3

60-74 year olds (men & women)

Bowel Screening [Age Group]

Time sequence Strength of association Dose-response relationship Specificity of association Biological plausibility Consistency of association Experimental evidence

Bradford-Hill Criteria

Adenocarcinoma There is an oestrogen receptor which (in response to estradiol) activates genes which enhance cell growth. ~75% of breast cancers are oestrogen receptor positive (ER+). Pharmacological oestrogen antagonism reduces tumour cell proliferation of ER+ Brest cancers (or removal of ovaries to remove oestrogen which drives growth of tumour). There may also be overamplification of Her2 (human epidermal GF receptor 2) gene. We can block interaction of Her2 with the GF via Herceptin, ∴ decreasing proliferation.

Breast Cancer Pathology

45-69 year old women

Breast Screening [Age Group]

Typical causes = Haemophilus, Gram(-)s. Common in those with underlying lung disorder.

Bronchopneumonias generally caused by...

*Disorder of B cell* Characterised by a mutation in Btk (Bruton's tyrosine kinase). Btk is expressed in B cells and monocytes, but mutation only leads to defective B cells. B cell maturation is arrested at the pre-B cell stage such that no antibodies can be produced.

Bruton's X-linked agammaglobulinemia

*Disorder of B cells* Characterised by a mutation in Btk (Bruton's tyrosine kinase). Btk is expressed in B cells and monocytes, but mutation only leads to defective B cells. B cell maturation is arrested at the pre-B cell stage such that no antibodies can be produced.

Bruton's X-linked agammaglobulinemia

Microdeletions in regions that involve genes of regulatory significance → genes controlled by these sequences would no longer be regulated → altered phenotype.

By mapping a deletion to the human genome sequence, what can we determine?

Selectivity: Either vaso-selective or cardio-selective. Function: Block L-Type calcium channels, therefore reducing smooth muscle and cardiac muscle contraction.

CCBs → Selectivity → Function

cystic fibrosis transmembrane conductance regulator

CFTR

CF and CAVD (congenital absence of vas deferens)

CFTR-Related Disorders

Reduced inhibition brain , so person is more likely to experience constant arousal. Further inhibition if there is withdrawal, so person will appear anxious with an overactive SNS. (Comparatively, acute consumption enhances inhibition of brain via interaction with GABA, GIRKS; also switches of arousal symptoms via NMDA receptors)

CNS Effect of Chronic Alcohol Consumption + Withdrawal

A patient is presumed competent unless there are reasonable grounds for the thinking the patient is not competent.

COMPETENCE In NZ, who is a patient determined to be competent?

• Unconsciousness • Intoxication • Immaturity • Cognitive impairment • Brain injury • Acute psychiatric condition

COMPETENCE What sort of factors may make a patient unable to make a decision?

Ask Qs of the pt. Use simple language. Explain technical language. Images / written info. Be aware of factors that may undermine comprehension (e.g., medication, time required for processing, shock, etc). Defer the decision.

COMPREHENSION How can comprehension be enabled?

Constitutive form. Inhibition of COX-1 accounts for gastric and renal SEs.

COX-1 Enzyme + consequence of its inhibition.

Inducible form. Produces PGE2 in inflamed tissues. Inhibition of COX-2 accounts for anti-inflammatory effects.

COX-2 Enzyme + consequence of its inhibition.

It is a major enzyme involved in drug metabolism, and accounts for 50% of CYP activity. Acts in liver (and SI epithelium). Regulates first pass metabolism. Present on the ER within cells. Iron atom aids its function. Its activity is regulated by inhibition or induction.

CYP3A → Where does it act? → What does it do? → Where is it located intracellularly? → How is it regulated?

Heat / Warmth

Calor

Fungus that colonises 50-80% of population. Two Forms: - Commensal, single cell yeast form. - Infective mould form.

Candida albicans → What is it? → % Colonised

*Active component:* THC *MOA:* Agonist of cannabis-1 and cannabis-2 receptors. CB1 agonism produces psychological effects. *Effects:* - High / euphoria - Hunger - Paranoia - Impaired CNS functioning *Tolerance:* can develop if multiple doses / day. *Dependence:* only if heavy use. *Harms:* - Less harms than alcohol. - Affects neurodevelopment of children (leads to cognitive and behavioural problems).

Cannabis → Active component → MOA → Effects → Tolerance → Dependence → Harms

Normal epithelium undergoes either atypical alveolar or bronchial hyperplasia, which leads to formation of pre-malignant adenomas or carcinoma in situ, respectively, then cancer.

Carcinogenic Effects of Tobacco

The proportion of individuals contracting a disease who die of that disease. No. of deaths due to virus ÷ Total no. diagnosed with virus.

Case Fatality Ratio

Vertical Answers #2 Page 113

Case-Based Learning: Lecture 13 (Clinical Pharmacology)

Associated with chronic inflammation. White, "cheesy" material. Observed in tuberculoses. Microscopic: structureless granular debris, eosinophilic.

Caseous necrosis

Acute infection by pyogenic bacteria. Usually *Staph. aureus*. Pathogens are ~age specific.

Causative Organisms: Osteomyelitis

*Staph. aureus* Young, sexually active patient: *Neisseria gonorrhoea*

Causative Organisms: Septic Arthritis

*Neonates*: Group B streptococci, E.coli, Listeria monocytogenes *≤ 10 years old*: Neisseria meningitidis *Adolescent*: Neisseria meningitidis *Adult*: Neisseria meningitidis, Strep. pneumoniae *Elderly*: Strep. pneumoniae, Listeria monocytogenes

Causative bacterial agents for meningitis: Neonates ≤ 10 years old Adolescent Adult Elderly

TB (and fungal causes)

Cause of Chronic Pneumonia

Meiotic non-disjunction

Cause of Klinefelter Syndrome

IHD HF Hyperthyroidism Diabetes Old age Excess alcohol

Causes & Risks of AF

MI / infarction Hypokalaemia Drug toxicity Thyroid disorders etc...

Causes of Arrythmias

Parasitic infection Allergic reaction

Causes of Eosinophjilia

· Pancytopenia → e.g. bone marrow disease. · Drug side-effect · Viral infection · Genetic neutropenia · Fulminant bacterial infections

Causes of Neutropenia

Infection (left-shift) Steroid-induced Smoking Obesity ...etc...

Causes of Neutrophilia

Ischemia (reduced BF). Inadequate oxygenation of blood due to cardiorespiratory failure. Decreased ox. carrying capacity of blood (e.g., anaemia or CO poisoning). Haemorrhage.

Causes of hypoxia

(1) Blockage of vessel (2) Thrombus (3) Embolism

Causes of ischemia

(1) Reactive chronic inflammatory states (chronic bacterial infxn). (2) Muelodysplastic syndrome (a bone marrow cancer).

Causes of monocytosis

Thick peptidoglycan layer. No outer lipid membrane. Stain: purple

Cell Wall of Gram (+) Bacteria

Thin peptidoglycan layer. Outer lipid membrane. Stain: pink

Cell Wall of Gram (-) Bacteria

Abnormal cell wall. Acid-fast bacillus. Rich in cell wall lipids (*mycolic acids* & glycolipids) → hydrophobic. Slow growing (15-20 hours). Facultative intracellular pathogen (can live in host cell, but doesn't have to). Neither Gram(+) or (-).

Cellular Features of Mycobacterium Tuberculosis

(1) *Margination & Rolling*: Margination: Circulating cells are swept by laminar flow against vessel wall. Rolling: Activated endothelial cells express adhesion molecules that allow loose attachment of leukocytes. The cells binds and detach, tumbling along the endothelial surface. (2) *Adhesion & Transmigration*: Adhesion: WBCs firmly adhere to endothelial surface via integrins exposure of their cell surface. Transmigration: WBCs migrate through vessel wall (via intercellular junctions). (3) *Chemotaxis & Activation*: Chemotaxis: Chemical gradient draws WBCs to site of infection. Activation: WBCs are activated by microbes and other mediators. Enhances activity of WBCs. (4) Leukocytes participate in: - Phagocytosis & degranulation. - Leukocyte-induced tissue injury.

Cellular component of acute inflammation

*Risk Group*: Trauma, diabetes, pregnancy, obesity, elderly. *Location*: Demis + Hypodermis (acute spreading) *Features*: Ill-defined margins; Reddish / pink; No necrosis. *Organism*: S. pyogenes (tissue destroying enzymes) / S. aureus (wounds, post-surgery). *Treatment*: ~Oral / IV antimicrobials. *Complications*: Bacteraemia, abscess, septic arthritis, etc.

Cellulitis → Risk Group → Location → Features → Organism → Treatment → Complications

- Changes in other factors (e.g., age distribution) - Improved treatment ( mortality decline) [but doesn't affect incidence] - Diagnostic changes - Improved case recording (e.g., by cancer registry) - Changes in causes of disease; prevention programmes.

Changes in rate of disease overtime may occur because...

Meningococcus. Gram-negative diplococci. Located intracellularly (within CSF neutrophils). Only communicable form of meningitis.

Characteristics of Neisseria Meningitidis

day-to-day cellular needs.

Chemical modifications of histone proteins regulate gene expression in response to...

Used to distinguish between non-cardiac pain and typical cardiac pain. 0 = Non-cardiac pain 1-2 = Atypical pain 3 = Typical pain

Chest Pain Score

gene regulation.

Chromatin is dynamic. This is important for...

a generalised, genome-wide survey for imbalances

Chromosomal Microarray

No. of chromosomes change. Severe gene under-/over-dose. Natural abortion (except in Down Syndrome).

Chromosomal Mutations

ANS is dysregulated. Reduced activity of HPA-axis. Also associated with change in metabolism (cells are under oxidative stress). Lower anaerobic threshold (impaired ability to extract O2). Immune abnormalities. Neuroinflammation within fatigue nucleus (basal ganglia) leads to changes that induce energy conservation - this cannot be turned off.

Chronic Fatigue Syndrome: Aetiology

Also called ME (myalgic encephalomyelitis) or post-viral fatigue syndrome, CFS is diagnosed based on the following criteria: A. ≥6 months of severe, persistent fatigue that is not relieved by bed rest and which causes substantial functional impairment. B. ≥4 of the following symptoms: - Brain fog - Sore throat - Tender cervical / axillary nodes - Muscle pain - Multipoint pain without joint swelling - Headaches - Unrefreshing sleep - Post-exertional malaise lasting >24 hours

Chronic Fatigue Syndrome: Diagnosis

Low rates of recovery Give up work Remain in bed Long-term Do not feel 'believed' Get shunted to psychiatric services :-( May develop other mental disorders.

Chronic Fatigue Syndrome: Impact

<1%

Chronic Fatigue Syndrome: Prevalence

CBT Adaptive pacing therapy (helps to plan activities, formulating ways to avoid fatigue; enables adaptation to syndrome). Graded exercise therapy Pharmacotherapy → NSAIDs → Antidepressants → Antiviral drugs / monoclonal antibodies

Chronic Fatigue Syndrome: Treatment

*Defect in phagocyte function* Mutations in phagolysosome components (including in NADPH oxidase, G6PD, myeloperoxidase) impair the killing ability of the phagocyte such that it cannot eliminate ingested microbes. The hostility of the phagolysosome is not as potent! The bacteria thus survive within the phagocyte, and this leads to a chronic inflammatory response that involves granuloma formation. Individuals are highly susceptible to bacterial and fungal infections.

Chronic granulomatous disease

adaptive immune system

Chronic inflammation is associated with which arm of the immune system?

*Sodium-channel antagonist* (blockers) Example: Lignocaine *Not examined?? Reduce Phase 0 slope and peak of acton potential.

Class I Antiarrhythmic Drugs → Mechanism → Example

*Beta-blockers* Mechanism: Competatively block beta receptor sites in heart and kidneys. Decrease HR, cardiac out, and excitability. Slow conduction through AV node. Examples: Metoprolol, Atenolol. Effects: Block effect of NA on heart. Reduce rate and conduction velocity. Indications: Useful for rate control in AF. Stress-induce tachycardias. Adverse Effects: Bronchospasm, Neg. ionotropic effects, Fatigue, Uncompensated HF.

Class II Antiarrhythmic Drugs → Mechanism → Example → Effects → Indications → Adverse Effects

Mechanism: Block potassium channels (reduce K+ efflux). Example: Amiodarone. Effect: Prolong AP. Increase the refractory period of cardiomyocytes → delay Phase 3. Indication: Most arrhythmias (esp. rate control in AF). Caution: Reduces warfarin / digoxin renal clearance. Additive effect with beta-blockers.

Class III Antiarrhythmic Drugs → Mechanism → Example → Effects → Indications → Caution

Mechanism: CCBs. Example: Diltiazem, Verapamil. Effect: Reduce calcium entry into nodal cells and cardiomyocytes. Site of Action: SA and AV nodes. Indication: Atrial tachycardia and flutter. Caution: Avoid use with beta-blockers.

Class IV Antiarrhythmic Drugs → Mechanism → Example → Effects → Site of Action → Indications → Caution

Weight loss Night sweats Fatigue Persistent cough → progresses to haemoptysis. No response to erythromycin

Classic Symptoms of TB Infection

Lymphoid Myeloid

Classification of blood cancers

Volume of plasma cleared of drug per unit time.

Clearance

KuraCloud

Clinical Pharmacology: Lab 2

End-organ damage secondary to excessive iron storage

Clinical Presentation of HFE-HH

*Antiplatelet* Used if patient cannot tolerate aspirin. MoA: Blocks ADP (P2Y) receptors, preventing activation of fibrinogen (GP2b & GP3a) receptor, thus reducing platelet activation. Synergistic with aspirin.

Clopigodrel → What is it? → When used. → MoA → Interaction

Strongly associated with broad-spectrum antibiotic use. [Reduced commensals population and thus protective mechanisms allows C. diff to proliferate]. Risk groups: Immunosuppressed, elderly, those undergoing chemotherapy. The infection ranges from having less severe, more common effects (such as diarrhoea) to more severe, less common effects (pseudomembranous colitis; toxic megacolon). Infection normally associated with watery diarrhoea, abdominal pain and neutrophilia.

Clostridioides difficile (C. diff) Infection → Risk groups → Effects → Clinical symptoms [opportunistic organisms of gut]

Secretes toxins (TcdA / TcdB). These inhibit Rho signalling pathways, leading to loss of tight junctions. The toxins are cytotoxic and cause the immune system to destroy cells → since presence of toxins leads to production of pro-inflammatory cytokines form epithelial cells. Also, toxins that reach sub-epithelial layer stimulate monocytes to produce cytokines, leading to neutrophilia. Nerves can also be harmed, and this can implicate peristalsis and lead to toxic megacolon.

Clostridioides difficile (C. diff) Infection → Toxins → What do the toxins do? [opportunistic organisms of gut]

Non-anatomic areas of pain. Absence of other expected symptoms / signs for that body system. Swelling / redness / heat out of proportion to injury. Maladaptive psychosocial factors (e.g. poor self-efficacy, negative emotions).

Clues that suggest a functional illness: Clinical Signs

Symptoms don't correspond with a known pathophysiology. Time correlation of symptoms with life event. Pain out of proportion to event. Pain doesn't improve with time (i.e. central sensitisation or nociplastic pain). Similar previous history. Multiple neg investigations. Ineffective pain medication.

Clues that suggest a functional illness: Symptoms & Previous History

Staph. aureus

Coagulase production is a virulence trait of...

Cause: ischemic conditions → hypoxia. Alteration / denaturation of cellular proteins. Cell shape & organ structure are preserved by coagulation of proteins. The architectures of dead tissue are preserved for at least a couple of days. Necrotic tissue that remains firm! Often pale.

Coagulative necrosis

· Secrete bacteriocins and SCFA · Lower pH · Cause host to thicken mucous layer · Cause host to upregulate antimicrobial peptides (defensin, IgA) · Prime host neutrophils and macrophages

Commensal make the environment actively hostile to pathogens. How?

bacteria normally found at various non-sterile body sites

Commensal organisms

· Block colonisation niches · Compete for nutrients · Modify environment to change virulence factor expression

Commensals prevent pathogens from successfully colonising / invading host. How?

Infection in foot bones (diabetics). Vertebrae and pelvis.

Common site of osteomyelitis in adults.

Metaphysis of long bone.

Common site of osteomyelitis in children.

*Disorder of B cells* There is a normal population of B cells, but the cells are functionally different. Maturation and differentiation of B cells is prevented, and this leads to a predominantly humoral immunodeficiency in IgG (in particular), as well as IgM and IgA. This is not as severe as other conditions, as some B cell function has been retained. Patients are often diagnosed in adulthood.

Common variable immunodeficiency (CVID)

Infectious diseases Example: Tuberculosis, Measles.

Communicable Diseases

*Causative Organisms*: Legionella, Chlamydia pneumoniae, Mycoplasma pneumonia (intercellular bacteria which lack cells wall, so cannot be targeted with penicillin). *Clinical Presentation*: Absence of typical symptoms and CXR signs. Vague, flu-like symptoms. Low-grade or absent fever. Can occur in healthy. *Treatment*: Generally don't respond to treatment.

Community Acquired Pneumonia: Atypical Features → Causative organisms → Clinical presentation → Treatment

*Causative Organisms*: Strep. pneumoniae, Haemophilus, Moraxella. *Clinical Presentation*: Typical symptoms and CXR signs. Usually occurs in elderly or those with comorbidities. *Treatment*: Penicillin.

Community Acquired Pneumonia: Typical Features → Causative organisms → Clinical presentation → Treatment

Drugs A and B have the same efficacy. Drug A is more potent than Drug B. Drug C has lower potency and lower efficacy.

Compare the potencies and efficacies.

adaptive mechanism that enables certain organs to regenerate Example: resection of the liver

Compensatory hyperplasia

Hypokinetic atria → blood stasis → thrombus formation → ischemic stroke.

Complication of AF

Bilirubin can cross BBB and cause neurological damage. If foetal amniotic fluid becomes severe, an intra-uterine blood transfusion can be performed.

Complication of high bilirubin in babies

- Haemorrhagic colitis (most common). - Haemolytic uraemic syndrome (HUS). - TTP (thrombotic thrombocytopenia purpura). TTP and HUS → occurs because ADAMTS13 is inhibited (it normally prevents coagulation). Therefore, there is increased clotting in blood → thrombi become lodged in capillaries → causes RBC shearing → damage to kidneys and CNS; anaemia.

Complications of E. coli Infection

Death Amputation Hearing loss Blindness Epilepsy / Cerebral palsy Cognitive issues

Complications: Meningitis

Altered bone growth. Pathological fracture. Chronic / Recurrent OM. DVT Sepsis Septic arthritis

Complications: Osteomyelitis

Infectivity Pattern of mixing Duration of infectiousness R0 = P(infection | contact) x (No. of contacts / Period of time) x Duration of infectiousness

Components of R-naught (How is it approximated?)

*Invitation & recall system.* *Screening test.* *Effective management strategy* / treatment that can be offered to those who are later diagnosed. And quality control + monitoring of the programme!

Components of a Screening Programme

4000+ chemicals 50+ of these are known carcinogens.

Composition of a Cigarette

- Food allergies - Hay fever - Bronchial asthma - Anaphylaxis - Allergies

Conditions associated with Type 1 hypersensitivity

Autoimmune haemolytic anaemia Sjörgen's syndrome Antibody-mediated glomerulonephritis

Conditions associated with Type 2 hypersensitivity

Vasculitis Glomerulonephritis Arthritis SLE (Systemic Lupus Erythematosus)

Conditions associated with Type 3 hypersensitivity

Rheumatoid arthritis Contact dermatitis Multiple sclerosis Tuberculosis Crohn's disease Leprosy

Conditions associated with Type 4 hypersensitivity

"-itis"

Conditions associated with inflammation usually end in...

Deficient absorption of water → watery colonic contents → diarrhoea.

Consequence of 'too rapid' motility in GIT.

Excess absorption of fluids → *constipation*.

Consequence of 'too slow' motility in GIT.

Cp reaches >MTC (i.e., toxicity)

Consequence of *too rapid* absorption

Cp fails to reach MEC (i.e., no treatment effect)

Consequence of *too slow* absorption

Excessive breakdown of RBCs ↓ Increased bilirubin production ↓ Jaundice

Consequence of excessive haemolysis

Increased ICP → puts pressure on brainstem and can result in hernia at base of skull → ischemia & hypoxia.

Consequence of inflammation within the CNS

Either: - Unfavourable and decrease the fitness of the virus. - Favourable and increase the fitness of the virus. Multiple mutations can lead to resistance.

Consequence of mutations in HIV

Detection of the antigen can be achieved first. It is ~5 days until the immune response is detectable. IgG persists for a long time, while IgM diminishes overtime. See Graph, Page 69 (Vertical Answers #2)

Considering the timeline in an acute illness, when can the following be detected? (1) The infectious (causative) agent. (2) The immune response.

Neutrophils Bacteria Fibrin-rich inflammatory exudate

Contents of Pus

Deletions and duplications of tiny parts of a chromosome.

Copy number variants

plasma concentration

Cp

Steady state plasma concentration Plasma concentration of drug when the maintenance rate of drug administration is equal to the rate of elimination.

Cpss (Clinical Pharmacology)

(1) Disclosure (2) Comprehension (3) Competence (4) Voluntariness

Criteria for Informed Consent

Refers to the patient's ability to make the necessary decision.

Criteria for Informed Consent: Competence

Refers to the patient's understanding of the information. Two Key Factors: (1) How the info is presented. (2) The receptivity and understanding of the patient.

Criteria for Informed Consent: Comprehension

Provision of information.

Criteria for Informed Consent: Disclosure

A voluntary decision is a decision that is free of any coercive influence.

Criteria for Informed Consent: Voluntariness

· Condition is suitable for screening · There is a test available · Effective and accessible treatment / intervention · High quality evidence for effectiveness of programme · Potential benefit > harms of screening · Health care system can support all necessary elements in screening pathway · Social and ethical issues are considered · Cost-benefit is considered

Criteria for Screening Programme

*Focuses on the patient* and provides space for patients to be involved in decision-making about their own care and contribute to the achievement of positive health outcomes and experiences. Cultural Safety Principles: - Cultural safety focuses on the delivery of quality care through changes in thinking about power relationships and patients' rights. - Cultural safety initiatives therefore should target both individual health professionals and health professional organisations to intervene positively towards achieving health equity.

Cultural Safety

Individual CYP genes: Family number + Subfamily letter + Number for individual enzyme within the subfamily + Asterisk + Number & Letter for each allelic variant.

Cytochrome P450 Nomenclature

Structural changes in host cells that are caused by viral invasion.

Cytopathic Effect

Measures the *oxidative burst* which is required to produced ROS (hydrogen peroxide) for intracellular killing of microorganism ingested in phagocytes. Incubate cells with DHR then stimulate neutrophils to undergo oxidative burst. DHR is converted to rhodamine (fluorescent). It can be detected via flow cytometry.

DHR Test for Phagocyte Function

If you chemically stimulate the population of phagocytes, it produces a right shift [see white]. This right-shift will not be as significant in individuals with a phagocytic dysfunction.

DHR Test for Phagocyte Function: What occurs in normal vs. phagocyte impairment?

Necessity of treatment. Benefits. Risks and SEs. Costs. Expected timeframe of treatment & recovery. Alternatives. Recommendation (if patient requests it).

DISCLOSURE What kinds of information should be disclosed to the patient in gaining informed consent?

When the 'reasonable patient' thinks the information is sufficient. This requires both spontaneous and responsive disclosure.

DISCLOSURE When has sufficient information been given?

disease-modifying antirheumatic drugs

DMARDs stands for...

Salirumab (biological) Etanercept Tofacitinib Methotrexate

DMARDs used for RA

Small alterations to DNA sequence. Usually viable. Point / Insertion / Deletion / Frameshift / Dynamic. Missense / Nonsense / Silent.

DNA Mutations

chromatin

DNA is packaged into...

≥1 somatic symptom (medically explained or unexplained) for > 6 months. Causes distress and/or disruption to daily life and functioning. Excessive thoughts, feelings (negative) or behaviours (such as repeatedly booking GP visits; excessive googling) related to the somatic symptom.

DSM-5 Criteria for Somatic Symptom Disorder

SUD is diagnosed when the criteria has been apparent for >12 months. Mild (2-3 criteria), Moderate (4-5 criteria) or Severe (6+ criteria). (1) Impaired control (2) Social impairment (3) Risky use (4) Pharmacologic dependence

DSM-5 Criteria for Substance Use Disorder (SUD)

i. Taking more drug or taking drug for longer than intended. ii. Unsuccessful efforts to stop or cut down use. iii. Spending a great deal of time obtaining, using, or recovering from us. iv. Craving for substance.

DSM-5 Criteria for Substance Use Disorder (SUD): (1) Impaired control

i. Failure to fulfil major obligations due to use. ii. Continued use despite problems caused / exacerbated by use. iii. Important activities given up or reduced because of substance use.

DSM-5 Criteria for Substance Use Disorder (SUD): (2) Social impairment

i. Recurrent use in hazardous situations. ii. Continued use despite physical or psychological problems that are caused or exacerbated by substance use.

DSM-5 Criteria for Substance Use Disorder (SUD): (3) Risky use

i. Tolerance to effects of the substance. ii. Withdrawal symptoms when not using or using less.

DSM-5 Criteria for Substance Use Disorder (SUD): (4) Pharmacologic dependence

A genetic alteration that is present for the first time in one family member ass a result of a mutation in a germ cell of one of the parents, or a variant that arises in the fertilised egg itself during early embryogenesis.

De novo mutation

*Defect in C3 or in activation of C3:* susceptibility to pyogenic infections (e.g., S. pneumoniae). Results in a similar spectrum of infections as humoral immunodeficiencies. *Deficiencies in MBL* (mannose-binding lectin): common (~5%) and mild condition that results in an excess of bacterial infection in early childhood. *C1-C4*: these are important for the elimination of immune complexes and apoptotic cells. They are associated with autoimmune diseases such as SLE. *Defects in MAC* (membrane attack complex C5-C9): limited effects, with increased susceptibility to Neisseria sp. only (10,000x risk).

Defects in Complement (primary immunodeficiency)

Reentrant circuits occur when a wave of excitation repeatedly enters a region of cardiac tissue. By continuously reentering this region, the reentrant circuit becomes a new, autonomous pacemaker for the heart.

Defects in Impulse Conduction: Re-entrant Circuit

Spirituality is an awareness of one's inner self and a sense of connection to a higher being, nature, or to some purpose other than oneself.

Define Spirituality

A treaty is a formal, legally binding written agreement between actors in international law. It is usually entered into by sovereign states and international organisations.

Define Treaty.

The concentration of drug required to occupy 50% of the receptors.

Define affinity in terms of concentration-binding curves.

Pain that occurs for period of >3 months. Secondary Pain: arises from cancer / arthritis. Primary pain disorders: Migraine, CRPS, fibromyalgia, LBP.

Define chronic pain, and provide examples for secondary vs. primary pain.

Decreased motility and difficulty defecating. It is usually mild and intermittent. Try non-medication methods (exercise, dietary fibre). Can be caused by a range of drugs, ESPECIALLY anti-cholinergic drugs. *Treatment*: To increase motility, need D2 antagonists.

Define constipation. What are the principles of treating constipation?

SEE PAGE 3-4 HAUORA MĀORI NOTES

Define cultural safety. What is expected of Doctors in NZ?

Elimination of liquid faeces. Caused by toxins, viral or bacterial infections, and antibiotic-associated colitis. Treatment needed when >2-3 days, and when severe in elderly or small children. *Treatment*: Reduce ACh receptor activity (e.g., with M-receptor antagonists). The rate of propulsion through GIT will decrease, promoting segmentation and enhancing absorption.

Define diarrhoea. What are the principles of treating diarrhoea?

A localised response to an injury or to the destruction of tissues. Intends to eliminate initial causes of cell injury (as well as necrotic cells) and to initiate process of repair.

Define inflammation.

Tapu = sacred, special, not ordinary. Restricted. The proper attitude towards things tapu is respect and care. Tapu may be assigned to body parts (e.g., Head), times in life - birth, dying and death, body tissues (e.g. parts removed during operations, samples), objects (e.g. taonga), places (e.g. urupā - burial places). Noa = freedom from restriction. Rituals, such as Karakia or Powhiri, support the transition from tapu to noa. Example: wai (water) outside of anatomy dissection room.

Define tapu and noa and describe their relevance in the health sector.

a. Tikanga - beliefs, tika (correct way), values b. Manaakitanga: Hospitality, Upholding Mana c. Aroha: Love and caring d. Whānau: role of whānau in healthcare e. Whakawhanaungatanga: Building a strong sense of connection f. Whakapapa: Genealogy and connection to past g. Tapu / Noa - as earlier h. Wairuatanga: spirituality, connection with environment, ancestors i. Kaitiakitanga: Guardianship / Stewardship e.g., of environment, of people j. Kaupapa Māori: doing and seeing things in a Māori way

Define the following: a. Tikanga b. Manaakitanga c. Aroha d. Whānau e. Whakawhanaungatanga f. Whakapapa g. Tapu / Noa h. Wairuatanga i. Kaitiakitanga j. Kaupapa Māori

the period between when the disease is detectable, and when symptoms appear

Define: Lead time

Used to detect potential health disorders / disease in people who are *asymptomatic*. It screens those who have a high probability of having the disease.

Define: Screening Test

Different forms of the same gene - i.e. there are some sequence variations between them.

Define: Alleles

Different mutations (or mutations at different locations) but within the same allele / gene. Can result in different severities. Examples: α-Thalassemia β-Thelassemia

Define: Allelic heterogeneity

An abnormal hypersensitivity / inappropriate immune response of the body to non-pathogenic antigens. The development of an allergy is by repetitive low-dose allergen stimulation.

Define: Allergy

Binds to a receptor but does not activate (or inactivate) it. They are *blockers* - prevent the natural agonist from binding.

Define: Antagonist

The phenotype of a dominant condition becomes more severe with each generation and.or develops earlier with each generation. Associated with *repeat expansions* with each generation.

Define: Anticipation (Genetics)

Genetic tendency to develop allergic diseases.

Define: Atopy

genetic tendency to develop allergic diseases

Define: Atopy

A surface-coating colony of one or more species of prokaryotes that engage in metabolic cooperation.

Define: Biofilm

A cancer-causing agent. They may be naturally occurring substances, and their risk for causing cancer in human depends on... Where they are. What they are doing with them. Length of exposure. Natural susceptibility (genetic predisposition).

Define: Carcinogen

ability to interact effectively with people of different cultures (respectful & responsive to health beliefs, practices, and needs of diverse population groups).

Define: Cultural Competence

• Patient-focused. • Involves patient in decision-making. • Contributes to achievement of positive health outcomes and experiences.

Define: Cultural Safety

Normal propagation of electrical signaling is corrupted by extra electrical activity that doesn't follow the usual, organized route. May have additional activity that is initiated elsewhere, or activity that follows a different route through the heart. Examples: Re-entrant circuit

Define: Defects in Impulse Conduction

The excitation of the heart is initiated inappropriately. Pacemaking of the SA node is lost. Patients may experience tachycardia or bradycardia.

Define: Defects in Impulse Generation

Compulsive drug-taking behaviour; loss of ability to control use; intrusion into normal activities (+ tolerance + withdrawal).

Define: Dependence [SUD]

Drug effect reduces in a few minutes.

Define: Desensitisation

a chemical entity used non-medically, self-administered for its psychoactive effect.

Define: Drug

EC50: Half-maximal effective concentration. It is the concentration of a drug which induces a response halfway between the baseline and maximum after a specified exposure time.

Define: EC50

Ability of a drug to bind to a receptor & cause a change in the receptor's ability. Measured by Emax.

Define: Efficacy

chemical modifications to DNA that can turn genes on and off

Define: Epigenetic Markers

Genuine uncertainty of the risks and benefits of a particular treatment.

Define: Equipoise

The degree to which a trait / phenotype is expressed between different individuals. High expressivity = severe disease phenotype. Low expressivity = mild disease phenotype.

Define: Expressivity

Results in the production of an abnormal metabolite.

Define: False Substrate

Inflammation of the lining of the stomach. SYMPTOMS: Diarrhoea Vomiting Abdominal pain

Define: Gastritis

Internal sense of being a man, a woman, or something else entirely. It is seperate from sex assigned at birth.

Define: Gender / Gender Identity

Describes people who do not conform to their society / culture's expectations for men and women.

Define: Gender Diverse

External representation of one's gender.

Define: Gender Expression

The number of copies of a gene. Changes to the two-copy gene dosage leads to abnormal phenotypic traits if gene dosage-sensitive genes are affected. Gene dosage is related to the amount of functional gene product expressed, which is in turn dependent on regulation of gene expression.

Define: Gene Dosage

The process by which information from a gene is used in the synthesis of a functional gene product (Protein OR ncRNA).

Define: Gene Expression

The insertion of functional copies of a gene into the cells of a person with a genetic disorder in an attempt to correct the disorder. Either to: - Replace missing protein. - Inhibit expression of a deleterious protein. - Kill (cancer) / Protect (degenerative conditions) cells.

Define: Gene Therapy

The study of the genome, including interactions of those genes with each other and with the person's environment.

Define: Genomics

An individual's allele combinations (set of genes that it carries) responsible for a particular trait.

Define: Genotype

inflammation of the liver

Define: Hepatitis

an exaggerated response by the immune system to a particular antigen.

Define: Hypersensitivity

Branch of clinical immunology wherein different tests are carried out to decipher the diseased state of the patient through the activity of different markers expressed through blood, serum, plasma, and other biological components.

Define: Immunodiagnostics

Proportion of exposed persons who become infected.

Define: Infectivity

Refers to the right of every patient to make an informed decision whether to accept / refuse treatment.

Define: Informed Consent

Procedure that involves passing a tube into a person's airway.

Define: Intubation

When someone is known to be sick, we isolate them.

Define: Isolation

Same phenotype but mutations are in different genes.

Define: Locus heterogeneity

substances that increase or decrease enzyme activity (i.e., result in an *increased or decreased opening probability*)

Define: Modulators

deficiency of neutrophils

Define: Neutropenia

Increased neutrophils.

Define: Neutrophilia

Care for people of all ages with a life-limiting or life-threatening condition which aims to improve quality of life and support the individual and their family. It is provided according to need, whether death be years, months, or days away.

Define: Palliative Care

Deficiency of all types of blood cells. In other words: anaemia + neutropenia + thrombocytopenia.

Define: Pancytopenia

Any microbe that can cause infection (e.g., bacteria, viruses, parasites, prions, fungi).

Define: Pathogen

The likelihood of a microbe causing infection.

Define: Pathogenicity

Rate of contact per time. (No. of contacts / Period of time)

Define: Pattern of Mixing

The percentage of individuals with a specific genotype who also express the expected phenotype. Example: If 70% penetrance, then 70% of the individuals with the disease genotype will display the disease phenotype.

Define: Penetrance

Area of pharmacology that examines the role of genetics in drug response.

Define: Pharmacogenetics

Physical expression of a gene / trait.

Define: Phenotype

Describes bacteria that are freely floating in wate → *homogenous mixture*.

Define: Planktonic

Actions other than those for which the agent was specifically developed. These effects may be related or unrelated to the primary mechanism of action of the drug.

Define: Pleiotropic Effects of Drugs

A measure of drug activity expressed in terms of the amount required to produce an effect of given intensity.

Define: Potency

Measures that control risk factors in order to delay or prevent illness. Help to limit the incidence of disease.

Define: Primary Prevention

Prevention of the development of risk factors for disease.

Define: Primordial Prevention

Privilege refers to systematic and interpersonal advantage that works in concert with systemic discrimination and marginalisation to produce population group differentials in access to, among other things, societal goods and services and exposure to stressors.

Define: Privilege

An inactive compound which can be converted into an active drug.

Define: Prodrug

Pus-producing (Also: Suppurative / Purulent)

Define: Pyogenic

What happens to people at risk but not currently sick.

Define: Quarantine

The ability of bacteria to sense the presence of other bacteria via secreted chemical signals.

Define: Quorum Sensing

Affect <1 in 2000 people They have ~high mortality, There are ~6000 rare disorders. Usually polygenic, but can be monogenic. Examples: autism, diabetes, obesity, cancer.

Define: Rare Disorder + features

Loss of sensitivity to cytotoxic / antimicrobial drugs.

Define: Resistance

Measures which reduce prevalence of disease by shortening its duration, severity and recurrence.

Define: Secondary Prevention

The provision of assessment, counselling, support and ritual in matters of a person's beliefs, traditions, values and practices enabling the person to access their own spiritual resources.

Define: Spiritual Care [Clinical Definition]

Spiritual care can help you feel more connected with yourself, other people or to something beyond. It may involve your religious beliefs and practices or the values that are important to you. It is about supporting what gives meaning and purpose to your life.

Define: Spiritual Care [Consumer Definition]

Spirituality is an awareness of one's inner self and a sense of connection to a higher being, nature, or to some purpose other than oneself.

Define: Spirituality

Ability to discern how a host of issues (symptoms / attitudes / diseases) also represent the downstream implications of a no. of upstream decisions (such as HC, food delivery systems, zoning laws, infrastructure, medicalisation, etc.).

Define: Structural Competence

interaction of two or more medicines that results in a greater effect than when the medicines are taken alone

Define: Synergistic Effect

Intimate companion of same sex. Or refers to Māori people from any part of the rainbow community.

Define: Takatāpui

Measures which reduce the number or impact of complications; improve rehabilitation.

Define: Tertiary Prevention

Drug effect reduces over hours to days.

Define: Tolerance

Reduced response after repeated administration. Due to desensitisation of receptors. It may lead to increased use.

Define: Tolerance [SUD]

The *quantification of pathogenicity* in a susceptible host. The severity or harmfulness of a disease or poison. It is defined as the relative *ability of a microorganism to overcome host defences and cause disease*, or the *degree of pathogenicity* within a group or species.

Define: Virulence

Gene products that enable colonisation of a susceptible host.

Define: Virulence Factors

Describes the physiological effects that take place in response to cessation of drug / reduced intake. Symptoms usually opposite to those produced by drug.

Define: Withdrawal [SUD]

*Demographic Characteristics* Onset peak of panic disorder: late 20s. MI (CVS): >45 years (men), >55 years (women).

Demographic Characteristics: Panic Disorder vs MI (CVS) [Psychological Medicine]

Heterochromatin (30nm) Does not physically enable RNA Pol II to bind, hence deeming the gene inactive.

Densely packed chromatin is called... (+ diameter size)

Use of an agonist. Over-activation inhibits the cell's ability to restore itself.

Depolarising Block

Pink, soft, granular tissue located beneath the scab of a skin wound. It has small blood vessels and fibroblast proliferation. Components: new capillaries, fibroblasts, collagen, remaining inflammatory cells.

Describe *granulation tissue*.

Produced through enzyme pathways. Vasodilators (ACh, Histamine) binds to receptors present on cell surface and increase NO production. NO is synthesised intracellularly from L-arginine, and this is controlled by eNOS (a calcium-dependent enzyme). NO is released from endothelial cells and acts upon adjacent vascular SM → vasodilation.

Describe NO synthesis.

Holistic and cyclic

Describe Ta Ao Māori.

Addition of acetyl group to lysine amino acids. Neutralises the positive lysine, preventing histamine tails from interacting with (-)DNA. Inhibits nucleosome formation. Genes are accessible for transcription!

Describe acetylation.

With clonal expansion of B cells in lymphoid tissue, mutations in the variable region of the IgM (or IgD) antibody occur, thus altering the antibody's ability to bind. Cells with disadvantageous mutations undergo apoptosis, but those with improved affinity get T cell help to enable the *switch of antibody classes*, such that other types of antibodies can also bind better. This *somatic hypermutation* is the reason why there is affinity maturation. *Early in infection*: low avidity. *Distant infection*: high avidity.

Describe affinity maturation, and how avidity changes with time.

Removal of methyl groups from lysine and arginine AAs, making genes accessible for transcription.

Describe demethylation.

Gut = different pH environments, with varying degrees of hospitability to organism growth. Hence, pH gradient along gut corresponds with microbial biomass. Stomach is a harsh acid environment, so there are few microorganisms compared to colon.

Describe gut environment, and how this facilitates survival of commensal organisms.

Past: Plasma → required hospitalisation. Current: • Factor VIII concentrates from plasma. • Recombinant FVIII / rAHF. Recent: Recombinant antibodies. Future: Gene therapy

Describe historical, current and future treatments for haemophilia.

Depletion of CD4 cells can lead to Acquired ImmunoDeficiency Syndrome (AIDS). Immunodeficiency means that patient will have increased susceptibility to intracellular infections and increased cancer (e.g. Kaposi's sarcoma).

Describe how HIV causes AIDS.

MRSA is resistant to all beta-lactams. The mecA gene encodes for PBP 2' which can replace the normal PBP, allowing peptidoglycan cross-linking in the presence of methicillin.

Describe how MRSA is resistant to beta-lactams.

Bacteria has a virulence factor against PIgR which allows it to translocate across the epithelium. It can also recognise receptors on the capillary endothelial cells, allowing it entry into the bloodstream.

Describe how bacteria reach the subarachnoid space.

Anticonvulsants achieve this by inducing the expression of metabolic proteins such as CYP3A. *CYP3A Induction* (Consequences are not immediate, since new proteins must be synthesised; steady-state reached in ~2 wks).

Describe how drugs (such as anticonvulsants) can reduce plasma concentration of other drugs (administered concurrently).

Comprises receptor + associated ion channel. Involved in fast synaptic transmission. 5 subunits (pentameric). ACh binds, causing an influx of sodium ions into the cell.

Describe inotropic receptors.

Likelihood of CF microbial lung colonisation increases with age. In youth, infxn in airways occurs intermittently, then undergoes transition to chronic in early 20s. CF patients are more likely to be colonised and more likely to transfer the organism to each other! Keep patients apart.

Describe lung colonisation with age (for the CF patient).

Methyl is a neutral and hydrophobic molecule. Hydrophobic groups attract each other (degree of attraction depends on extent of methylation). Methylation of histone proteins results in tight packing of methylated nucleosomes, preventing access to genes & inhibiting transcription.

Describe methylation.

Mechanism by which the death of neutrophils produces *neutrophil extracellular traps (NETs)* that trap and kill pathogens. The neutrophil nucleus swells and bursts, releasing chromatin. These strands trap antigen / bacteria, and also have antimicrobial components.

Describe neutrophilic *netosis*.

Sialic acid receptor on the surface of RBCs bind to hemagglutinin glycoprotein located on surface of influenza virus. Creates a network of interconnected RBCs and virus particles.

Describe the Hemagglutinin Test

Holistic approach. Te Whare Tapa Whā Model of Care informs much of NZ palliative care practice.

Describe the NZ approach to palliative care.

Glyceryl trinitrate (GTN): Sublingual / Patch to avoid first pass metabolism. Isosorbide mononitrate: Oral → 100% bioavailability. Longer release drug. Isosorbide dinitrate: Oral. Metabolised to form mononitrate with extended half-life.

Describe the administration of nitrate drugs.

Interact with different receptors, and lead to dopamine release into nucleus accumbent. This elicits a euphoria. Also have increased SNS activity.

Describe the basic mechanism for drugs associated with drug abuse / dependence.

Inhibit virus replication. They inhibit specific viral proteins; hence resistance can develop by mutation of these target proteins. Also note that, since the specific antivirals are specific for certain viruses, the drugs cannot be repurposed.

Describe the basic mechanism of antiviral drugs.

Epithelial cells line the nephron. Their basal membrane faces the blood and contains Na+/K+ pumps. These *remove* sodium from the cell and deliver it into the blood, while potassium is drawn in.

Describe the cells in the TAL. (???)

Histone tails comprises positively-charged amino acids.

Describe the charge of histone proteins.

Addition of a methyl group to cytosine (a DNA base). This inactivates gene expression. Direct Effect: methyl groups are recognised by methyl-binding proteins, which block the TFs & RNA Pol II from accessing promoter. Indirect Effect: Recruitment of enzymes that deacetylate the histones, thereby inducing the formation of heterochromatin.

Describe the chemical alteration of gene promoters.

Clumping indicates the conversion of fibrinogen to fibrin by coagulase. Hence, bacteria is coagulase-positive. B = Coagulase (+)

Describe the coagulase test.

See BLOCK Module.

Describe the depolarisation of ventricular muscle. [Clinical Pharm. Background Knowledge]

BRITISH: Chiefs cede [give up] "all the rights and powers of sovereignty." MĀORI: *Kawanatanga* → Chiefs give to the Queen forever the complete *governance* over their land.

Describe the differences between the British and Māori versions of the Treaty. *ARTICLE 1*

BRITISH: Queen guarantees "full exclusive and undisturbed possession of Māori land, estates, forests, fisheries and other properties." → *Property rights* MĀORI: *Tino rangatiratanga* → Queen agrees to protect the chiefs in the unqualified exercise of their chieftainship over their lands, villages and all their treasures. The chiefs will sell land to the Queen (at an agreed price for owner and seller). → *Sovereignty*

Describe the differences between the British and Māori versions of the Treaty. *ARTICLE 2*

BRITISH: The Queen extends her protection to Māori. Māori are given the rights and privileges of British subjects. → *Equal rights as British subjects* MĀORI: *Oritetanga* → The Queen will protect all the people of NZ and will give them the same rights and duties of citizenship as the people of England. → *Equal rights as citizens*

Describe the differences between the British and Māori versions of the Treaty. *ARTICLE 3*

A drug with *positive efficacy* will activate a receptor to promote cellular response.

Describe the efficacy of *agonists*.

A drug with *no efficacy* will bind to the receptors but have no effect on activity.

Describe the efficacy of *antagonists*.

A drug with *negative efficacy* will binds to receptors to decrease basal receptor activity. Note: an inverse agonist produces an effect opposite to that of an agonist, yet binds to the same site.

Describe the efficacy of *inverse agonists*.

17th & 18th Century: caused 25% of adult deaths (Europe). Since 20th century, there has been reducing mortality from TB. This is due to: - Decreased transmission (improved socioeconomic conditions, decreased over-crowding, improved nutrition). - Increased availability of anti-mycobacterial agents. Currently, ~10mill cases / year and 1.6 mill deaths / year. There is a co-pandemic of HIV → over 50% of those diagnosed with TB also have HIV.

Describe the epidemiology of TB in the past vs. now. What has contributed to this difference?

In order to be ethical, the RCT must... (1) Provide a *reliable answer to a relevant Q* → participants from the population which will benefit from trial; sound design; good practice guidelines. (2) Incorporate *individual ethics* → equipoise, informed consent, safety (beneficence & non-maleficence), independent oversight. (3) Consider *group ethics* → approve beneficial treatment as rapidly as possible; avoid approving ineffective / harmful treatments.

Describe the ethics of a Phase 3 trial.

[1840-1860] Rapid European settlement. Colonial Government formed. Limited rights to vote. "Unproductive land" (i.e., non-farmed) could be claimed as Crown property. [1858] Kingitanga Movement: Māori King was elected. Vision of shared leadership with Crown. Colonial Government used this as a pretext to invade the Waikato and confiscate productive land that Māori refused to sell. Between 1840s and 1880s → NZ wars. Land confiscation occurred through legislation → contributed to a rapid process of land appropriation. (Owned 80%, dropped to 40%). [Late 1800s] Māori population had declined. Decreased fertility rates and increase in mortality. Pessimistic view by Pakeha that Māori would die out by 1900s. 1907 Tohunga Suppression Act → illegal to practice Māori healing. WW2 and Māori Battalion → Māori fought in WW2 in the hopes that they would be treated like other civilians; but they returned to their land confiscated.

Describe the events following the signing of the Treaty.

Anaphylatoxin C3a and C5a are released, resulting in a local pro-inflammatory effect. C3 concertase and C3 bind to generate *C5 convertase*, which cleaves C5 to C5a and C5b. C5a is released an an anaphylatoxin, while C5b binds to the pathogen surface and initiates formation of the MAC. Pores form in the bacteria, leading to leakage of ions and thus depolarisation of the cells membrane → DEATH of bacteria.

Describe the events that lead to formation of the membrane attack complex and eventual death of the bacterium.

Different demographic characteristics. More distress. Body-wide symptoms. Anxiety. Atypical pattern. Pain - not main symptom. Feel like passing out, don't pass out. Hyperventilation. Nausea w/o vomiting. Calming down = ends panic attack. Can occur at rest / asleep (whereas CVS events often brought about by exertion).

Describe the features of a panic attack that can distinguish it from a cardiovascular disease.

· Inject antibody into animal (e.g. mouse) → antibody synthesis → harvest WBCs from spleen, then fuse these with tumour cells to immortalise the white blood cells → select for the cells that make antibody to your antigen.

Describe the formation of recombinant antibodies. [Haemophilia Treatment]

(1) Engagement (reassurance, validation, commitment). (2) Address anxiety (provide a positive diagnosis reduces tests and referrals). (3) Education (use models / explain pathways). (4) Self-management (lifestyle modifications). (5) Increase in Para-SNS (describe techniques to patient). (6) Pain education (PNE = pain neuroscience education) (7) Cognitive re-training (beliefs, trauma, ongoing conflicts).

Describe the general approach to patient management [in context of a functional illness].

Genetic but can be acquired (rare). *X-linked recessive*.

Describe the genetic basis of Haemophilia A.

These have depleting and/or non-depleting effects: · Non-depleting: block interaction of cytokine with its receptor. · Depleting: effects on complement and cytotoxic functions induce apoptosis or lead to cytotoxic killing by effector cells.

Describe the immunosuppressive action of monoclonal antibodies (mAbs).

Synthesised in liver. Processed through ER. Undergoes a PTM (glycosylation → only occurs in mammalian cells).

Describe the in vivo synthesis of the FVIII protein.

Autosomal recessive manner, but both are expressed when inherited (co-dominance).

Describe the inheritance pattern of the SERPINA1 mutated Z-allele.

Individual is asymptomatic. Immune system has controlled infection, but the bacteria can survive a long time so there is risk of reactivation (risk varies with age & immunosuppression), leading to post-primary TB. BOTH primary & post-primary TB are infectious. Reactivation will occur for... ~10% of health adults ~30% of HIV+ patients

Describe the latent TB infection.

Platelets exposed to collagen, vWF, etc. Platelet glycoproteins enable its binding, such that the platelet can adhere to ECM proteins. The aggregated platelets secrete thrombin, which potently activates platelets and causes a platelet shape change. Platelets release more compounds from their granules (incl. TXA2 and ADP). Fibrin stabilises the platelet clot. Inappropriate thrombosis can result in ccclusion to BV.

Describe the mechanism of thrombus formation. [Clinical Pharmacology]

(1) Rolling (2) Tight adhesion (3) Migration through endothelium Bacteria cross the BBB and replicate. They express PAMPs, leading to cell activation and the secretion of cytokines. The cytokines enable activation of endothelium → upregulation of selectins → adhesion → accumulation of WBCs in meninges.

Describe the mechanisms of meningeal inflammation.

point-mutation or small deletions.

Describe the mutation(s) which cause mild-moderate haemophilia.

40% of severe cases are due to an *intron 22 inversion*. A repeat structure is repeated just proximal to the telomere, affecting meiosis (there is recombination between intragenic and the proximal / distal repeat).

Describe the mutation(s) which cause severe haemophilia.

Mostly anaerobes. Primarily: → Bacteriodetes → Clostridia Every human gut has hundreds of species. 1/3 of these are conserved, 2/3 are variable between people. Gut microbiota has >100 times as many genes as human genome.

Describe the normal GI microflora.

Helicobacter pylori • Gram(-) bacterium. • Common to general population (20% NZ, 50% globally). • Transmission via saliva, vomit, faeces. • To diagnose, we detect antigens (faecal), antibodies, or use endoscopy. • Higher incidence in European population. Pathogenesis: Enters the mucous layer and adheres to cells beneath. It produces enzyme urease to catalyse conversion of urea to ammonia (alkaline so neutralises acid). The immune system is activated, leading to inflammation which damages mucous, BVs, gastric epithelium. The lack of protective mechanisms means that acid and enzymes can reach GI wall cells, increasing the risk of cancer.

Describe the pathogenesis of an infection with H. pylori, and how it leads to peptic ulcers.

Template strand of DNA is used to make a copy of the coding strand. TFs bind to promoter region (TATA box) of the gene, and recruit the enzyme Pol II, which performs transcription (RNA synthesis).

Describe the process of transcription.

Produced in mammalian cells. (1) Plasmid containing a mammalian promoter region and cDNA encoding for FVIII (9kb). (2) Plasmid is transfected into CHO or BHK (baby hamster kidney) cells, both of which can perform effective glycosylation. (3) Secretion of FVIII protein into cell culture media. (4) Purification steps.

Describe the production of recombinant Factor VIII / rAHF.

Gradual progression of symptoms (eye muscles → facial muscles → limbs → respiratory system). Reversal of these symptoms allows respiratory muscles to be first to recover.

Describe the progression of symptoms when using a neuromuscular block.

Decide: Suppress or Eliminate. NZ decided to eliminate (because we must consider health system capacity). To eliminate... • Prevent virus entry into country. • Surveillance: identify cases. • Prevent spread: decreased contacts between people; decrease risk of infection following contact; treat infected (if possible).

Describe the public health response to an infectious diseases such as COVID-19.

Medical advances → increased knowledge of human body, development of anaesthesia, safe surgery, antibiotics, etc. We have developed a biomedical process that follows linear logic to help diagnosis. Applicable to physical / biological evidence of disease, hence biomedical model restricts us from investigating unexplained symptoms.

Describe the relationship between medical advances and the way in which we perceive unexplained symptoms.

Aldosterone is a steroid-receptor agonist which requires nuclear transport in order to carry out effects. Acts in distal tubules and CDs to increase sodium and water retention and decrease plasma potassium. HOW? Increases the synthesis and activation of Na+/K+ pumps (hence promotes sodium reabsorption from tubule and potassium loss). This increases blood volume and thus CO.

Describe the renal effects of aldosterone.

Protease inhibitor (a SERPIN → serine protease inhibitor). Inhibits elastase in vivo. Binds 1:1 with elastase, but when elastase cleaves it there is a confromational changes which completely disrupts the protease, and leads to its degradation (as well as the alpha-1-antitrypsin). Hence, it is a *suicide inhibitor*.

Describe the role of alpha-1-antitrypsin in the lungs.

Spleen = immunological organ. Function to clear poorly opsonised and non-opsonised bacteria from the blood. Removal of Spleen = increased risk of infection (often with encapsulated bacteria).

Describe the role of the spleen in protecting against invasive infection with encapsulated bacteria.

(1) Environmental exposure [crowding, poor ventilation]. → Only 30% of those exposed will become infected. → Host (immune status, age, malnutrition, smoking) & bacterial (infectious dose, duration, proximity) factors determine if you become infected, (2) Infection → either develops into *primary TB* (5-10%, requires treatment) or the immune system will control the infection, leading to a *latent infection* [containment & persistence] (90-95%). (3) Reactivation in those with a latent infection → leading to post-primary TB, extra pulmonary or miliary TB.

Describe the sequence of events that lead to TB infection.

(1) LDL docks to receptors of the vesicles of cell surface (2) Internalisation of LDL. (3) Receptors are recycled back to the cell surface. (4) Lysosome vesicle breaks down the LDL. (5) Cholesterol is provided to the cell for metabolic purposes. (6) There will be a: ↓ LDL receptors ↓ HMG CoA reductaseA ↑ ACAT (cholesterol acyltransferase)

Describe the steps involved in cholesterol delivery to cells.

Collection of bacteria adhered to a surface, embedded in DNA and sugar matrix (EPS). If host-associated, it includes host-produced fibrin and mucous layer. Difficult to eliminate because it contains many metabolic persisters. Has differential bacterial colonies or a single type of cell.

Describe the structure of a biofilm.

- Reduce preload and ox. demand. - Can also vasodilate arteries to reduce afterload. - Beneficial antiplatelet effect. Indications: *Angina* (ischaemic pain) due to decreased coronary flow and oxygen delivery to heart.

Describe the therapeutic applications of organic nitrates.

SNEEZE: Largest droplets fall to ground. Medium-sized droplets breathed in, then become trapped and cleared within the upper airways. Smallest droplets (<25mm) evaporate, leaving *droplet nuclei* of bacilli that can be breathed into the lungs and reach alveoli, enabling TB transmission.

Describe the transmission of TB when an infectious person sneezes.

Reduce enviro. impact (smoking, infection). Genetic counselling (reproduction). Exercise. IV AAT augmentation. Liver / Lung transplant (late stage).

Describe the treatment of COPD / Cirrhosis for AATD patients.

*Blood transfusion* (Complications: iron overload, which then requires chelation therapy). Cure: bone marrow (stem cell) transplant. Mild Cases: intermedia is treated with hydroxyurea (↑ gamma expression). New Drugs: promote RBC formation & CRISPR to correct / raise gamma in trials.

Describe the treatment of thalassemias.

Q4 & 5 Public Health (Lecture 5)

Describe the trends in the graphs.

Privilege contributes to inequities in outcomes due to positive features such as social inclusion, health and wellbeing being disproportionately experienced by certain population groups. It can be viewed as the inverse of structural disadvantage within a society where individuals accrue advantage due to structural oppression of others through racism, discrimination and marginalisation.

Describe the two-sided nature of inequity.

Stimulates neutrophil production after chemotherapy.

Describe the use of GM-CSF in cancer patients.

(1) *Nociceptive Pain:* physical damage or potential damage to the body. Example: acute knee injury, infected tooth, arthritis. (2) *Neuropathic Pain:* caused by inflammation, irritation, or nerve compression. Example: diabetic peripheral neuropathy, funny bone. (3) *Nociplastic pain:* [central sensitisation] altered functioning of central and peripheral neurophysiological pathways, reversible sensory and CNS pain processing (spinal cord, brain). Example: chronic pain, functional illness.

Describe three different mechanisms of pain and give clinical examples.

Physiological hyperplasia

Development of breast tissue is an example of what type of cellular morphological change?

≥1 phenotypic features with evidence of an abnormality in CFTR based on ONE of the following: - Presence of two CFTR pathogenic allelic variants. - Sweat Test: two abnormal sweat chloride values >60mEq/L. - Transepithelial nasal potential difference (NPD) measurements characteristic of CF. CFTR mutation detection rate varies by test method & ethnic background. May not be detectable in some symptomatic individuals, nor carriers.

Diagnosis of CF

Elevated transferrin-iron saturation (>45%). Serum ferritin concentration above upper limit of normal (>300ng [M] >200ng [F]). Two pathogenic variants on confirmatory HFE molecular genetic testing.

Diagnosis of HFE-HH

Early, serum aminotransferases will be elevated. PCR can determine viral load. *IgM* will decrease rapidly (within first 6 months since initial exposure). This is indicative of acute infection. *IgG* will remain raised for some time after this. It indicates that individual is in convalescent stage of infection. ESSENTIALLY: IgM anti-HAV = active or recent infection. IgG anti-HAV = current or past infection.

Diagnosis of Hep A

Antigens → HBsAg (surface) → HBcAg (core) → HBeAg (core) HBsAg appears first. If only this is detected, patient is in early stage of infection. Will decrease within 5-6 months → unless chronic infection. HBeAg detected next. Anti-HBcAg detected next. THEN, antibodies for HBsAg and HBeAG appear later. Once Anti-HBsAg appears, this is indicative of patient having attained immunity against Hep B.

Diagnosis of Hep B (and C)

Sputum culture Gram stain (only typical causes). Blood culture (if sputum unsuccessful). PCR (if atypical). AST [antimicrobial sensitivity testing]. Procalcitonin (differentiates bacterial and viral pneumonia).

Diagnosis of Pneumonia

Arthrocentesis of synovial fluid (gram-stain & culture). Imaging.

Diagnosis: Septic Arthritis

Culture & gram-stain Imaging • MRI = early detection. • CT-scan = requires time before osseous changes are visible.

Diagnosis: Osteomyelitis

Body weight (BMI *18.5-24.9*). Reduce sodium intake. DASH-style dietary pattern (fresh fruit & vege; dietary fibre; low-fat dairy). Increase potassium intake. Moderation of alcohol intake (1 standard /day for women, 2 standards / day for men).

Diet-Related Lifestyle Recommendations to ↓BP

Slows the ventricular response rate to AF (slows rate). Provides positive inotropic support in HF (increases force of contraction). See slides... pg. 112

Digoxin → Mechanism

LD = 500 * 1.5 LD = 750 ug for an IV dose. If F = 80%, then the corrected oral loading dose must be 937.5 ug.

Digoxin has a Vd of 500L, and its target Cp is 1.5 ug/L. Calculate the loading dose.

*Emotional and mental wellbeing.* It also refers to our capacity to communicate, think and feel. In a healthcare setting, aspects relevant to Māori patients could be: · Ability for doctor to engage with the patient and their whānau in a meaningful way. · Mental state / emotions / mood. · Having cultural beliefs honoured and respected within a clinical space.

Dimensions of Te Whare Tapa Wha: Taha Hinengaro

*Physical health and wellbeing.* It also refers to the physical environment, and includes variables such as housing, income, schooling, and daily activities - all of which can impact on the wellbeing of individuals and whanau. In a health care setting, aspects relevant to Māori patients could be: · Understanding concepts of tapu & noa to interact respectfully with patients. · Understand how physical environment and social determinants of health shape health outcomes.

Dimensions of Te Whare Tapa Wha: Taha Tinana

*Spiritual wellbeing.* Not just about religion, but the capacity for faith and acknowledges the relationship a person has with the environment, their ancestors, and wider whanau. In a health care setting, aspects relevant to Māori patients could be: · Understanding Māori values and tikanga to support patients wairua during consultations and treatment plans. · Working with kaumatua and Māori support staff within your hospital or organisation to support patients in your care.

Dimensions of Te Whare Tapa Wha: Taha Wairua

*Wellbeing of the whānau*. It places the individual within the collective of the whānau. Considers the capacity to belong, care and share. In a health care setting, aspects relevant to Māori patients could be: · Including whānau in consultations (if desired by patient). · Considering connections patient may have with whānau, their roles and responsibilities within the whānau, and how these shape their hauora.

Dimensions of Te Whare Tapa Wha: Taha Whānau

Asymptomatic (healthy) carriers may give false positive results. So, diagnosis should be made in the presence of clinical symptoms.

Disadvantage of C. difficile detection techniques.

· Longer morbidity / DALYs · Overtreatment of questionable abnormalities · False reassurance to those with false negatives · Anxiety for those with false-positive · Unnecessary intervention for false positives · Risks associated with test / invasiveness · Stigma for those who test positive · Insurance implications increased price

Disadvantages of Screening

NZ: If condom is being used, you do not have to legally disclose your HIV status.

Disclosure of HIV Status (sexual intercourse)

RF reduces life expectancy by ~15 years. 159 people die each year from RHD. Most diagnosed children are Māori and Pasifika, with most cases occurring in the North Island. Combination of poverty, crowded housing conditions, barriers in access to primary health care and the subsequent high incidence of strep throat infections contribute to this inequity. No evidence to support an increased genetic susceptibility to RF for Māori and Pacific people. *Two-Sided Nature of Inequity*: It is also likely that wealth, warm and dry housing conditions, relatively easy access to primary healthcare and the subsequent lower incidence of strep throat infections contribute to low rates of RF among Pakeha.

Discuss RF and RHD in Māori and Pasifika communities.

Loss of lymphoid aggregates (groups of immune cells). Depletion of memory CD4 T cells in intestine.

Discuss a person's intestinal lumen following an HIV infection.

(1) *Hypermethylation of promoter region in tumour suppressor genes* → turns off genes which would normally slow down cell division. (2) *Hypomethylation of promoter region in tumour oncogenes* → activation of genes which stimulate cell division.

Discuss cancer in relation to methylation changes in the promoter region of certain genes.

Higher incidence in NMNP than in Māori.

Discuss epidemiology of colorectal cancer in Māori vs NMNP.

More common in Māori than NMNP (non-Māori, non-Pacific).

Discuss epidemiology of lung cancer in Māori vs NMNP.

Batten Disease = lysosomal storage disease affecting brain. Current: Protein therapy. Since it doesn't cross the BBB, it requires direct infusion. Future: Gene therapy.

Discuss gene therapy for: Batten Disease

Good therapy target because condition is: - Loss of function - Recessive - Molecular defect is well-defined - Readily accessible target tissue - cDNA fits in some viral vectors - Precise control of protein not required (since it is regulated via thrombin).

Discuss gene therapy for: Haemophilia → Why is this considered a good therapy target?

SCID = severe combined immunodeficiency. Place gene into lentiviral vector, transduce into cell, transplant cell into patient.

Discuss gene therapy for: SCID

Excess laxatives → neurotransmitter imbalance in gut → causes constipation → patient uses more laxatives. Ongoing cycle! DETAILS: With laxative use, it takes a longer time to refill colon. Patients misinterpret this as constipation → repeated laxative use. Also, loss of water and salts causes release of aldosterone. This stimulates intestine reabsorption but increases renal K+ excretion → hypokalaemia → reduces peristalsis → misinterpreted as constipation → repeated laxative use.

Discuss laxative abuse.

The condition is DOMINANT if the normal gene product is not enough to provide the full phenotype. The condition is RECESSIVE if 50% of the normal gene product is sufficient to produce a normal phenotype. Note: threshold is not 50% for all diseases.

Discuss recessive / dominant in relation to gene dosage.

Bacterium colonises. Antigen taken up by M cell (embedded amongst epithelial cells). M cell transports antigen to lamina propria where it is displayed on APCs. Activation of immune response. Production of antibodies against capsule. B cells produce IgA and IgM antibodies. Their J-chains are recognised by PIgR present on BM of epithelial cells. Initiates their translocation across the epithelium. Antibodies prevent further colonisation and protect against invasive infection.

Discuss the immune mechanisms at mucosal surfaces and in the blood that protect against invasive infection with encapsulated bacteria.

Epitopes (antigen peptides) recognised by T-cell receptors are buried, so antigen must be broken down into peptide fragments. The T-cell receptor binds to the MHC-epitope complex. In HIV patients, epitope mutations occur, and are no longer recognised by patient's CD8+ T cells. Mutations become more frequent (due to immune selection pressure) then fixed. HIV has: • High rate of mutation. • High rate of viral turnover. • Huge intra-individual diversity amongst the virus. Also, CD4 cells aid CD8 cells. CD4 cells are also important for B cell activation. So loss of CD4 cells impairs these responses.

Discuss why the immune response fails to control HIV.

Metastasis to different organs. Neural & vascular consequences that occur secondary to local effects. Paraneoplastic syndromes (may initially present with these rather than primary tumour).

Distant Effects of Lung Cancer

See Page 95 Vertical Answers #2

Diuretic Quiz

:-)

Do MCQs (Lab 6, I & I)

No, only genes which need to be turned ON / OFF.

Do all genes have a TATA box?

*YES* GAD highly prevalent in pts with CVD (point prevalence = 11%). Panic disorder less prevalent in CAD, but associated with 2x increased risk of CAD.

Do cardiac conditions increase risk of anxiety disorders?

*YES* Acute Coronary Syndrome → 20-30% pts have ↑ anxiety levels. Fear-avoidance behaviours. Risk of ACS low during sexual activity with marital partners, but increased with extramarital partner.

Do cardiac conditions increase risk of anxiety symptoms?

*YES* Pts with ICD (implantation) have increased levels of PTSD (risk factors: young age, emotional distress before implantation, Type D personality, non-constructive support, greater freq. chest pain). Phantom shocks (shocking sensations that individuals feel in the absence of a true firing of the device) = PTSD symptom?

Do cardiac treatments increase risk of anxiety disorders?

First world

Do first world or third world countries have higher incidence of allergy?

No, as they do not have iron overload.

Do non-expressing individuals with Cys282Tyr mutation require phlebotomy?

STEC / VTEC

Do not use antibiotics if __________ is suspected → as it stimulates more toxin release.

Blood (Lecture 4, PART 1 Questions)

Do the following:

Blood (Lecture 4, PART 2 Questions)

Do the following:

Question 23, Public Health (Lecture 5)

Do the following:

Question 5, Blood (Lecture 4)

Do the following:

Break occurs near or at the centromere in the acrocentric Chromosome 21, and at another acrocentric chromosome (frequently Chr 14). The cross-fusion of these two products results in Down Syndrome. NOTES: Problems arise at gametogenesis; there is no maternal age effect; there is a risk of recurrence.

Down Syndrome: Robertsonian Translocation

Extra copy of chromosome 21 (95% of cases). Robertsonian translocation (5% of cases).

Down syndrome (causes)

Metaphase karyotype Interphase FISH Chromosomal microarray Whole genome sequencing

Down syndrome is diagnosed using which technique(s)?

<0.05% BAC Thought, judgement, and restraint are loosened.

Drink Driving Limit (BAC)

Alcohol Other drugs that cause vasodilation / reduce BP. Phosphodiesterase inhibitors (e.g. Sildenafil [Viagra]).

Drug Interactions of Nitrate Drugs

Usually not required. Includes anti-craving medication (naltrexone) and aversive medication (disulfiram as an aldehyde DH inhibitor). TMS therapy can be performed to reduce craving (switch of dACC beta activity) → requires continuous stimulation.

Drug Treatment for Alcoholism

*MDR TB* → Multidrug resistant TB. *XDR TB* → Extensively drug resistant TB. Resistant to second-line drugs → isoniazid and rifampin + any fluoroquinolone + at least 1 (of 3) injectable second line drugs. ~5% of MDR cases are XDR. *To Treat:* Use combinations of 2nd and 3rd line drugs (this poses risk of increase toxicity, is less effective, and requires 18-24 months of treatment).

Drug-Resistant Forms of TB + Treatment

NSAIDs Corticosteroids (Glucocorticoids) DMARDs (biological and synthetic) Anti-TNFa

Drugs used to treat RA

*Microbial imbalance* that causes adverse effects in humans. • Decrease in microbial diversity. • Loss of beneficial bacteria; gain of potentially pathogenic bacteria. • Associated with many diseases - difficult to determine whether it is the cause or consequence of such diseases. OR, may not be the direct cause of disease, but can perpetuate disease progression. IN OTHER WORDS, dysbiosis is associated with many off-site effects, but causality is not necessarily established.

Dysbiosis

difficulty swallowing

Dysphagia

Abnormal development or growth of cells. IRREVERSIBLE. Occurs at genetic level. Can lead to tumour formation.

Dysplasia

abnormal gene expression and thus disease.

Dysregulation of epigenetic modifications (such as methylation) leads to...

A *quantitative test* that measures bacterial susceptibility to antimicrobials. Commercially prepared strips containing an antimicrobial gradient are applied to a lawn of bacterial isolate under test. The MIC is the point at which the zone of inhibition bisects the strip.

E-Test

Question 2 Question 9

EBP: Lecture 2 (Page 27 & 29)

Enteropathogenic E. coli

EPEC

Extended Spectrum Beta-Lactamases A group of bacterial enzymes which can hydrolyse beta-lactam antimicrobials.

ESBL

Enterobacter spp Serratia spp Citrobacter freundii Aeromonas spp Proteus vulgaris Providencia spp Morganella morganii *** Clavulanic acid fails to inhibit these Class C beta-lactamases produced. (They are initially susceptible but then become resistant due to increased beta-lactamase production).

ESCAPPM Organisms

Early Onset (<3 mths): *Staph. aureus*. Late Onset (3-24 mths): *Staph. epidermis* [biofilms form on surgically introduced items; treatment is same, unless methicillin-resistant → use vancomycin).

Early Onset vs. Late Onset: Septic Arthritis

Abdominal pain Weakness Lethargy Weight loss Cirrhosis (↑risk if serum ferritin >1000ng/mL) Other symptoms: skin pigmentation, DM, CHF, arrythmia, arthritis, hypogonadism.

Early Symptoms of HFE-HH

First pass metabolism via CYP3A4 inhibited by grapefruit juice. Due to ↓CYP3A4 activity, there is greater chance of overdose. Half-life increases, but clearance remains constant.

Effect of Grapefruit Juice on Drug Metabolism

the process of flowing out

Efflux

2 correctors + 1 potentiator. Suitable for treatment of 90% CF patients. Patients must be >12 years old and have at least one of the F508del mutation in the CFTR gene.

Elexacaftor-Tezacaftor-Ivacaftor (Trikafta)

confined to a particular country or area

Endemic

route of administration involving GI tract Examples: oral, sublingual, rectal.

Enteral

The autonomic nerves in the walls of the GI tract. It is operates independently of the CNS, but uses the same NTs.

Enteric Nervous System (ENS)

CCR5 Inhibitors: Prevents binding of gp120 to co-receptor. Fusion Inhibitors: Peptide analogue of fusion domain of gp41 inhibits fusion.

Entry Inhibitors (MoA)

*Age* (e.g., with increasing age, there is increasing risk of cancer). *Ethnicity*

Epidemiology of Cancer: Person Factors

*Geographical* Ex: oesophageal cancer 300x higher in Iran than Nigeria. Ex: HBsAg (Hep B surface antigen) distribution geographically correlates with incidence of liver cancer.

Epidemiology of Cancer: Place Factors

Number and rates of cancer registrations overtime - NZ rates of cancer are higher in men than women. - Overall rates of cancer have decreased overtime. - Cancer deaths per 100,000 have decreased overtime.

Epidemiology of Cancer: Time Factors

Increasing incidence with age. Decreasing incidence incidence overtime. Higher rates in Māori. Higher rates in males.

Epidemiology of Stomach Cancer

Unjust use of government power, Lack of respect for persons to the point of dehumanising difference. Disregard for reproductive autonomy. Simplistic and incomplete understanding of the causes of disease and difference.

Ethical Issues: Eugenics

Patient wants to 'fight' / hold onto false hopes. Difficult to determine prognosis and if death is inevitable / not. Some patients want everything to be done.

Ethical tensions surrounding the acceptance of death.

Q4 Q5

Ethics: Lecture 3 (Pages 43 & 44)

study of factors that influence the hereditary qualities of the human race and ways to improve those qualities

Eugenics

(1) Protein intake (2) Fat intake (3) Sugar intake (4) Salt intake (5) Physical activity (6) Alcohol

Evidence Linking Lifestyle Factors with CVD

J-shaped curve. Low consumption of alcohol (red wine) = potential protective factor against CHD. But this could be due to confounding. Mechanism: Lipid effects (increased HDL). Platelet effects (aspirin-like). Glucoses metabolism (decreased diabetes). But there are other health conditions associated with alcohol!

Evidence Linking Lifestyle Factors with CVD: *Alcohol Intake*

High intake of SFA & TFA associated with increased risk of CVD. High SFA consumption = increased plasma cholesterol. Limit SFA consumption, and replace these calories with PUFAs (as opposed to TFA, which will still result in elevated risk of CVD).

Evidence Linking Lifestyle Factors with CVD: *Fat Intake*

Reduces risk of CVD. Mechanisms: Reduced BP. Reduced cholesterol. Increased HDL. Improved HbA1C / diabetes preventions. ↓ obesity. Decrease inflammation.

Evidence Linking Lifestyle Factors with CVD: *Physical Activity* + Mechanisms

Increased intake of ANIMAL proteins = increased risk of CVD. Increased intake of PLANT proteins = decreased risk of CVD.

Evidence Linking Lifestyle Factors with CVD: *Protein Intake*

Increased salt intake = increased BP. Lowered sodium intake will result in reduced systolic BP.

Evidence Linking Lifestyle Factors with CVD: *Salt Intake*

More % calories from added sugar = increased risk of CVD.

Evidence Linking Lifestyle Factors with CVD: *Sugar Intake*

They are more common in adults. · Chemotherapy · Neoplastic disease (cancers / leukaemia) · Infectious → AIDS · Infectious → Measles

Examples of Acquired Immune Deficiency Disorders

HPV (human papilloma virus) Hepatitis HIV HHV-8 H. pylori

Examples of Cancer-Causing Infections

Tobacco, alcohol, diet, occupational factors, etc.

Examples of Carcinogens

Bronchitis Bronchiolitis Pneumonia

Examples of LRT Infections [LRTIs]

SARS SARS 2.0 MERS

Examples of Novel Coronaviruses

CRPS NCCP Irritable bowel syndrome Chronic fatigue syndrome

Examples of Persistent Symptoms & Syndromes

Anaphylactic shock Allergic rhinitis Asthma Eczema

Examples of Type I Hypersensitivity

Rhinosinusitis Pharyngitis Otitis media

Examples of URT Infections [URTIs]

Ultraviolet radiation e.g., sunlight. Ionizing radiation e.g., X-rays.

Examples of carcinogenic radiation sources.

Langerhans cells (Skin) Osteoclasts (Bone) Alveolar macrophages (Lung)

Examples of macrophages

Newly-emerged SARS, MERS and avian influenza H5N1 and H7N9 viruses.

Examples of viruses which cause severe respiratory disease.

(AVINDICATED PI + Functional illness = AVINDICATED PIF) So that we don't overwhelm the patient with unnecessary tests and treatments.

Explain why functional illness needs to be included in the differential diagnosis.

Agonists are drugs described as having affinity and efficacy, partial agonists are drugs which bind with affinity, but do not produce maximal response - even at 100% receptor occupancy, thus they are less efficacious than full agonists. Antagonists are drugs which have no intrinsic efficacy - they can bind to the receptor (i.e. they have affinity), but do not induce a conformational change in the receptor. They produce their effects by preventing agonist from binding. Antagonists can be competitive reversible (bind non-covalently to the orthosteric site) or competitive irreversible (bind covalently to the orthosteric site). Inverse agonists have affinity and negative efficacy - they turn the receptor off - reducing the constitutive activity of the receptor. An inverse agonist may look like an antagonist if the receptor has only minimal constitutive activity.

Explain, using the terms affinity and efficacy, the difference between an agonist, an antagonist and an inverse agonist.

F = Bioavailable Dose / Administered Dose The fraction of dose that reaches the systemic circulation in the active form following administration.

F (Fraction of Dose) =

Nutrition (Protein, Vit C) Metabolic status (e.g., diabetes) Steroids Infection Mechanical / movement Blood supply

Factors which influence inflammation & repair

Can survive in BOTH aerobic and anaerobic conditions.

Facultative anaerobe

Bronchial thickening / remodelling. Increased mucous production. Airway hyperresponsiveness.

Features of Asthma

Bacterium Features: Anaerobic Gram-positive Endospore-forming It is present in low numbers in the healthy intestinal tract.

Features of C. difficile

Potency Slipe Maximal efficacy

Features of a concentration-response curve

(1) Drug absorbed from GI tract. (2) Passes via portal vein into liver. (3) May be metabolised in liver. Consequence of metabolism: not all of the drug reaches systemic circulation!

First Pass Metabolism

Diet Exercise

First interventions to dyslipidaemia?

Isoniazid Rifampin Ethambutol Pyrazinamide

First-Line Drugs for TB Treatment

(1) Formulate clinical Q (2) Find evidence to answer Q (3) Appraise the evidence (4) Apply the evidence (5) Evaluate performance

Five Steps of EBP

Diagnostic tool. Label different immune cells by binding a fluorescent antibody to their unique surface makers. Labelled cells are passed in laser beam → the fluorescent tag is excited → emits light. Different colour tags emit light at different wavelengths, and this allows the separation of cells (allows us to differentiate between the different cells).

Flow Cytometry

Flow

Flux

Alcoholism throughout pregnancy. Affects child development. CNS defects / abnormalities (less white matter, underdeveloped corpus callous). Appearance: shorter, small eyes, facial abnormalities. Cognitive and behavioural issues.

Foetal Alcohol Syndrome

*Location*: Infection of hair follicles. *Gross Appearance*: Papules become pustules. *Organism*: S. aureus (coagulase & adhesions). *Treatment*: Resolve by itself (if not, topical antimicrobials).

Folliculitis → Location → Gross Appearance → Organismpe → Treatment

AChE inhibitor (e.g. Neostigmine).

Following surgery, how can the effects of a non-depolarising NMB be reversed?

*Floor:* family as a foundation. *Roof:* culture (values and beliefs). The four *pou*: not only connect the culture and the family but are also continuous and interactive with each other. The pou are spiritual, physical, mental, other.

Fonofale Model of Health

<50ng/mL Start when serum ferritin >500ng/mL.

For HFE-HH, phlebotomy is required to maintain serum ferritin concentration at...

SEE PAGE 49 (Vertical #4)

For each recreational drug, outline the... - MOA - Effects - Tolerance - Dependence - Withdrawal - Treatment DRUGS: → Cocaine → Amphetamines → Opioids → Indoleamines → Phenethylamines → NMDA antagonists → Indoleamines

Similar presentations. Large proportion (30%) of ED patients with chest pain actually have panic disorder. To differentiate, we must assess: → Quality of symptoms → Relation to physical exertion Doctors are not trained to recognise SNS arousal and have bias towards biological disease. This may be because there are clear treatment pathways for "real" cardiac problems, but treatment of anxiety is ~more difficult. Mental health stigma.

For those patients with panic / anxiety, 90% are not recognised. Why not?

Supraventricular & Ventricular

For what type of arrhythmia is the following drug used? Amiodarone

Supraventricular

For what type of arrhythmia is the following drug used? Digoxin

Supraventricular

For what type of arrhythmia is the following drug used? Diltiazem

Supraventricular & Ventricular

For what type of arrhythmia is the following drug used? Metoprolol

Increased vascular permeability ↓ Transudate (low protein concentration; little RBCs). ↓ Exudate (protein-rich fluid) ↓ Oedema

Formation of transudate / exudate

Vd = Ab / Cp Units: Litres or Litres/kg body weight

Formula for Vd

Large cell carcinoma Adenocarcinoma Squamous cell carcinoma Small cell carcinoma

Four Major Histologic Types of Lung Carcinomas

Usually peripheral, with a central scar. Glandular appearnce. Invades pleura (pt may present with malignant pleural effusion).

Four Major Histologic Types of Lung Carcinomas: *Adenocarcinoma*

Peripheral or central. Production of anaplastic large cells (arise from basal cells). Metastases occur early.

Four Major Histologic Types of Lung Carcinomas: *Large cell carcinoma*

Usually occurs centrally (hilar region). Arises from neuroendocrine tissue (cells with neuroendocrine granules). Associated with chromosomal abnormalities (Chr3 short arm deletion). ADH secretion → hyponatremia. High mortality.

Four Major Histologic Types of Lung Carcinomas: *Small cell carcinoma*

Usually arises in major bronchi (secretions pool distal to tumour → infection & pneumonia → pt may present with cough). Characterised by keratin production & intercellular bridges. Slow growing.

Four Major Histologic Types of Lung Carcinomas: *Squamous cell carcinoma*

HIV antibodies p24 antigens It is an antigen-antibody test.

Fourth generation tests detect...

a callus.

Fracture bones ends are joined by...

*Scope / Definitions* *Models* (Te Whare Tapa Whā, Fonofale, Hospice framework). *Evidence informed* (spirituality is an emerging research field). *Zeitgeist*

Framework for understanding spirituality

*Type of Drug*: Loop diuretic *Site of Action*: TAL (thick ascending limb). *Mechanism of Action*: Inhibits luminal NKCC2 co-transporter by competing with chloride for binding, inhibiting (up to ~25% of) sodium reabsorption. ALSO, this disrupts transmembrane potential such that other electrolytes (calcium, magnesium and ammonia cannot be reabsorbed). *Pharmacokinetics*: Rapid oral absorption with max. effect within 1-2hrs. Extensively protein bound and does not pass directly into glomerular filtrate, but is actively excreted into proximal tubules by OAT. *Therapeutic Uses*: Hypertension, Oedema, Hyperkalaemia. *Side Effects*: Hypokalaemia, Hyponatraemia, Hypovolemia, Hyperuricaemia.

Frusemide → Type of Drug → Site of Action → Mechanism of Action → Pharmacokinetics → Therapeutic Uses → Side Effects

Hepatic failure from severe acute hepatitis.

Fulminant Hepatitis

No apparent function. Have a tendency to insert randomly into proteins / ncRNA / regulatory elements. If they insert into a new location within a gene, this can lead to the acquirement of a genetic disorder.

Function & consequences of jumping genes

Untranslated regions are responsible for regulation of gene expression.

Function of *UTRs*

initiation of transcription

Function of *promoter region*

Normally, NKCC2 has the capacity to reabsorb ~25% of filtered sodium load.

Function of NKCC2

Immunity against worms Regulate chronic allergic inflammation. (Functions NOT CONFIRMED)

Function of basophils

Transcribed then translated into functional gene product. Contains introns and exons.

Function of coding sequence

Regions which give rise to protein.

Function of exon

Regulatory components which must be spliced out in order for translation to proceed.

Function of intron

Hepatic LDL receptors facilitate the removal of LDL cholesterol from blood. The PCSK9 protein *degrades these LDL receptors* before they reach the cell surface, so more cholesterol can remain in the bloodstream. A low number of receptors on the cell surface can thus leading to atherosclerosis.

Function of the PCSK9 protein

Symptoms caused by maladaptive functioning of 1+ body system(s), without any underlying tissue or organ damage.

Functional illness

Energy salvage Gut function Pathogen resistance Mucosal system immunity Immune tolerance

Functions of GI Microflora

caused by dimorphic fungal pathogens (exists as mould in environment and yeast in body). The primary site of infection is pulmonary. These are geographically restricted!

Fungal Infection: Dimorphic systemic mycoses

*Opportunistic systemic mycoses*: in immunocompromised patients. Cosmopolitan fungi → very low virulence. Ex: invasive candidiasis, invasive aspergillosis, zygomycosis.

Fungal Infection: Opportunistic systemic mycoses

skin, hair, nail, mucosa. Ex: dermatophytosis (ringworm), candidiasis (thrush).

Fungal Infection: Cutaneous mycoses

chronic, localised infections of the skin and subcutaneous tissue.

Fungal Infection: Subcutaneous mycoses

surface of skin, hair shaft. Ex: Seborrheic dermatitis, dandruff.

Fungal Infection: Superficial mycoses

immunosuppressed.

Fungi are not a common cause of lung infection unless the patient is...

A graphical display used in meta-analysis to look for publication bias (missing studies).

Funnel Plot

(Serotonin) Released by ECL cells. Acts through 5HT receptors on sensory neurons. Triggers nausea and peristalsis.

GIT Neurotransmitters: *5HT* → Receptor → Location of receptor → Function

Produced by interneurons. Acts through muscarinic receptors on muscle and gastric parietal cells. Induces nausea, motility, secretion.

GIT Neurotransmitters: *ACh* → Receptor → Location of receptor → Function

Produced by muscle and mucosal epithelial cells. Acts on D receptors in myenteric plexus, and inhibits NT release. This decreases motility and contributes to nausea.

GIT Neurotransmitters: *Dopamine* → Receptor → Location of receptor → Function

Produced by mast cells, ECL cells, and neurons. Acts through H1 receptors in brain, or H2 receptor in GIT. Induces nausea and gastric acid secretion.

GIT Neurotransmitters: *Histamine* → Receptor → Location of receptor → Function

Produced by neurons and inflammatory cells in response to stress. Acts through NK-1 (neurokinin-1) receptors in brain, gut immune and mucosal cells. Induces vomiting.

GIT Neurotransmitters: *Substance P* → Receptor → Location of receptor → Function

Granulocyte (monocyte) colony stimulating factor

GM-CSF

Occurs to limb that has lost BS and undergone necrosis (typically ischemic coagulative necrosis). Superimposed bacterial infection → more liquefactive necrosis due to action of degradative enzymes in the bacteria and attached leukocytes → "wet gangrene".

Gangrenous necrosis

Two copies of alpha gene on Chr16. Normal adult will possess 4 functional copies of the alpha chain gene.

Gene for Alpha Chain

One copy of beta gene on Chr11. Normal adult will possess 2 functional copies of the beta chain gene.

Gene for Beta Chain

Act directly on kidneys. Decrease salt and water reabsorption in the tubules → excretion of more liquids → decreasing blood volume.

General Action of Diuretics

Extensions of drug action: - Facial flushing - Constipation - Bradycardia - AV block - HF Do not use in conjunction with beta-blocker → can cause cardiac depression. Caution with other drugs.

General Adverse Effects of CCBs

*Effects:* Vasoconstriction; Decrease vascular permeability; Decreased itch. *Use:* Therapeutic use against allergic disease (IgE-mediated hypersensitivity responses). Also used as secondary treatment in anaphylactic shock (due to its vasoconstricting properties). SEE SUMMARY ON SLIDES 36 & 37 (Lecture 17, Pharmacology)

General Effects & Uses of Antihistamines

CCBs bind to LTCC located on vascular smooth muscle, cardiac myocytes, and cardiac nodal tissue. Block calcium entry into the cell. EFFECTS: • Vascular SM relaxation (vasodilation). • Decreased myocardial force generation (negative inotropy). • Decreased HR (negative chronotropy). • Decreased conduction velocity within the heart.

General Mechanism of CCBs

Only replicate in host cells. Change / damage host cell (*cytopathic effect*). Contains nucleic acid. Shape determined by protein coat. dsRNA or ssRNA. Circular or straight genome. Viral capsid is composed of protein subunits (capsomeres).

General features of a virus

3' to 5'

Genes in Journal Articles: what is the direction of the gene? ←

5' to 3'

Genes in Journal Articles: what is the direction of the gene? →

GENETICS TUTORIAL 6

Genetics Tutorial 6: Cancer

Autosomal recessive inheritance. Mutation → C282Y (Cys282Tyr) mutation. · Although the molecular mechanism is not clear, these common variants increase the chances of low hepatic production of hepcidin, leading to increased iron absorption. · NZ Caucasian Population: Carrier frequency (Aa) is 1/7. · NZ Caucasian Population: Affected homozygous frequency (aa) is ~1/200. · Low clinical penetrance

Genetics of HFE-HH → Inheritance → Mutation → Effect → Carrier frequency → Affected frequency → Pentrance

Q8

Genetics: Lecture 7 (Page 34 & 35)

All have ssRNA (except Hep B, which has dsDNA).

Genome Type (RNA or DNA) of Hepatitis Viruses

*Genotype MM* = Normal. *Genotype ZZ* = High risk for emphysema / chronic obstructive lung disease / liver cirrhosis / hepatitis. *Genotype MZ* = Heterozygote (small increase in risk).

Genotypes & Phenotypes for SERPINA1 Gene

Occur in gametes. All cells in the body will carry the mutation. Inherited from parent to offspring.

Germline mutations

Second leading cause of death globally (10 mill / year; 1 in 6 deaths are cancer-related). >60% cases occur in Africa, Asia, Central & South America. >70% cancer deaths occur in these regions.

Global Burden of Cancer

Increase in use Lower age of initiation Growth in world supply Use of multiple substances Increasing levels of intoxication, alcohol poisoning, ODs. Increasing use by women Age group: adolescents & young adults. Males > Females

Global Trends in Substance Use

Delay transition from non-mucoid to mucoid (chronic). · Pre-colonisation = Avoid exposure to organism; regular monitoring. · Initial colonisation = Oral ciprofloxacin + nebulized antibiotic (tobramycin for 28 days). If fails, early & aggressive IV antibiotic treatment required.

Goal of treatment for biofilms in CF patients

(1) Acknowledgement / honesty surrounding death. (2) Care for the whole person. (3) Multidisciplinary approach to death. (4) Research and evidence based.

Goals / Philosophies of Palliative and Hospice Care

*Preventor*: Anti-inflammatory agents *Reliever*: Bronchodilators

Goals of Asthma Treatment

https://www.justintimemedicine.com/CurriculumContent/p/2310

Good explanation of unidirectional blocks and re-entry:

Population-based. Applies to all young drivers, and provides a response to the high risk of RTIs for young people. Alternative to raising the driving age. (1) LEARNERS: Supervised learner's stage (BAC <0.03mg%). (2) RESTRICTED: Intermediate stage with restrictions (passenger required between 5am & 10pm; BAC <0.03mg%). (3) FULL: Full privilege licence.

Graduated Driver Licence (GDL) System [1980s]

3-5 days

Granulation tissue appears how many days post-injury?

Exists in stomach (colonises ~10% of population; most remain asymptomatic). Associated with reduced risk of asthma / allergy. Infection may progress to superficial gastritis → chronic inflammatory gastritis → eventually, cause gastric cancer, chronic active gastritis, or peptic ulcer disease. Diagnosis: Stool antigen tests. Other tests such as serology (detects previous exposure status due to antibody presence).

H. pylori → Location in gut → Statistics → Consequence of infection → Diagnosis [opportunistic organisms of gut]

*Amoxicillin:* broad spectrum beta-lactam antibiotic that inhibits bacterial peptidoglycan cell wall synthesis. ADRs: allergy, abnormal taste, antibiotic-induce colitis.

H. pylori Antibiotics: Amoxicillin

*Clarithromycin:* broad spectrum macrolide that inhibits bacterial protein synthesis. ADRs: pregnancy and cardiac problems, CYP3A4 drug interactions.

H. pylori Antibiotics: Clarithromycin

*Metronidazole:* inhibits DNA synthesis in anaerobic bacteria. ADRs: High dose or long-term use can cause CNS and kidney toxicity, pre-term birth, and act as a carcinogen.

H. pylori Antibiotics: Metronidazole

negative results

HBeAg mutants cause...

Delivers fat and cholesterol to the liver.

HDL (Function)

Non-expressing Cys282Tyr homozygotes with neither clinical or biochemical manifestation.

HFE-HH: Non-Penetrant Individuals

HFE-related heredity haemochromatosis

HFE-HHC

Entry inhibitors Reverse transcriptase inhibitors (RTI) Integrase inhibitors Protease inhibitors

HIV Drug Mechanisms

A strategy for identifying interventions that can be applied to any type of illness or injury. Interventions proceed through three stages: pre-event, event, and post-event.

Haddon Matrix

Increased haemolysis can be caused by maternal antibodies that bind to foetal RBCs. Common Cause: RhD blood group. Maternal antibodies cross the placenta and elicit a response against foetal red blood cells. Rh (Rhesus factor) is an antigen on surface of red blood cells of Rh+ individuals.

Haemolytic Disease of the Foetus and Newborn (HDFN)

Severe: <1% activity Moderate: 1-5% activity Mild: 5-50% activity

Haemophilia A Severities

Time for concentration of drug in plasma to halve.

Half-Life

Increased

Has the HIV prevalence in NZ increased / decreased / stayed the same?

Read examinable *required readings*. Focus on causes and strategies toward inequalities.

Hauora Māori (Lecture 2, Māori Health Determinants)

Scarring / fibrosis: replacement of parenchymal cells by collagen. Myocardium = permanent cells. Hence, healing is scarring (not regeneration). SEQUENCE: ~5 Days: Angiogenesis + fibroblast proliferation. ↓ Maturation of granulation tissue. ↓ Fibroblasts lay down collagen (ECM). ↓ Infarction repaired by dense collagenous scar.

Healing of a myocardial infarction

If CT framework has remains, cells can regenerate so long as: (1) cell can re-enter cell cycle (i.e., NOT a permanent cell). (2) can form the correct architecture.

Healing: (1) Regeneration

(1) *Angiogenesis*: formation of new blood vessels. Granulation tissue indicates this is taking place. Early progenitor cells are mobilised from the bone marrow to assist with this. (2) *Fibroblast Migration*: through BV wall, then proliferation. (3) *Deposition of ECM*: CT proteins are lain down. Collagen (from fibroblasts) provides strength. (4) *Maturation & Remodelling* of fibrous tissue. Organisation / remodelling occurs in response to GFs, cytokines & mechanical stress. Involves gradual contraction of scar.

Healing: (2) Scarring

Support networks / groups. Create supportive legal environment (e.g. NEP). Support committed leadership (involve Ministry of Health). De-stigmatise.

Health promoting strategies in terms of HIV

Most contagious Hep virus (hence, "infectious hepatitis"). *Transmission:* Faecal-oral → spread in camps, military institutions, daycare. *Symptoms:* Jaundice (less common in children, who are often asymptomatic). *Outcomes:* Complete recovery (>99%) or fulminant hepatitis (rare).

Hepatitis A Infection → Transmission → Symptoms → Outcomes

Responsible for 80% liver cancers. AKA "serum hepatitis". *Transmission:* Blood, Sexually, Perinatally. *Outcomes:* Normally eliminated, or 5% risk of chronic infection (95% in neonates). May progress to chronic active hepatitis, then cirrhosis or liver cancer (hepatocellular carcinoma) at some point. *Coinfection*: HDV can coinfect those with HBV infection (increases risk of fulminant infection).

Hepatitis B Infection → Transmission → Outcomes → Coinfection

*Transmission*: Faecal-oral *Outcome*: Mild & self-limiting. However, high risk of fulminant hepatitis during pregnancy. It is a significant cause of mortality in 3rd trimester. *Risk Groups*: Pregnant, Travellers, Elderly. Zoonotic infection.

Hepatitis C Infection → Transmission → Outcomes → Risk Groups

*Transmission*: Blood (and sexually, perinatally). *Symptoms*: Usually subclinical (asymptomatic) then progresses to chronic disease. *Outcome*: 70-90% become chronic carriers; this may progress to chronic active hepatitis, then cirrhosis / liver cancer at some point.

Hepatitis C Infection → Transmission → Symptoms → Outcomes

Describes the proportion of vaccinated people where R drops below 1.

Herd Immunity Threshold

Considers the combined CV risk. Treating people with an increased risk of CHD / CVD. Manages to target all individuals with >10% 5-year risk, while also treating those with increased overall risk. (??)

High Baseline Risk Strategy (in the context of CVD)

Have specialised virulence factors that allow them to infect healthy hosts + susceptible hosts. These are *obligate pathogens*.

High virulence pathogens

Interventions aimed at high-risk individuals

High-Risk Approach

Formed via carboxylation of L-histidine.

Histamine Synthesis

Pyogenic (pus-producing) or Granulomatous (presence of granuloma).

Host Response to Osteomyelitis

pH of 4-5. Reactive oxygen and nitrogen species [ROS, RNS]. Hydrolytic enzymes. Antimicrobial peptides which permeabilise the cell membrane.

Hostile Features of a Phagolysosome

According to size

How are chromosomes ordered?

Concentrated from a pool of donated blood. Must be screened for viruses. Undergoes purification. Contains both Factor 8 and vWF. Limitation: Highly dependent on sufficient blood supply.

How are the Factor 8 plasma concentrates obtained and prepared?

Methylated cytosine bases are susceptible to deamination. → become thymine base → introduces potentially harmful point mutation. ↑ Methylation caused by enviro/lifestyle may increase the incidence of cytosine → thymine base changes (thus, generating more point mutations). Can have downstream effects.

How can DNA methylation lead to DNA mutation?

A PET scan uses FGB to identify the elevated glycolytic rate that it characteristic of malignant cells. It is used for staging of cancers - but limitations include inability to assess T stage and false positives with other hypermetabolic states such as inflammation.

How can PET scans assess tumours?

(1) Blocking ACh receptors = non-depolarising block. (2) Over-activating ACh receptors = depolarising block.

How can a post-synaptic neuromuscular block be achieved?

Need to pay attention to non-physical pain. Listen to / acknowledge what is important to the patient. Addressing suffering requires: - Compassion - Humility (recognise that your own skills won't be sufficient to help pt, so incorporate a team approach). - Restoration of a sense of control.

How can doctors contribute toward the relief of suffering? [Palliative Care]

They can inappropriately alter the chemical modifications of histones and gene promoters. Examples: smoking, toxin exposure, medication, diet, exercise, sleep, alcohol, stress.

How can environment & lifestyle modulate gene expression?

FVIII is required for FIX and FX interaction. If a person is FVIII deficient, then *recombinant antibodies* can be used to mimic its action. The *bispecific* antibody will be able to recognise the FX and FIX antigens and bring them close together to enable activation of FX to FXa. Structure: Contain heavy and light chains, plus variable regions.

How can recombinant antibodies be used to treat haemophilia?

Electrophoresis or inhibition assay (to determine activity). (Note: these can be confounded by acute phase response).

How can the amount of AAT in blood be determined?

(1) Inflammation: more activated T cells, so more targets. (2) Disruption of Mucosal Barriers: e.g. ulcers. Easier for virus to enter.

How can the presence of STIs elevate likelihood of HIV sexual transmission?

*Recurrent pyogenic infection?* Defect of antibody, complement, or of phagocyte function. *Persistent fungal skin infection and recurrent viral infections?* Defect in T cells.

How can the type of infection suggest the type of immune deficit?

See paragraph (Page 54, Vertical #4) *DO NOT:* · Say "it is all in your head." · Take the perspective that the patient's experience is entirely psychological, and thus that they need referral to a psychiatrist. · Only provide reassurance that they do not have an organic disease. This is not sufficient! *DO:* Validate Show compassion Remain open minded. Open dialogue about involvement of psychological factors. Assess for anxiety / depression. Be confident to stop further investigations. Provide a conceptual, plausible model.

How can we approach patients with persistent physical symptoms?

Effective and unambiguous reassurance. Early communication. Acknowledge reality of symptoms. Avoid blanket terms. Give explanation of causes. Reproduction of symptoms → apply behaviour expmt to provoke symptoms. Explain that symptoms are common, well-recognised and have good prognosis. Understand pt's and family beliefs & worries. Plan and agree simple self-help. Provide written info and plans. Offer to see pt's partner and follow-up.

How can we manage presentations with psychological components (e.g. NCCP) in ED?

Normal response to perceived / actual threat. Phantom pains = severe pains that have nothing to do with peripheral tissues. How brain constructs pain experience depends on sensory cues + other influences. Brain activates systems to get you out of danger (SNS, endocrine, etc). When pain persists, the danger alarm becomes more sensitive (central sensitisation), and thoughts / beliefs can now acts as triggers. Education & understanding critical to overcome pain → reduces the threat value of pain, which reduces activation of our protective systems. Pain doesn't mean ongoing harm, but rather that NS is using pain to protect you at all costs rather than to inform about real danger. Carefully graded activities can help gradually increase functioning and life involvement. Choose activities that produce danger-reducing internal chemicals (e.g., ParaSNS). Note: Pain education prior to surgery will reduce post-operative pain.

How can you explain pain to patients?

Start nucleotide: gt End nucleotide: ag Everything in between in spliced / removed.

How can you identify an intron in a gene sequence?

Inoculate an appropriate tissue culture cell line with the virus along with some of the patient's serum. If antibody is present, it will bind and neutralise the virus, preventing receptor-mediated entry into the cell and subsequent multiplication, inhibiting the formation of CPE.

How can you prove that a virus isolated from a patient is really causing the disease?

40%

How common are ED presentations of chest pain with non-cardiac diagnoses?

(1) Recognition: APC displays antigen on MHC Class 1 to naive T cells. (2) Proliferation & Differentiation: T cells proliferate + generates memory T cells. (3) Effector Function: Effector T cells kill virus-infected target cells.

How do CD8+ T-cells kill virus-infected cells?

Lipotechoic/teichoic acid

How do Gram(+) bacteria induce inflammation?

LPS (endotoxin)

How do Gram(-) bacteria induce inflammation?

(1) *Substratum conditioning*: comprises a substance which facilitates attachment and growth of the bacteria (plasma proteins, platelets, fibrin, polymorphs). (2) *Initial attachment* of bacteria. QUORUM SENSING: (3) *Microcolonies + EPS production* (4) *Mature biofilm + dispersal*

How do biofilms form?

Mannitol is filtered through the glomerulus. Most other diuretics are highly protein bound (so are not filtered, and rather transported in association with other weak acids / bases). The proximal tubule mediates secretion and reabsorption of weak acids / bases, and hence most diuretics.

How do diuretics enter into the tubules?

Have adhesion receptors (*selectins*) which bind loosely to endothelial *integrins*, enabling rolling. Further activation of neutrophils enables adhesion, then transmigration.

How do neutrophils enter the peripheral tissues? Describe the surface receptors that allow this.

Anti-inflammatory. Slow collagen synthesis.

How do steroids influence inflammation & repair?

Example: Screening of HIV in blood donations needs to be highly sensitive, so we use HIV RT-PCR and anti-HIV-1/2 immunoassay. Since there is a low pre-test probability of HIV, screening in pregnancy involves a rapid result process using the anti-HIV-1/2-immunoassay method.

How do the circumstances determine how we test the patient for HIV?

*ACh* acts via M receptors to initiate contraction of longitudinal muscle. *Serotonin* (produced by ECL cells) acts via 5HT receptors to increase ACh production and secretion → induces peristalsis. *Dopamine* (produced by epithelial muscle cells) acts via D receptors to decrease ACh production → slows peristalsis.

How do the following NTs enables peristalsis and / or segmentation? ACh Serotonin Dopamine

Look at all available evidence, determine which are best studies. Consider type of study design and rank studies according to hierachy of evidence. Then, *appraise the study*: • Internal validity • Evidence for cause-effect relationship • External validity

How do we assess evidence for causation?

Group 1 = Carcinogenic to humans. Group 2A = Probably carcinogenic to humans. Group 2B = Possibly carcinogenic to humans. Group 3 = Not classifiable as to whether carcinogenic or not. Group 4 = Probably not carcinogenic to humans.

How do we classify agents according to their carcinogenicity? (IARC)

It's difficult to distinguish between the causative organisms. All cause diarrhoea and abdominal pain, often with vomiting. HOWEVER, if... · Abdominal pain is usually severe = Campylobacter. · Lower right quadrant pain = Yersinia enterocolitica. · Typhoid / Paratyphoid → can present with rose spots, bacteraemia, no diarrhoea.

How do we distinguish between the causative organism based on clinical presentation of gastroenteritis?

Full history + examination. Measure CD4 count. Measure viral load. Baseline measurements (renal function, liver function). Multiple conditions (hepatitis, STIs). Genotype (to determine appropriate drugs). Vaccinations (check / conduct). Advice.

How do we manage and assess patients with HIV?

Liver *bile salts* are secreted to aid fat absorption. They are primary or secondary. *Primary*: enable C. diff to recognise that it is in intestines, thus promotes germination. *Secondary*: inhibit growth of C. diff. Many of gut flora promote deconjugation of biles salts into primary, but there is a small population that promote biotransformation of primary into secondary (this is necessary to prevent C. diff infection). Antibiotics used → small population is eradicated → no secondary bile salts → no inhibition of C. diff growth → infection proceeds and C. diff produces toxins. Proper state of colon = almost all secondary bile salts!

How do we normally prevent a C. difficile infection? How does antibiotic use lead to C. diff infection?

CAGE AUDIT-C

How do we screen for alcoholism?

Cease original antimicrobial therapy. Use narrow spectrum antibiotics (*vancomycin* / metronidazole). If symptoms abate, but then there is relapse (~25% pts), we can do *faecal matter transplant* (FMT).

How do we treat a C. diff infection?

*C. difficile diarrhoea / colitis* = oral vancomycin / metronidazole. FMT if recurrent. *Enterobacteriaceae* = gentamicin, fluroquinolone, cephalosporin (3rd gen). *Anaerobes* = metronidazole, amoxycillin, carbapenems (C. perfringens = penicillin). *Necrotising enterocolitis* = broad-spectrum (e.g., imipenem). Reduce its likelihood with breastmilk and probiotics. *Dysbiosis* = potentially probiotics and FMT.

How do we treat infections caused by the GI microbiome? • C. difficile • Enterobacteriaceae • Anaerobes • Necrotising enterocolitis • Dysbiosis

- Vertical line = null valve. - Size of square = weighting of study. - Location of square = estimated valve of measure of association. - Horizontal line = confidence interval of study.

How do you read a meta-analysis?

(1) Attachment - envelope receptor (gp120) binds CD4 + coreceptors (CCR5 or CXCR4) with high affinity. Exposure of gp41 enables fusion to occur. (2) Fusion - of virus to cell. (3) Entry of nucleocapsid. (4) Uncoating - nucelocapsid releases contents into cytoplasm. (5) Reverse Transcription - RNA to DNA via reverse transcriptase. (6) Formation of pre-integration complex (PIC) (7) PIC imported into cell nucleus. (8) Integration of viral genome into host cell via integrate enzyme (9) Transcription via RNA Pol II. (10) Nuclear export of RNA. (11) Translation and generation of HIV proteins. (12) Assembly of HIV. (13) Budding of virus from cell membrane. (14) Release of virus from cell. (15) Maturation - protease is activated during budding. It cleaves Gag and Gag-Pol into their respective proteins.

How does HIV infect a cell? (STEPS)

Acts on vascular SM to increase guanylate cyclase activity, forming cGMP. This activates cGMP-dependent protein kinases to promote SM relaxation. cGMP is then terminated by PDE5.

How does NO cause vasodilation?

*Chest pain* is presenting symptom. Resembles heart pain (but no cardiac abnormalities). Presentation: oppressive / squeezing pain behind sternum. May radiate to neck, left arm. Precipitated by food intake. Reflux.

How does Non-Cardiac Chest Pain (NCCP) mimic cardiac symptoms?

Post-zygotic loss of an X-chromosome (leading to chromosomal mosaicism).

How does Turner Syndrome occur?

*Palpitations* or racing heart are the usual presenting symptoms.

How does a panic attack / panic disorder mimic cardiac symptoms?

Protein enzyme that enables the conversion of fibrinogen to fibrin. Enables immune evasion / clumping. Coagulase producing bacteria surround themselves with a fibrin coat, which protects them against phagocytosis.

How does coagulase function as a virulence factor?

Most drugs are hydrophobic (to allow travel through membranes). Metabolism converts these to water soluble metabolites, allowing drugs to travel through bloodstream (thus, aiding excretion). The metabolic products can have different activities & toxicities to original drug.

How does drug metabolism determine excretion pharmacokinetics for hydrophobic drugs?

Due to plasmids, transposons and integrons. Selection by one class of antibiotics can induce resistance to other classes (cross-selection). There is cross-selection pressure for all of these resistance genes when an antibiotic is used.

How does multi-drug resistance develop?

Histone proteins have positively charged amino acid tails. These interact with the negative phosphate group of DNA, thus allowing dense packing of the chromatin fibres.

How does nucleosome formation occur biochemically?

Semen / mucosal surfaces. Does not transmit easily. STIs ↑ chance of HIV transmission. The virus infects sub-mucosal CD4+ T cells, macrophages and DCs → amplification of infected cells → transport of HIV to lymphoid tissues via CD4+ T cells and DCs. Transmission may also occur across virological synapses (occurs hidden from immune sys).

How does sexual transmission of the HIV virus occur?

Humans mostly consume carbs as good source, but we only have a limited no. of enzymes (8 genes) for carb digestion. Our microbiome secretes a large number of enzymes which aid digestion (via *glycoside hydrolases*).

How does the gut microbiome aid digestion?

(1) *MUCOUS* In the gut, mucous separates bacteria from host tissue, and bacteria don't cross due to the presence of antimicrobial peptides (AMP). The presence of commensal bacteria continually promote production of this mucous and AMP, which serve as a beneficial barrier against pathogens. (2) *IMMUNE SYSTEM* Antigen sampling in the gut (due to presence of commensal organisms) drives IgA production, keeping the immune system primed. (3) *PREVENT AUTOIM.* Commensals & their metabolites prevent an overactive immune system by driving the production of regulatory T cells. Hence, effector T cells will be more tolerant, and respond ~only to pathogens (rather than commensals) → avoids an autoimmune response. (4) *SURVIVAL COMPETITION* Pathogens and commensals must compete for nutrients, making it harder for pathogens to survive and invade.

How does the presence of commensal organisms protect humans, in an immune context?

Labyrinth in ear → contains *vestibule* (important for balance). Signals from here are transmitted to vestibular nuclei in pons. This contains H1 and M receptors. When stimulated, these signals are transmitted to CTZ → stimulates VC. The *CTZ* is in floor of 4th ventricle. It has poorly developed BBB, so is exposed to blood toxins, drugs, etc. and consequently triggered. It contains D2 and 5HT receptors (and is also responsive to substance P and histamine). When stimulated, the CTZ produces ACh to stimulate M receptors of VC, therefore inducing emetic reflex. Within the medulla oblongata, there is the *vomiting centre*. It contains M receptors → trigger emetic reflex.

How does vomiting occur?

Double proteolytic cleavage by thrombin to Factor VIIIa.

How is FVIII activated?

Orally

How is HIV testing consented for?

Released Hb (from dying RBCs) is split into globin and haem components The iron is removed from the haem and the remaining structure is broken down to bilirubin.

How is bilirubin produced?

Inversely Cl = Dose / AUC

How is drug clearance related to the AUC?

Evidence of cellular immune response to M. tuberculosis antigens is indicative of TB. This is achieved via *TST (tuberculin skin tests)* and *IGRA (interferon gamma release assay)*. Note that neither of these tests can distinguish between latent TB (LTBI) and active disease [rely on clinical signs & symptoms for distinction]. Only test pts who would benefit from treatment (examples → recent infxn, decreased capacity to contain latent infxn). Treatment is: · Isoniazid for 9 months · Rifampicin for 4 months · Isoniazid + Rifapentine for 3 months

How is latent TB tested for? Outline treatment against latent TB.

Bacteria is recognised by the immune system (via PAMPs or adhered complement protein). However, the bacteria may have capsules which mask the antibody and complement binding sites, leading to inhibition of opsonisation. So, *anti-capsular antibody* is required for efficient opsonisation and phagocytosis (IgG) and complement deposition (IgM and IgG).

How is opsonisation of capsulated bacteria achieved?

Viscous mucous layer (comprises glycosylated polypeptides (mucin), water, HCO3-). Functions to neutralise acid and maintain inner mucous layer at pH 7.

How is the gut protected from acids?

Heel-prick test → blood onto blood spot (Guthrie) card. Screens for CF based on IRT (immunoreactive trypsin).

How is the screening test done?

Intracellular conc. of most enzymes higher than blood conc. So, changes in their plasma conc. could indicate cellular damage, as well as provide info as to which cells are likely to be leaking the isoenzyme.

How is the tissue specificity of isoenzymes useful in clinical medicine?

~100 human cytochrome P450 genes. Only a small # of these contribute to drug metabolism (specifically CYP1, CYP2, CYP3 families).

How many CYP genes are there?

Only once copy on a single Chromosome 11.

How many copies are there of the beta-thalassemia gene?

8 (two of each type)

How many histones are in a nucleosome?

12%

How many kiwis smoke daily?

3-6

How many mutations are sufficient to cause cancer?

Don't acknowledge reality of pt's condition. Don't consider impact of treatment on pt. Uncertainties around diagnosis / prognosis. Poor communication with pt. Fear of complaints.

How might doctors fail to correctly judge whether or not to continue providing a curative treatment?

Overtreatment Undertreatment Failure to communicate Insensitivity

How might medicine negatively affected the quality of a person's death?

(1) Genetic Level Variation: coding regions of genes vary. (2) Non-Coding Variation

Human Genetic Variation occurs at which two different levels?

Gut + other sites are colonised by a complex community of microbiomes. Aids maturation of human immune system.

Human Microbiome

Soluble molecules in blood and tissue fluids which have roles in activating complements as well as opsonisation and phagocytosis processes. Includes: antibodies, collectins, pentraxins.

Humoral Immunity

A hypothesis that suggests the environments of Western children are unnaturally clean, dramatically decreasing their exposure to routine microorganisms. This limited exposure to pathogens may lower immune tolerance and the ability to cope with harmless antigens.

Hygiene Hypothesis

Early childhood exposure to particular microorganisms protects against allergic diseases by contributing to the development of the immune system. Lack of exposure is thought to lead to defects in establishment of immune tolerance.

Hygiene Hypothesis

*Disorder of B cells* There is normal B cell development, with high IgM and no other antibody isotypes. This is because class-switching is inhibited (either a gene required for B cell activation is mutated, or class-switching machinery is defective).

Hyper IgM syndrome

increase in number of cells Can be physiological, compensatory or pathological.

Hyperplasia

See MCQs at end of Lecture 10 (I & I)

Hypersensitivity MCQs (I & I)

Increase in cell size. Examples: Physiological: pregnancy. Pathological: cardiac hypertrophy. Stimulus is hormonal or increased functional demand.

Hypertrophy

Activate the latent reservoir to make these cells visible to the immune system. We need to purge the latent reservoir = cure.

Hypothetically, how could HIV be cured?

Lecture 1

I & I

Q6 Q7 Q8 (Vertical Answers #2)

I & I: Lecture 8 Page 71-72

Converts hydrogen peroxide to oxygen and water, so is a virulence factor. Increased resistance to phagocytic intracellular killing.

Identifying Yeast Infections: Catalase Test

Useful for presumptive identity (most likely organism). It involves substrates linked to dyes. If the organism uses that substrate, it produces a colony with a particular colour.

Identifying Yeast Infections: Chromogenic agar

Attempts to convert yeast into mould via hyphae formation ('germ tubes' → round oval structure is yeast, with germ tube extending from it). · *Straight and lateral hyphae* = candida albicans · Thick and constricted at end = not candida albicans

Identifying Yeast Infections: Confirmatory test for Candida albicans

They will appear purple (since lack peptidoglycan), and exhibit budding. This is suggestive of yeast cells. They also look ~larger than bacteria.

Identifying Yeast Infections: Gram stain

750 / 0.8 = 937.5 ug

If LD = 750 ug for an IV dose, and F = 80%, calculate the oral loading dose.

Each existing infection causes less than one new infection. In this case, the disease will decline and eventually die out.

If R0 < 1...

Each existing infection causes >1 new infection. The disease will be transmitted between people, and there will be exponential spread, leading to an *epidemic*.

If R0 > 1...

Each existing infection causes one new infection. The disease will remain stable (as an *endemic*).

If R0=1...

The treatment is likely to have a successful outcome.

If a 1/8 (or greater) dilution of the patient's serum is capable of killing the infecting organism, then...

LTRAs = Leukotriene Receptor Antagonists. Either used in adjunct or as alternative to ICS. Example: Montelukast MoA: Blocks the effect of lipooxygenase products (inhibits the action of leukotrienes). Side Effects: Neuropsychiatric risks including suicidality and nightmares.

If a person exhibits intolerance / inadequate response to ICS, what drug should be used? Provide example, mechanism and side effects.

"Contra proferentem" = where a promise, agreement or term is ambiguous, the preferred meaning should be the one that works against the interests of the party who provided the wording. Hence, the Māori version of the Treaty will be deemed the legitimate version.

If there are different versions of a Treaty, which one is considered valid under international Treaty law?

Wells are coated with antigen. Add patient serum. Add chaotropic agent (e.g., urea). • Low affinity antibodies are washed away. • Higher affinity antibodies tend to remain bound. THUS, high affinity is evident when a higher proportion of an antibody remain bound.

IgG Avidity Test

(1) Infectious agent (2) Immune response against the infectious state (i.e. antibodies or T cell response).

Immunodiagnostics enable us to detect the...

Direct: detection of antigen. Indirect: detection of antibody.

Immunofluorescence: Direct vs. Indirect

*Risk Group*: All ages. *Location*: Epidermis (exotoxin breaks desmosomal connections, forming fluid-filled vesicles). *Organism*: S. pyogenes / S. aureus. *Treatment*: Hygiene & topical antiseptic.

Impetigo (bollous) → Risk Group → Location → Organism → Treatment

*Risk Group*: Children. *Location*: Epidermis; around mouth. *Organism*: S. pyogenes / S. aureus. *Treatment*: Hygiene & topical antiseptic.

Impetigo (non-bollous) → Risk Group → Location → Organism → Treatment

Sick person enters population → most people immunised, so small chance of infecting others → smaller R-naught.

Importance of Immunisation

Liver Skin Pancreas Heart Joints Testes

In HFE-HH, excessive storage of iron occurs in which organs?

(1) A larger sample size (2) Less chance of bias (3) More significant findings

In a meta-analysis, greater weight is given to studies with...

IL-4

In hypersensitivity Type I, which interleukin (released by TH2 cells) stimulates the class-switching of B cells?

pharyngitis

In individuals at risk, treatment of WHAT will prevent the development of RF?

Check for carrier status using karyotype. Check for imbalance with chromosomal microarray. Check family history and investigate recurrent miscarriages.

In order to spot balanced reciprocal chromosomal translocations, it is important to...

Formation of granulation tissue

In tissue repair, when is the beginning of actual repair?

· Clinical possibility of HIV (signs / symptoms). · During a STI / sexual health check-up. · Sexual assault / Rape · HCWs → needlestick injury. · Risk of HIV (IDUs, Sexual practices, etc.) · All pregnant woman (opt-out). · Blood donations · Immigration

In what situations should HIV testing be offered?

*Mana*: power, prestige, leadership, or authority. - It is bestowed, gained, or inherited individually or collectively. - It infers that each individual has the right to determine their own destiny upon their own authority. - Mana is an influencing factor in leadership and interpersonal and inter-group relationships, including those entailed in research. Shared knowledge upholds the mana of research participants. - Mana relates to equity and distributive justice, and to power and authority.

In what ways can Mana be applied? [Te Ara Tika]

*Manaakitanga*: cultural & social responsibility; respect for others. - Nurturing relationships. - Hospitality - Being careful of how we treat others. - Upholding the Mana of others.

In what ways can Manaakitanga be applied? [Te Ara Tika]

Consider components of R-naught, and establish interventions: • Alter infectivity = vaccinate. • Alter pattern of mixing = isolate sick individuals to decrease rate of contact per time.

In what ways can R-naught be used as a framework when thinking about disease control?

*Tika*: what is right and good in any ethical situation. - Design of study should benefit Māori community. - Requires respectful relationships with Māori in all studies. - Should engage with communities.

In what ways can Tika be applied? [Te Ara Tika]

*Whakapapa*: genealogy. - Relationships and the layers within / quality of these relationships. - How you engage and relate to Māori. - Involves trust, respect, integrity. - It is about the collective (not the individual).

In what ways can Whakapapa be applied? [Te Ara Tika]

joint prostheses

Increasing association with septic arthritis and...

Regulate gene activity or contribute to the regulation of gene activity by recruiting other proteins which either activate / inactive transcription of genes.

Indirect effects of histone modifications

Tissue death due to inadequate blood supply (to the affected area).

Infarction

See worksheet / note sheet at start of lecture + self-assessment questions. ***ASSESSMENT QUESTIONS***

Infection & Immunity: Lecture 10, Allergy & Hypersensitivity (VERTICAL ANS #3)

Virus which has a haemagglutinin receptor (also present on epithelial cells). When virus binds, it is taken up by the cell, initiating infection.

Influenza A

Segmented ssRNA genome (non-linear, non-circular). Enables evolution in host. Hemagglutinin (HA → promotes viral entry) and neuraminidase (NA) antigens. H1,2,3,5,7,9 cause infection in humans. New strains emerge regularly.

Influenza A Virus

the process of flowing in

Influx

(1) Consumer is to participate in research. (2) Procedure is experimental. (3) Consumer will be under general anaesthetic. (4) Significant risk of adverse effects on the consumer.

Informed consent must be in writing in what situations?

Carrier mother / father → 50% affected offspring. Affected individuals normal found in each generation. Both genders equally affected.

Inheritance Patterns Of: Autosomal Dominant Alleles

Carrier parents: 25% affected, 50% carrier, 25% unaffected. One carrier parent: 50% unaffected, 50% carrier. Often skips generations. Transmission of allele follows Mendelian patterns of inheritance. More common is relative have children.

Inheritance Patterns Of: Autosomal Recessive Alleles

Only mother's mitochondrial DNA is passed onto children, since the region of the sperm containing the mitochondria does not penetrate the egg. Hence, mitochondrial DNA is *maternally inherited*. All of the affected female's children will be affected, but her sons cannot pass it on to their children.

Inheritance Patterns Of: Mitochondrial Diseases

Dominant or Recessive. Child's status depends on whether mother or father is affected.

Inheritance Patterns Of: X-Linked Alleles

100% affected sons. No daughters affected.

Inheritance Patterns Of: Y-Linked Alleles

Recessive mutations (often on X chromosome)

Inheritance of Primary Immune Deficiencies

lipoproteins

Insoluble fats are carried in...

Prevent integration of HIV cDNA into host genome.

Integrase Inhibitors (MoA)

· Determine if +, - or other · There is strong and weak staining · HER2 is evaluated by immunohistochemistry as 1+, 2+ or 3+. · If 2+ / equivocal, we need to do FISH (Fluorescence in situ Hybridisation) to determine whether gene amplification has occurred. The level of gene of interest is compared to a control probe to get relative amount. · Oncotype Dx is precision medicine (via PCR) that can determine risk of recurrence based on gene expression → to determine need for chemotherapy. · There are also molecular sequencing tests to identify treatment targets.

Interpreting Pathology Reports: Breast Cancer

Atypical causes

Interstitial pneumonias generally caused by...

RCTs

Intervention Study(s)

Need to restore ecosystem. In neonates (at risk of NEC), this requires breastmilk and probiotics. For C. difficile infections, we use FMT (faecal matter transplant).

Interventions for Dysbiosis

Chromosomally encoded resistance. Ex: Gram(-) and vancomycin; AmpC beta-lactamase.

Intrinsic Resistance

Non-immune, and include: - Physical barriers - Secretions - Physical removal (e.g. cilia) - Microbiome - pH

Intrinsic defences

CXR Sputum cytology Bronchoscopy Fine needle aspiration Advanced imaging techniques (CT, MRI, PET) Tissue sample is received, then examined to identify malignancy, then immunohistochemistry is used to look for markers. DNA mutations are assess to provide prognosis and guide therapy.

Investigations to Determine if Cancer is Present

Pore-forming membrane proteins that specifically allow water molecules to pass through the membrane. Either ligand-gated or voltage-gated.

Ion Channel

Ligand-gated ion channels

Ionotropic receptors are also known as...

Drug binds *covalently* to the receptor's active site. Not surmountable. Reduces the no. of receptors available to the natural agonist.

Irreversible Competitive Antagonism

Dysregulated interaction between ANS and ENS. This interaction is influenced by genetics, environment, psychosocial factors (e.g., stress, personality traits). Alters the physiological of the gut: → Dysmotility → Immunological changes → Changes in gut membrane permeability → Altered microflora → Central sensitisation Diminished QoL and functioning.

Irritable Bowel Syndrome: Aetiology

IBS is an example of a FGID (functional GI disorder). It is characterised by disordered interaction between the brain (ANS) and gut (ENS).

Irritable Bowel Syndrome: Definition

*Rome IV* Criteria A. Recurrent abdominal pain, on average, for ≥1 day / week in the last 3 months. The pain is also associated with 2+ of the following: (1) Abdominal pain with defaecation (2) Change in frequency of stool (3) Change in form (appearance) of stool B. Symptom onset occurred >6 months before diagnosis. The Bristol Stool Chart is used to differentiate between the various subtypes of IBS (IBS-C, IBS-D, IBS-M).

Irritable Bowel Syndrome: Diagnosis

· Inflammatory Bowel Disease · Celiac disease · Bowel cancer · Lactose intolerance

Irritable Bowel Syndrome: Differential Diagnosis

Prevalence = 3.2% Risk Groups: • Women • Young people (<50)

Irritable Bowel Syndrome: Prevalence + Risk Groups

Dietary modifications Pharmacotherapy → Antispasmodics → Antidepressants CBT Stress management programmes (e.g. hypnotherapy)

Irritable Bowel Syndrome: Treatment

Yes, if it has occurred via a Robertsonian Translocation.

Is Down Syndrome recurrence possible?

R-naught is NOT a fixed property of the virus. Depends on individual factors and societal factors (e.g., over-crowding).

Is R-naught a property of the virus?

Yes

Is Staph. auerus capsulated?

Yes

Is Strep. pyogenes capsulated?

Yes, being colonised and asymptomatic is normal (even in healthy). BUT, if colonised patient starts antimicrobial therapy, they are at increased risk of infection.

Is it normal to have C. difficile in gut?

No, it continues into bereavement period.

Is palliative care only necessary during the period leading up to death?

*Monoarticular* If polyarticular → consider Staph. aureus & N. gonorrhoea

Is septic arthritis monoarticular or polyarticular?

Often not, due to mosaicism and tissue variability in X-inactivation.

Is the clinical phenotype of Turner Syndrome predictable?

A specialized method of separating proteins by their isoelectric point using electrophoresis; the gel is modified to possess a pH gradient.

IsoElectric Focusing

Potentiates the function of defective chloride channels. Useful for gating mutations; binds to defective protein at cell surface and opens the chloride channel so that the Cl- can flow through, thus regulating the amount of water at the surface of the cell.

Ivacaftor (Kalydeco)

45% of human genome

Jumping genes make up what proportion of human genome?

47, XXY (the extra X-chr undergoes X-inactivation). Clinical Signs: Reduced testicular function, Tall stature, IQ Left-shifted (but normal).

Klinefelter Syndrome → Karyotype → Clinical Signs

See Page 53, I & I Lab Book

Know how to calculate MIC & MBC based on dilution.

(long-lasting calcium channels) Present in cardiac muscle and vascular smooth muscle. Enable large, sustained conductance. Inactivate slowly and are responsible for the plateau phase (slow inward current) of the AP.

L-Type Calcium Channels → Location → Function

Delivery of fats for consumption and use by the body.

LDL (Function)

Example: *Enoxaparin* MoA: Potentiate the action of AT III on Factor Xa and similar factors, but less effect on thrombin. *Safer than UFH* Administration: Subcutaneous. Half-Life: 4-6hrs, longer than UFH. Bioavailability: Greater than UFH. Side Effects: Less than UFH. But, can still promote haemorrhage. Indications: Prevention / treatment of DVT; Coronary syndromes (e.g. MI). Interactions: Protamine acts as an antagonist, neutralising heparin (formation of an inactive complex). Elimination: Affected by renal impairment.

LMWH (Low Molecular Weight Heparin) → Example → MoA → Administration → Half-Life → Bioavailability → Side Effects → Indications → Interactions → Elimination

Increased neutrophils New neutrophils (metamyelocytes) Raised ESR Raised CRP

Lab findings in acute inflammation

Cells that continuously divide and regenerate. EXAMPLE: squamous skin epithelium

Labile cells

PAGE 74, Vertical Answers #3 (See Table)

Latent TB infection vs. TB disease

SEE WORKSHEET + *exam questions* at end. Lecture 19, I & I (Questions on Pg 36, Vertical #4)

Lecture 19 Questions (I & I)

Immature white and red cells. Indicates *severe bone marrow disease*. Features: myelocytes, tear-drop RBCs, nucleated RBCs.

Leukoerythroblastic blood film - what does it exhibit and what does it indicate?

*Example:* Montelukast *Indications:* Adjunct / alternative to ICS in patients with intolerance. NOT appropriate for acute asthma exacerbations. *MoA:* Blocks the effect of lipoxygenase products. In other words, it inhibits the action of leukotrienes [it is a CysLT1 receptor antagonist]. *Effect*: Blocks bronchoconstrictor response to allergen as well as exercise induced bronchoconstriction. *Side Effects*: Neuropsychiatric risks (suicidality, nightmares, behavioural problems).

Leukotriene Receptor Antagonists (LTRAs) → Example → Indications → MoA → Side Effects

(1) *Lifestyle Choices* → education opportunities, diet, physical exercise, etc. Income inequity. (2) *Social Determinants of Health* → income, education, quality of housing, etc. Māori have been deprived of access to land and resources; in NZ, land = wealth. (3) *Access to Health Services* → There is pakeha privilege. (4) *Differentiation Treatment by Health Professionals* → Personally mediated racism (between people). (5) *Structure of Our Health System* → Institutional racism and political power. + *COLONISATION*: Appropriation of Māori land occurred and continues to occur through the following mechanisms: purchase, confiscation, land courts, Government policy.

Life Expectancy: When we talk about health inequities between Māori and non-Māori New Zealanders, what are some of the explanations that we draw upon to make sense of these inequities?

There is no T-cell help (hence, poor memory formation). Only IgM...

Limitation of polysaccharide vaccine

• Only study one outcome. • Control selection is difficult. • Susceptible to recall bias & selection bias.

Limitations of Case-Control Studies

· Loss to follow up · Misclassification · Not good for studying rare outcomes · Time consuming · Costly

Limitations of Cohort Studies

Multiple infusions. Immune responses to exogenous protein (inhibitor issues). Costs. Contaminants in concentrates.

Limitations of Protein Therapy [Haemophilia]

- Difficult to identify genes that could alter drug response. - Need to determine interaction between enviro/lifestyle with genetics. - Need detailed knowledge of individual's genome + epigenetics.

Limitations of precision medicine

Transformation of necrotic tissue into a liquid viscous mass. If triggered by infection, liquid will contain neutrophils (pus). Abscess keeps the pus contained. In CNS, leaves a cavity due to no healing by scar formation.

Liquefactive necrosis

(1) Alofa (Love) (2) Respect (3) Relationship (4) Reciprocity (physical gifting; gifting of knowledge) There are also the associated values of mamalu (honour), tautua (service), fa'aaloalo (respect), and usita'i (discipline).

List the Pasifika ethical principles.

Taha Hinengaro Taha Tinana Taha Wairua Taha Whānau

List the four dimensions of Te Whare Tapa Wha.

(1) Inhibit ACh release pre-synaptically. (2) Inhibiting ACh esterase. (3) Blocking the action of ACh post-synaptically (NDB or DB).

List the ways in which a neuromuscular block can be achieved.

comparatively large dose given at the beginning of treatment to rapidly obtain the therapeutic effect of a drug LD = Vd * Target Cp

Loading dose

Typical causes = Strep. pneumoniae

Lobar pneumonias generally caused by...

Liver Intestine ~Lung ~Nasal mucosa

Locations of Drug Metabolism

Euchromatin (10nm)

Loosely packed chromatin is called... (+ diameter size)

Recessive

Loss of function disorders, such as thalassemia, are often RECESSIVE or DOMINANT?

*Antiplatelet* Amount: 75-150mg / day. Type of Drug: NSAID. Absorption: Small intestine. Metabolism: First pass metabolism. MoA: Irreversible inhibition of COX-1 → reduces TXA2 → inhibits platelet aggregation, and vasoconstriction. The platelet remains inactivated as it does not have a nucleus (for lifespan, 7-9 days). *Reduces risk of thrombus formation*. Risk: Haemorrhage.

Low Dose Aspirin (ASA) → Amount → Type of Drug → Absorption → Metabolism → MoA → Risks

Less likely to overcome host defences. Requires a susceptible host. These are *opportunistic pathogens*.

Low virulence pathogens

It is a corrector (Lumacaftor) + potentiator (Ivacaftor) combination therapy. Works for F508 del mutation. Lumacaftor is a corrector, meaning that it helps the CFTR protein form the right shape and traffics it to the cell surface and helps it to remain there longer. Ivacaftor improves its function by holding the gate open (on the CFTR protein) for longer → more chloride can flow through → reduced symptoms of CF.

Lumacaftor-Ivacaftor combination (Orkambi)

Solidification of lung tissue due to presence of fluid.

Lung Consolidation

increase in lymphocytes

Lymphocytosis

(1) Precursor lymphoid neoplasms (2) Mature lymphoid neoplasms But is this examinable??

Lymphoid cancers

lymphocytes

Lymphoid cells are also called...

the viral material is embedded into the host DNA, now becoming a prophage → this remains dormant until it enters the lytic cycle.

Lysogenic Cycle

injection of viral material into a host cell → virus used cellular machinery to replicate → cell lyses → infection of other cells.

Lytic Cycle

Streptococcus pyogenes

M-protein is associated with what bacteria?

Minimum Bactericidal Concentration

MBC

The wells showing no growth in the MIC test are then sub-cultured onto an agar plate and incubated. Wells yielding colonies on the agar plate indicate the bacteria were prevented from replicating but not killed at that particular concentration of antimicrobial.

MBC (Method)

Minimum effective concentration Concentration of drug required to produce a therapeutic effect.

MEC (Clinical Pharmacology)

Minimum Inhibitory Concentration

MIC

Minimum toxic concentration Concentration of drug that produces dose-related toxic effects.

MTC (Clinical Pharmacology)

Motor Vehicle Traffic Crash

MVTC

N & V Others: • Rash • Arthralgia • Polyarthritis • Necrotising vaculitis • Glomerulonephritis [see table pg 12, Vertical #4]

Main Symptoms of Viral Hepatitis

*Treatment /prevention of pulmonary complications* → oral, inhaled or IV antibiotics; bronchodilators; anti-inflammatory agents; mucolytic agents; chest physiotherapy; transplantation; etc. *Prevention of secondary complications* → Airway clearance with CPT (chest physiotherapy) + ACTs (airway clearance techniques); antibiotics; immunisations. *Surveillance*: Visits to CF care providers to monitor for subtle changes in physical examination, PFTs, chest radiographs, blood & urine tests.

Management of CF

Type of Drug: Osmotic diuretic Mechanism of Action: Freely filtered by glomerulus. Not reabsorbed in proximal tubules, hence water is retained in the region of the proximal tubule. This prevents the normal absorption of water back into blood, due to the presence of a countervailing osmotic force. As a result, urine volume increases. Only use in *acute emergencies* (as there are long-term consequences).

Mannitol → Type of Drug → Mechanism of Action → When is it used?

Relative risk. Risk difference. Odds ratio. REVIEW POPH192.

Measures of Association

Incidence proportion. Incidence rate. Point prevalence. REVIEW POPH192.

Measures of Occurrence

Modulate TNF-alpha. TNF receptors are located in cell membrane. The TNF-alpha component of these receptors is extracellular. When it is cleaved from the receptor, it becomes soluble within ECF. The TNF-alpha inhibitors mop up this TNF-alpha in the circulation, or directly inhibit it at the receptor site. Example: Salirumab, Infliximab.

Mechanism of Action: Biological DMARDs [Rheumatoid Arthritis]

(1) Inhibit movement of inflammatory cells such as macrophages and neutrophils (hence, they are immunosuppressant drugs). (2) Act on steroid receptors in cellular cytoplasm --> alter transcription of various proteins --> block Phospholipase A2. This enzyme is required for break down of phospholipids to arachidonic acid, so inhibition of this pathway means that inflammatory prostaglandins (PGE2) are not produced. Used as a bridging therapy.

Mechanism of Action: Corticosteroids [Rheumatoid Arthritis]

Inhibits calcineurin (an enzyme which activates T-cells), thus decreasing T-cell proliferation. ↓IL-2 cytokines. = Reduce immune function.

Mechanism of Action: Cyclophosphamide (Synthetic DMARD, Xenobiotic) [Rheumatoid Arthritis]

*Folic acid antagonist* Inhibits purine synthesis (nucleotides required for nucleic acid synthesis), thus slowing DNA synthesis. This slows cell proliferation and therefore also pannus formation and bone erosion. Also, DNA replication does not occur smoothly due to increased occurrence of errors --> once the affected cell reaches a meiotic checkpoint, the DNA errors are recognised, and apoptosis is triggered --> the cell dies --> decrease in immune cell population and therefore immune function. Disease modifying.

Mechanism of Action: Methotrexate (Synthetic DMARD, Xenobiotic) [Rheumatoid Arthritis]

Reversibly inhibit prostaglandin synthesis by *inhibiting COX*. Inhibit both COX-1 and COX-2. Through inhibition of COX-2, NSAIDs are able to achieve their intended effect (reduced inflammatory response). Do NOT alter disease progression.

Mechanism of Action: NSAIDs [Rheumatoid Arthritis]

Remain bound to the Class A beta-lactamase, inhibiting its action. Ex: clavulanic acid. Fails to inhibit AmpC beta-lactamases (Class C) produced by ESCAPPM organisms (which are initially susceptible but then become resistant due to increased beta-lactamase production).

Mechanism of Beta-Lactamase Inhibitors + example

Intracellular binding of inducer to nuclear receptor → heterodimer forms → acts as transcription factor → upregulates gene → increases CYP3A levels.

Mechanism of CYP3A Induction

(1) Lectin pathway (2) Classical pathway (3) Alternative pathway

Mechanisms of Complement Activation

Deposition of C3b on pathogen surface is following by binding of Factor B. Further cleavage then leads to the formation of *alternative pathway C3 convertase*. These deposit large numbers of more C3b fragments on pathogen surfaces. C3b is recognised by complement receptors on phagocytes, leading to phagocytosis.

Mechanisms of Complement Activation: Alternative Pathway

C1 binds to IgM or IgG (the region to which it binds is only exposed when the antibody is antigen-bound). Enzymatic reaction triggered → initiates complement cascade.

Mechanisms of Complement Activation: Classical Pathway

Col*lectins* circulate in blood and binds to microbial glycan (sugar) residues on the pathogen surface → activation of complement and opsonins.

Mechanisms of Complement Activation: Lectin Pathway

Conjugation (bacterial sex → bacteria have plasmid on DNA that can encode sex pili that enables plasmid transfer). Transformation. Transduction. Mutation. Transposons (jumping genes) → carry an integral containing accumulated resistance genes.

Mechanisms of Horizontal Gene Transfer

NORMAL: The APs cannot reenter either branch because the branches are in a refractory state. ABNORMAL: Unidirectional block in branch B this will block excitation in the forward direction. But propagation of excitation is not blocked in branch A. The excitation entering through A then progresses along the myocardium, and it can now enter the branch B in a retrograde direction. Branch B is no longer in a refractory state because it was never excited. The wave of excitation can then propagate backwards through B because the block is only unidirectional. If it reaches the fork between A & B at a time when A is no long refractory, then branch A can be excited again and the loop can be repeated over and over and over.

Mechanisms of a Re-entrant Circuit

In cystic fibrosis, meconium plug obstructs intestine preventing stool passage at birth. Occurs in 15-20% of newborns with CF.

Meconium ileus

Inflammation of the meninges and CSF.

Meningitis

Rare malignant tumour arising in the pleura and associated with asbestos exposure. Has a biphasic cellular pattern.

Mesothelioma

A technique where the results from a number of different studies are combined into a single estimate of the measure of association. *Weighted-average* Displays info as a *forest-plot*.

Meta-analysis

centromere in middle

Metacentric

Mature cell type is replaced by a different mature cell type. REVERSIBLE. Reprogramming of stem cells to produce 'tougher' cells. Example: epithelial metaplasia in cigarette smokers (pseudostratified ciliated columnar epithelium → squamous epithelium).

Metaplasia

Non-Viral (DNA / RNA) Viral (vectors) Expression regulated for cell type → constitutive or inducible expression.

Methods for Gene Therapy

*Immunoassays* - Detect HIV antibody & p24. *Rapid tests*

Methods for HIV Diagnosis

Sexual transmission Drug injection Exposure of blood products Vertical transmission (mother to child)

Methods of HIV Transmission

Cut-and-paste mechanism Copy-and-paste mechanism

Methods of Transposition

Agglutination Immunofluorescence Neutralisation Enzyme immunoassay

Methods used to measure antigen and antibody

Microparticles are coated with antigen, and (if present) cross linked by antibodies. This results in clumps / aggregations. Alternatively, microparticles are coated with antibody (IgG) for antigen detection.

Methods used to measure antigen and antibody: Agglutination

A single antibody is directed against target of interest. The primary antibody is conjugated to a fluorochrome.

Methods used to measure antigen and antibody: Direct immunofluorescence

Detects antibody or antigen. Performed on plate or micro breads. (1) Antibody Detection: Add patient serum. If antibody is present, it will bind to antigen. Wash away excess and aadd secondary antibody (anti-human IgG → has enzyme that catalyses colour change). Wash away excess. Substrate of enzyme is added, and if there is a colour change = POSITIVE result for antibody. (2) Antigen Detection: Serum added to the antibody-coated well. Then there is addition of an enzyme conjugated antigen-specific antibody, followed by the addition of enzyme substrate.

Methods used to measure antigen and antibody: Enzyme Immunoassay

Uses two antibodies. The primary antibody is unconjugated, and a fluorochrome-conjugated secondary antibody directed against the primary antibody is used for detection.

Methods used to measure antigen and antibody: Indirect immunofluorescence

Measures the ability of the antibody to bind to the virus and neutralise it (prevent it from infecting a cell).

Methods used to measure antigen and antibody: Neutralisation

Harm-thresholds → I will be fine if I only smoke x-cigarettes. Compensatory behaviours → I exercise too, so smoking will be fine. Genetic immunity → My dad has smoked his whole life, but is fine.

Misconceptions / lies that smokers tell themselves

A point mutation in which a codon that specifies an amino acid is mutated into a codon that specifies a different amino acid.

Missense mutation

overestimation of benefits.

Missing studies / publication bias can lead to an...

(1) Restrict antibiotic from accessing target. (2) Inactivate the antibiotics via enzymes. (3) Modify antibiotic's target via enzymes / mutation.

Molecular Mechanisms of Antibiotic Resistance

[context: penicillin] PBP (penicillin binding protein AKA transpeptidase) cross-links peptide side chains of peptidoglycan to establish structure to cell wall. Beta-lactam inhibit the last step in peptidoglycan synthesis by binding irreversibly to PBP. Resistant cells have beta-lactamases. Class A & C beta-lactamases bind the beta-lactam and inactivate it, then repeat with another. Example: ESBL (extended spectrum beta-lactamase) → Class A and B beta-lactamase.

Molecular Mechanisms of Antibiotic Resistance: Inactivate the antibiotics via enzymes.

*MRSA* → PBP 2' replaces normal PBP. *Vancomycin* → binds to terminal D-alanine -- D-alanine to inhibit cross-linking. Resistance develops when it becomes D-alanine -- D-lactate. The acquisition of a whole operon of genes is necessary for this to occur. Fluoroquinolones show that, which more mutations, there is greater degree of resistance.

Molecular Mechanisms of Antibiotic Resistance: Modify antibiotic's target via enzymes / mutation. [Provide examples]

Either: (i) Decrease permeability to antimicrobial to inhibit its entry. Ex: Gram(-) bacteria have porin in outer membrane. Mutations may decrease expression of these. (ii) Increase antibiotic efflux from cell. Ex: efflux pumps.

Molecular Mechanisms of Antibiotic Resistance: Restrict antibiotic from accessing target.

Once serum ferritin <50ng/mL, routine monitoring of serum ferritin concentration every 3-4 months is required.

Monitoring of HFE-HH Patients

macrophages (phagocytic cells)

Monocytes that migrate from blood to tissue become...

increase in monocytes

Monocytosis

A single gene disorder. a.k.a Medelian disorder.

Monogenetic Disorder

Reversible cell swelling and blebbing Cell accumulations Change in cell type: →Metaplasia →Dysplasia Change in cell size / number: →Hyperplasia →Hypertrophy →Atrophy

Morphological changes of cells when exposed to stress

The top notifiable diseases in NZ are all organisms that cause gastroenteritis (except for COVID-19). · *Most*: Campylobacteriosis (caused by Campylobacteria jejuni) · Yersinia enterocolitica · Giardiasis · STEC / VTEC · Cryptosporidiosis · Salmonella (caused by Salmonella spp.)

Most Notifiable Diseases in NZ

Pseudomonas aeruginosa (P. aeruginosa) Autoinducer produced by this strain affects the host immune system as it leads to pro-inflammatory cytokine production then neutrophil recruitment. It adapts within the host and progresses from a non-mucoid to *mucoid infection* → does so via secretion of alginate (a carb). The non-mucoid infection involves increase in PMN and macrophages → less damaging to lung. The antibodies produced against alginate in a mucoid infection induce a chronic inflammatory response that damages lungs. Autoinducer released by commensal oropharyngeal flora activate virulence genes in P. aeruginosa, including efflux pumps.

Most common cause of CF mortality.

Breast cancer

Most diagnosed cancer for females in NZ?

Breast cancer

Most diagnosed cancer for females?

Prostate cancer

Most diagnosed cancer for males in NZ?

Lung cancer

Most diagnosed cancer for males?

allelic heterogeneity

Most genetic disorders that display locus heterogeneity also display...

Loop diuretics

Most potent diuretics are the:

*endemic* They are constantly maintained at a baseline level. Also, active during winter.

Most viruses are _____ in the global human population.

Example: Tiotropium MoA: Prevents ACh from binding to and activating M receptors, therefore preventing bronchoconstriction. Long half-life (27-45 hours). Once-daily LAMA for maintenance. Dry-powder inhalation or aqueous solution.

Muscarinic Receptor Blockers: LAMA → Example → MoA

Indications: Acute severe asthma MoA: Decreases ACh release on bronchial SM. Also increases adenyl cyclase production of cAMP.

Muscarinic Receptor Blockers: Magnesium Sulphate (LAMA)

Example: Ipatropium Indications: COPD, Emphysema, *Acute* asthma (only). Duration of effect ~3-5 hours. Administration: Inhaled; give *with beta-agonist*. MoA: Prevents ACh from binding to and activating M receptors, therefore preventing bronchoconstriction. Side Effects: Dry mouth, headache, constipation, cardiac effects, urinary retention.

Muscarinic Receptor Blockers: SAMA → Example → Indications → MoA → Side Effects

(1) Acute myeloid leukaemia (2) Myeloproliferative neoplasmas (3) Myelodysplastic syndrome But is this examinable??

Myeloid cancers

derived from bone marrow

Myeloid cells are...

(1) *Tika*: what is right and good in any ethical situation. (2) *Manaakitanga*: cultural & social responsibility; respect for others. (3) *Whakapapa*: genealogy. (4) *Mana*: power, prestige, leadership, or authority.

Māori Ethical Principles [Te Ara Tika]

Ta Ao Māori

Māori Worldview is referred to as...

· Depopulation of rural villages · Disconnection between whanau and their hāpu and iwi · Decrease in te reo Māori spoken · Challenges of urban living · Poverty

Māori urbanisation took place by the 1980s. What were the impacts of this?

Kia kaha

Māori: Be strong / keep going

Ata mārie / Morena

Māori: Good Morning

Pō mārie

Māori: Good night

Kia ora

Māori: Greetings (informal)

Tēnā koutou

Māori: Greetings (to 3+ people)

Tēnā koe

Māori: Greetings (to one person)

Tēnā kōruā

Māori: Greetings (to two people)

Whakarongo

Māori: Listen

Titiro

Māori: Look

Ingoa

Māori: Name

Kāore

Māori: No

Hongi

Māori: Pressing noses (greeting)

Aroha mai

Māori: Sorry

Huri

Māori: Turn / Rotate

Āe

Māori: Yes

A functional gene product is produced (right amount, right time, in correct cell type).

NORMAL Gene Expression

Probability that a person with a negative test actually does NOT have the disease. d/(c+d)

NPV

Fibrates

Name a drug which interferes with statin uptake into the liver?

ERBB2

Name the oncogene that causes breast and ovarian cancer.

Occurs in pre-term, low birth weight neonates (due to their immature immune system, poor gut blood supply, and "un-ideal" initial colonisers). Have not undergone normal colonisation of gut (which would normally build the immune system / barriers). This is due to disruptions in their early life such as C-section and exposure to hospital bacteria. They become colonised with opportunistic pathogens, and the absence of commensal community means there are no inhibitors to prevent proliferation of pathogens. Neonates can thus develop necrotising enterocolitis → tissue necrosis occurs.

Necrotising Enterocolitis → What is it? → Who is affected? [opportunistic organisms of gut]

Initial wound may appear trivial, but patient will be in extreme pain. Rapid spreading, destructive infection along fascia. High mortaility! *Organism*: Strep. pyogenes or Staph. aureus. *Treatment*: IV antimicrobials (initially empiric) and surgical debridement.

Necrotising fasciitis → What is it? → Organism → Treatment

Antibodies that inhibit the infectivity of a virus or the toxicity of a toxin.

Neutralising antibodies

Describes the shift to immaturity of neutrophils. Immature neutrophils are released from the bone marrow; typically due to infection.

Neutrophil Left-Shift

Left-shirt Toxic granulation Vacuolation

Neutrophilic responses to severe infection

*MOA*: Cholinergic agonist. Induces dopamine release in VTA. *Effects*: Increased alertness; systemic muscle relaxation. *Tolerance*: Can develop from prolonged use. *Dependence*: significant - hence, low rate of quiting. *Withdrawal*: irritability, impatient, anxious, restless, weight gain. *Therapy*: nicotine replacement. anti-craving (bupropion), nicotine partial agonists.

Nicotine [stimulant] → MOA → Effects → Tolerance → Dependence → Withdrawal → Therapy options

Nicotine delivery by nicotine patch never reaches the sharp peak delivered by cigarettes.

Nicotine delivery: Patch vs Cigarette

complete specificity.

No drug acts with...

Mostly chronic, non-infectious diseases. Examples: CVDs, Cancers, Diabetes.

Non-Communicable Diseases

These drugs competitively block the ACh nicotinic receptors (on the post-synaptic membrane). 70-80% of receptors must be blocked for transmission to fail. Can be overcome with ACh esterase inhibitors.

Non-Depolarising Block

There is cell-free placental DNA in maternal blood (which can be sampled via venipuncture). This allows us to determine foetal sex as well as other things!

Non-Invasive Prenatal Screening

the failure of homologous chromosomes to separate in Anaphase 1 or the failure of sister chromatids to seperate at Meiosis II. Gives rise to nullisomic or disomic gametes.

Non-disjunction

Premature stop codon.

Nonsense mutation

α2β2

Normal Hb

IHD Hormones Drugs Anatomical anomaly Resulting in arrhythmia and decreased cardiac efficiency.

Normal cardiac action is conducted in an orderly sequence. What can disrupt this pattern?

Blood lectures not featured in these flashcards!

Note:

Organic Anion Transporters

OAT

Always cause disease.

Obligate Pathogens

Cross-sectional Ecological Cohort Case-control

Observational Study(s)

CD8+ T cells: - Produce IFNy and TNFa → activate macrophages. - Kill infected macrophages. CD4+ T cells: - Th1 cells produce IFNy and TNFa → activate macrophages. - Th17 cells produce IL-17 → activates neutrophils. *IFNy* activates macrophages, leading to enhanced killing. Specifically, there is enhanced fusion of lysosome with phagosome, hence increased delivery of M. tuberculosis to the phagolysosome, increased ROS & RNS, increased antimicrobial peptides. HOWEVER, M. tuberculosis can still remain viable.

Once T cells are primed to Mycobacterium TB, what cytokines are released in response?

Normal microbiota that cause disease under certain circumstances (e.g. susceptible host).

Opportunistic Pathogens

*Offer of test* to those seeking medical attention for another reason.

Opportunistic Screening

large and medium sized coronary arteries

Organic nitrates may at high concentrations temporarily vasodilate...

o Respiratory tract o Exocrine pancreas → Pancreatic insufficiency leads to malabsorption. o Intestine o Male genital tract → 95% CF males are infertile. o Hepatobiliary system o Exocrine sweat glands

Organs Affected by CF

The site of endogenous ligand binding. (Normal binding site)

Orthosteric site

Thick mucous enables reduced bacterial mobility → higher concentration of bacteria in mucous → increased concentrations of autoinducer → facilitates biofilm formation.

Outline development of biofilms in CF lungs.

(1) Mihi (2) Whakawhānaungatanga (3) Kaupapa (4) Poroporoaki

Outline the Hui Process

Attending to the main purpose of the encounter. o Move onto history taking, examination, etc. o Meihana Model of history taking incorporates aspects of further contemporary and historical factors that may influence health experience (e.g., migration, colonisation, racism, etc.).

Outline the Hui Process: Kaupapa

Initial greeting and engagements. o Clinician clearly introduces themself and their role. o Confirm that patient identifies as Māori.

Outline the Hui Process: Mihi

Concluding the encounter. Only occurs if a relationship has been effectively developed! o Ensure you have understood what patient has said. o Ensure patient understands what you have said. o Ensure patient is clear about the next steps.

Outline the Hui Process: Poroporoaki

Making a connection. o Connect at a personal level with patient and whānau. o It is an extra step to building rapport. o Requires clinicians to draw on their understandings of Te Ao Māori. Connect to patient in terms of whenua, use of te reo, etc. o Some self-disclosure of the student / doctor about their own experience of these aspects.

Outline the Hui Process: Whakawhānaungatanga

CD4+ T cells are harvested (blood sample) and exposed to antigens specific to M. tuberculosis (ESAT-6 antigen → specific to TB). If pt has been exposed to TB, the T cells activate and produce IFN-y. This production can be quantified via ELISA. High levels of IFN-y indicate infection or previous exposure. Sandwich ELISA: antibody captures antigen (IFNy) which is then detected using a secondary antibody linked to biotin tag. An enzyme binds to biotin and cleaves substrate, yielding a colour that can be detected spectrophotometrically. Amount of colour is directly proportional to amount of IFN-y present. Advantage: Antigens are specific, so test is not subject to false positives because of prior BCG vaccination / exposure to non-tuberculous mycobacteria. Disadvantage: cannot distinguish between active or latent TB.

Outline the IGRA used for TB detection.

Measures IFNy production (by M.TB specific T cells) in response to TB antigen. The recombinant antigens are not present in BCR and most non-tuberculous mycobacteria, therefore greater accuracy. This technique is preferable to TST.

Outline the Interferon Gamma Release Assay (IGRA) for TB

See pharmacology document.

Outline the MOA and indications for IBD drugs.

See *Clinical Pharmacology* Drug Table

Outline the MOA for the four different classes of anti-emetics.

[Intradermal tuberculin skin test] Purified mycobacterial antigens (tuberculin) are injected intradermally into forearm. Tuberculin = non-specific antigen (shared by TB and BCG organisms → usually Ag85). Produces a hypersensitivity reaction in those who have current / previous infection. The skin test is read at 48-72 hours. The test is positive if the induration is... >10mm (if history of exposure). >15mm (no known risk factors). Disadvantage: Positive test result is pt has received previous BCG vaccine. Also, test cannot distinguish between active or latent TB.

Outline the Mantoux Test used for TB detection.

The Meihana Model involves four key elements: · *Te Waka Hourua* = Double Hulled Canoe Patient/whānau relationships, and its relevance to the presenting issue and future treatment plans. Explores the dimensions of physical, psychological, and emotional wellbeing, access to health services, connectedness, and physical environments. · *Ngā Hau e Whā* = Four Winds Represents the four winds of Tawhirimātea, including colonisation, racism, migration, and marginalisation. It reflects the historical and current societal influences on Māori. · *Ngā Roma Moana* = Four Ocean Currents Represents the four ocean currents of Tangaroa (Āhua, Tikanga, Whānau, Whenua). · *Whakatere* = Navigation

Outline the Meihana Model of Māori health.

See *Clinical Pharmacology* Drug Table

Outline the MoA for drugs used to treat diarrhoea and constipation.

Quicker than culture. Highly sensitive and specific. Can identify different species of mycobacteria in culture. *Real-time PCR*: This is a quantitative method. Amplification of DNA sequence is monitored using DNA-binding dyes or DNA probes. If a large amount of gene copies is present, a curve is generated quickly. This technique *enables distinction between true infection and casual contamination*. *Standard PCR*: Detect presence of target DNA sequences but give no indication of quantity. No, of copies of gene in original sample remain unknown.

Outline the PCR test for M. tuberculosis detection.

Intradermal injection of purified protein derivative (tuberculin). Look for delayed type hypersensitivity reaction (48-72 hrs) and measure size of induration. Limitation: cross-reactivity with BCG and non-tuberculous mycobacteria.

Outline the Tuberculin Skin Test (TST)

Diagnostic tool for detecting mycobacteria in samples. Mycobacteria are difficult to stain, but once stained, they resist decolourisation with acid (since they do not take it up → hence, "acid-fast"). Mycobacterium is the only truly acid-fast genus, so the ZN stain is a distinguishing test. A ZN positive sputum smear will be red, and indicates the patient is *infectious* (active disease).

Outline the ZN stain (Ziehl-Neelsen) stain.

*(1) Tumour cell detachment:* loss of cellular adherence, e.g., loss of cell adhesion molecule (E-cadherin). *(2) Epithelial to mesenchymal transition:* this change to mesenchymal morphology allows motility and invasion. *(3) Re-modelling of the ECM:* allows tumour cell motility. *(4) Promotion of tumour angiogenesis* → provides the vehicle for metastasis. *(5) Colonisation of metastatic sites (extravasation):* cancer cells express tissue specific receptors to aid colonisation e.g., chemokine receptors. Note that circulating cancer cells are generally inefficient metastasising cells - <0.01% of circulating tumour cells form deposits.

Outline the biological steps in the metastatic cascade.

Long-replication time = 20-22hrs. Grows slowly on solid culture media, and requires 2-6wks of incubation for colonies to form. Common culture medium = LJ agar. BUT, grows faster in liquid culture (detectable after 7-8 days). Hence, we use selective broth media. Culture is gold-standard for diagnosis but has low sensitivity (positive in 50-80% of cases).

Outline the culture process of Mycobacterium tuberculosis.

Direct detection via microscopy and NAAT. *Microscopy*: TB will stain RED as it is acid-fast. Detection in sputum sample requires ~10,000 organisms per mL. This test has sensitivity of~67%. *NAAT* (Nucleic Acid Amplification Test): PCR test → highly sensitive. *Culture*: Gold-standard test. Bacteria are cultured in solid media. 4-6 wks before colonies are apparent. MGIT (machine) is used for faster detection of growth (10-14 days), and increases sensitivity. This is ESSENTIAL test in order for susceptibility testing to occur. *Susceptibility Testing*: Performed in BACTEC MGIT 960. Growth determined in presence vs. absence of drug.

Outline the different methods of detection of TB.

· Early morning sample · Patient must know difference between sputum and saliva. · Patient should rinse mouth with water first. · Patient should cough deeply and expectorate into a sterile container. · Suspected fungal / mycobacterial infection → up to 3 separate early morning samples should be examined.

Outline the general rules for obtaining an adequate sputum sample with the least amount of contamination.

(1) *Medical history* → TB exposure, demographic factors, co-morbidities (immunosuppression?). (2) *Physical exam* (3) *Blood tests* (indicate infectious process). (4) *CXR* → lesions which may suggest TB. (5) *Evidence of immune responses* to M. tuberculosis (Mantoux test and IGRA). (6) *Microbiological diagnosis* → microscopy (Z-N stain), culture, PCR.

Outline the investigations that lead to a diagnosis of TB.

Contraction of the circular layer of muscle within the GIT enables chyme to propel forward. In peristalsis, there is proximal contraction and distal relaxation. Simultaneously, the longitudinal layer of the muscularis contracts to shorten the small intestine and aids this process (decreasing the distance that the bolus must move).

Outline the mechanism of peristalsis.

Segmentation primarily involves contraction of the circular muscle, thereby promoting stationary mixing of the GI contents with digestive secretions.

Outline the mechanism of segmentation.

Primary stain (RED) → Decolouriser (acid alcohol) → identifies if non-acid fast (BLUE, responds to decolouriser) or acid-fast (RED, does not uptake decolouriser).

Outline the method of the acid-fast microscopy test.

Specific antibody is conjugated to a fluorescent dye and applied to the sample. After incubation, unbound conjugate is washed away, and the sample observed under a fluorescence microscope. Uninfected cells will not fluoresce, as the antibody conjugate does not bind to them. NOTE: the actual virus particles cannot be seen. What is being observed is viral antigen expressed on the outside of host cells.

Outline the process of immunofluorescence

Bacteria secrete autoinducer and have receptors for autoinducer. The concentration of autoinducer is proportional to the concentration of bacteria within the biofilm. Low cell density = little sampling of autoinducer. High cell density = cells receive more signals from the autoinducer to activate genes which build the bacterial city (e.g. genes for EPS production & secretion).

Outline the process of quorum sensing.

Gastrin induces acid secretion. It is produced by antral G cells in response to ACh, local mechanical distension, or gastric contents. It then moves through circulation to act on fundal glands, stimulating acid release from parietal cells. An acid pH <3 triggers somatostatin release by antral D cells, inhibiting gastrin production.

Outline the regulation of acid secretion.

Mucous neck cells secrete bicarbonate and mucous. Local PGE2 activates HCO3- and mucous secretion via EP3 receptor. ACh also activates HCO3- transporter via M receptors.

Outline the regulation of mucous and bicarbonate secretion.

Screening: Heel prick blood samples → biochemical screening for trypsin in blood via spectrometry. *Immunoreactive Trypsinogen* (IRT). Trypsin in the blood is indicative of possible CF. Diagnostic: direct genetic analysis or sweat test. Carrier Testing: DNA analysis.

Outline the tests for CF: → Screening → Diagnostic → Carrier Testing

· Treatment of resistant depression = ketamine and psilocybin · GAD / social anxiety = ketamine. · Depression and anxiety in patients with terminal cancer = psilocybin and MDMA. · PTSD = MDMA. Promote growth of dendrites and improve depression ratings!

Outline the therapeutic use of hallucinogens.

(1) Population health strategy (2) Single raised risk factor strategy (3) High baseline risk strategy

Outline the three preventive strategies used in CVD.

Treatment is supportive (fluid and electrolyte replacement therapy). Does usually requrie antibiotics. If antibiotics *must* be used (such as in neonates, bacteraemia, and always in typhoid / paratyphoid fever), use those listed on Page 36 (Vertical #4).

Outline the treatment of gastroenteritis caused by a diarrhoeagenic infection.

Multiple drugs needed to prevent resistance. Initially: 4 DRUGS. 2 Months: 2 DRUGS (once susceptibility results are available). Treatment occurs over 6-9months. Dormant M. tuberculosis necessitates prolonged treatment in order to achieve cure.

Outline the treatment strategy for TB.

Abnormal macrophages → mouse behaviour is overgrooming. Bone marrow transplant from normal mouse → macrophages travel up to brain → differentiate into microglial cells → change mouse behaviour.

Overgrooming Mouse Experiment

fundus region of stomach. (hence, a.k.a fundic glands)

Oxyntic glands are located in the...

pathogen associated molecular patterns

PAMPs

Example: Sildenafil (viagra). Inhibition of PDE5 → cGMP accumulates → sustained relaxation of vascular SM in corpus cavernous (hence, treatment for impotence).

PDE5 Inhibitors

Probability that a person with a positive test actually does have the disease. a/(a+b)

PPV

route of administration NOT involving GI tract Examples: Systemic Delivery - IV bolus / infusion, IA, IM, SC. Non-systemic Delivery - Topical & inhalation, etc.

Parenteral

Person is not required to do something. E.g. New regulations surrounding car safety (but equity issues here!).

Passive Intervention

Entry via GI tract, then enters blood and travels to liver → eventually eliminated. Re-entry can occur via biliary tract to small bowel. Hep A and E result in an acute infection (there is no chronic infectious state).

Pathogenesis of Hep A and E Infections

Spreads via blood. Enter the blood → travel to liver → eliminated in 95% adults (but only in 5% neonates). If not eliminated → chronic hepatitis, which may progress into active hepatitis.

Pathogenesis of Hep B, D, C Infections

The gut microbiota or epithelial damage leads to bacterial sampling and detection by macrophages, dendritic cells, and mast cells. Cytokines are produced, activating inflammatory cells. These cells phagocytose microbes and dead cells, causing damage and oedema → this is acute inflammation. Normally, repair follows this. However, in IBD there is a leaky gut epithelium which increased pathogen exposure, or an inappropriate immune response takes place. This leads to chronic inflammation, and results in the activation of an adaptive immune response. T cells exacerbate the inflammation and tissue damage, causing relapse of IBD.

Pathogenesis of IBD

1-4 weeks after initial infection. Not an infection, but a consequence of an infection (GUT or GIT infection). Idiopathic → unknown cause (possibly molecular mimicry), but strong association with *HLA-B27 protein*. Self-limiting (resolves within 3-12 mths).

Pathogenesis: Reaction Arthritis

Colonisation of synovial fluid → Influx of inflammatory & immune cells → Effusion in joint space → Erosion of synovial membrane.

Pathogenesis: Septic Arthritis

• Colonise respiratory epithelium → aided by virulence factors such as sIgA proteases & adhesins. • Invasion of nasopharyngeal epithelium into blood. Capsule enables long enough survival for organism to cross BBB. It multiplies in CSF then re-enters blood → SEPSIS.

Pathogenesis: Meningitis

EPE Lecture 3; Important: See Slides 29-31 (and first few pages). Understand that pain is not under voluntary control; pain is an end result of many inputs; pain depends on context. Doctors need to recognise these patterns of illness / nociplastic pain and treat with education rather than medication. Patients can recover from chronic pain. The parasympathetic and sympathetic nervous systems are in constant tension, and each fluctuate in their activation. Help patient know how to identify when SNS is over-firing and learn how to increase their para-SNS activity. Examples → · Relaxation, down-time · Mindfulness training · Breathing techniques

Pathophysiology of Nociplastic Pain → migraine example.

Both experience the same reduction in relative risk of a CVD, but... Patient A experiences a less significant reduction in absolute risk. Patient B experiences a greater reduction in absolute risk.

Patient A and B both have high cholesterol. This is Patient A's only risk factor for CVD. Patient B, however, has multiple risk factors. Who will experience the greatest benefit of cholesterol-lowering treatment?

subjective humans → we bring our own biases to research.

Perils of Research: Supposedly 'objective' research is carried out by...

Dense layer of vascular CT enveloping the bones (except at joint surfaces).

Periosteum

Cells which cannot proliferate / undergo mitosis. EXAMPLE: Neurons, Myocardial cells.

Permanent cells

The study of drug effect, and mechanisms of action i.e. what the drug does to the body

Pharmacodynamics

The study of the movement of drugs into, within and out of the body. i.e. what the body does to the drug

Pharmacokinetics

Rapid absorption into bloodstream. Absorption rate is not affected by how much is drunk, so BAC will continue to rise. Alcohol dose is ~directly proportional to the BAC. Rate of clearance is limited by enzyme capacity so alcohol exhibits *zero-order kinetics*.

Pharmacokinetics of Alcohol

(1) Treat rate / rhythm. (2) Prevent embolic complications.

Pharmacological Treatments Aims of AF

Phase 1: Conversion of aspirin into salicylic acid. Phase 2: Salicylic acid undergoes detoxication and is conjugated to form glucuronide. Glucuronide can be easily excreted.

Phase 1 & 2 of Aspirin Metabolism

*Addition of FG* The drug is either: • Oxidised • Reduced • Hydrolysed This involves the addition of a functional group (-OH, -SH, -COOH, -NH2). Enzyme Responsible: CYPs

Phase 1 of Drug Metabolism

*Conjugation* Drug is conjugated to another molecule to enhance water solubility and improve recognition by transporters.

Phase 2 of Drug Metabolism

*Phase 1:* Addition of agonist → receptor is continually turn on → sodium entry. Repeated activation of the receptor causes loss of membrane potential in the post-synaptic cell → muscle fibre no longer responsive to ACh stimulation.

Phase I Depolarisation Block

*Phase 2:* Persistent activation of receptor causes desensitisation → body detects overactivation and *beta arrestin* internalises the receptors into the cell → nothing left for ACh to bind too. Must wait for regeneration of receptors into plasma membrane for only then is receptor activity returned.

Phase II Depolarisation Block

(1) Inflammatory Phase (2) Reparative Phase (3) Remodelling Phase

Phases of Bone Fracture Healing

1-2 days: Clot formation following haemorrhage. Necrosis of bone fragments. 2-5 days: Acute inflammatory response with exudate and beginnings of granulation tissue.

Phases of Bone Fracture Healing: (1) Inflammatory Phase

7 days: Osteoblasts differentiate from stem cells in granulation tissue. They synthesis ECM. Cartilage forms initially and is gradually replaced by woven bone (disorganised structure). *Soft callus* is formed. Next Few Weeks: Blot clot and bone fragments are cleared by phagocytosis. Building & organisation of the callus by the action of osteoclasts and osteoblasts. A *hard callus* forms.

Phases of Bone Fracture Healing: (2) Reparative Phase

Long-Term: Reorganisation of woven bone to lamellar bone (via balanced action of osteoclasts & osteoblasts). Occurs in response to mechanical stress.

Phases of Bone Fracture Healing: (3) Remodelling Phase

Phase 1 & 2 Trials: Screening processes to identify promising treatments and eliminate other treatments (due to insufficient promise of efficacy and/or unacceptably adverse events). Phase 3 Trials: *RCTs* which provide a definitive assessment regarding the effects of the intervention. Determines if there are tangible benefits that offset any risks. Trial must be ethically acceptable, must provide a reliable answer to relevant clinical Q, and must be efficient.

Phases of Treatment Evaluation

Via PPAR-alpha activation, statins can reduce *inflammatory processes*. May simultaneously block inhibitory pathways affecting SREBP and PPARs. ???

Pleiotropic Effects of Statins

Interventions used within large populations

Population-Based Approach

activity increases when modulator binds

Positive allosteric modulator

Non-union Fibrous union Possible Causes: infection, excessive movement, poor blood supply.

Possible complications associated with delayed bone healing

Less severe, more common effects - Diarrhoea More severe, less common effects - Pseudomembranous colitis - Toxic megacolon

Potential Consequences of C. diff Infection

Resolution → regeneration & repair. Abscess → localised collection of pus surrounded by granulation tissue. Chronic inflammation → can occur if offending agent is not removed. Scarring → injured tissue is filled in by CT.

Potential outcomes of acute inflammatory response

Küstner was sensitive to fish. Praustnitz took Küstner's serum and injected it into his own skin, then challenged himself with fish extract. Results showed that *sensitivity could be transferred by serum factor.*

Prausnitz-Küstner Reaction

test performance (influenced by disease prevalence in the population of interest).

Predictive Value is a measure of...

Elderly = Limit prescription of first generation H1 antihistamines unless treating insomnia or severe anaphylactic reaction. Elderly people have decreased CYP and PgP activity, hence an enhanced drug effect. Pregnancy / Lactation = non-teratogenic. Avoid in 3rd trimester. Non-sedating cetirizine and loratadine best options. Children = 1st gen should not be prescribed to <2-year-old, or those with comorbid diseases.

Prescription of Antihistamines for: Elderly Pregnancy / Lactation Children

Non-cardiac chest pain. Panic attack / disorder.

Presentations to cardiology clinics with a *psychological basis*.

Presumptive identification tests are less accurate than confirmatory tests. However, they indicate the likely identity. Usually, only a single confirmatory test is then necessary. Ex: Bacitracin

Presumptive Identification Tests [of bacteria]

To prevent transmission, maintain good hygiene and screen blood products (such as donated blood).

Preventing Viral Hepatitis

Hep A is highly contagious, so requires ongoing monitoring for potential outbreaks. Risk groups should be identified and vaccinated. Immunoglobin prophylaxis can be provided to those who have been exposed to HAV.

Preventing Viral Hepatitis: *Hepatitis A*

Vaccine against HBV. Hep B can cause chronic disease, so need to treat patients to prevent future liver damage. *Treatment*: Antiviral therapy, including entecavir (nucleoside analogue) or tenofovir (nucleotide reverse transciptase inhibitor). Treatment >6 months. *Lab Markers*: HBe antigen / antibody can be assessed to determine if diseasse is chronin. Use PCR to determine viral load. Serum ALT monitoring.

Preventing and Treating Viral Hepatitis: *Hepatitis B*

Screen blood products and semen to monitor for Hep C. *Treatment*: Maviret cures >98% infected patients. It is funded in NZ.

Preventing and Treating Viral Hepatitis: *Hepatitis C*

Behavioural Circumcision Antenatal screening & treatment PEP & PrEP Microbicides Vaccines (not yet available)

Prevention mechanisms against HIV infection

Smoking cessation Dietary advice Exercise advice

Primary Prevention: Ischaemic Heart Disease

Healing by primary intention. - *Edges can brought close together, forming a clean wound.* - Minimal scarring. - Line of closure fills with clotted blood (plug). - Scab forms, with granulation tissue beneath. - 3 months: 70-80% initial tensile strength. Example: Surgical wounds

Primary Union

Changes to transport system that promote active transport.

Primordial Prevention: Ischaemic Heart Disease

(1) Emphasis on primary prevention (2) Multidisciplinary in nature (3) Science-based (4) Population-based (utilitarian)

Principles which uphold the public health model for injury prevention

Drugs that are administered in an inactive form, then metabolised into an active form; the resulting metabolites produce the desired therapeutic effects. Example: Anti-cancer drugs are cytotoxic, so we provide them as pro-drugs to minimise SEs.

Pro-drugs

Generally self-limiting (2-7 days). Some require hospitalisation. Children at risk of severe dehydration. Bacteraemia can occur in elderly / immunocompromised. Risk of immune-mediated effects ('sequelae') such as reactive arthritis, Guillain-Barre syndrome, erythema nodosum.

Prognosis and Features of Diarrhoeagenic Infections

• More than one type of subunits (i.e., have a multimeric quaternary structure). • Different forms in different tissues. • Different locations within the same cell. • Easily analysed by electrophoresis.

Properties of Isoenzymes

Acellular Require host (obligate intercellular pathogens) Cause mild-severe infections DNA or RNA nucleic acid

Properties of Viruses

Gap and Pol require cleavage by protease for virus assembly. Drug behaves as a substrate analogue and binds to active site, preventing viral maturation.

Protease Inhibitors (MoA)

Exercise Fruit & Veg Medications / supplements (calcium, Vit D)

Protective Factors for Colorectal Cancer

· Impairs phagosome maturation · Lipid-rich cell wall which protects against H+ and antimicrobial peptides · Secretes urease to raise pH · Enzymes to protect against RNS and ROS

Protective Mechanisms of Mycobacterium Tuberculosis (in the phagolysosome)

IsoElectric Focusing

Protein isoform variant detection in AATD cases occurs via...

Coagulation proteins Complement Kinins Lysosomal proteases Elastase AAT CRP hs-CRP

Proteins involved in acute phase response

Avoid unprotected sex with someone who does not know their HIV status or is HIV+. Avoid risky sexual behaviours. Avoid sharing needles & syringes. Avoid other STIs. PrEP PEP

Provide HIV-prevention advice for individuals at risk.

Bronchial carcinoid → presents with haemoptysis since it is a highly vascular tumour.

Provide an example of a benign lung tumour.

Decamethonium *Suxamethonium* Muscle spasms occur before paralysis. Causes paralysis by maintained depolarisation of the muscle. Cannot be reversed since it acts as an agonist.

Provide an example of a depolarising NMB.

Keloid (too much collagen)

Provide an example of a hypertrophic scar.

e.g. ribotype 027 These are becoming more problematic.

Provide an example of a hypervirulent strain of C. diff.

Curare: a drug that blocks nicotinic acetylcholine receptors. *Tubocurarine* is not absorbed orally and will not cross placenta (so safe to use in hunting). Causes flaccid paralysis.

Provide an example of a non-depolarising NMB.

Staph. aureus

Provide an example of antimicrobial resistant pathogen.

(1) Mannitol (2) Frusemide (Furosemide) (3) Bendroflumethiazide (4) Spironolactone and Amiloride

Provide an example(s) for the following. (1) Osmotic diuretic. (2) Loop diuretic. (3) Thiazide and thiazide-like diuretics. (4) Potassium-sparing diuretics.

SCID = severe combined immunodeficiency No cell-mediated immune response, nor T cell-dependent antibody response.

Provide example of immunodeficiency relating to defect in T cell development.

(1) *Unexplained symptoms / Functional illness* → major unexplainable symptoms. (2) *Placebo response* → where people get better when given inert substances or after sham surgery. (3) *Nocebo response* → where patients have negative outcomes from inert substances e.g., in RCTs or from changing medication brands (perpetuated by media). (4) *Multimorbidity and polypharmacy* These observations are known as anomalies to the biomedical paradigm. A narrowly constructed biomedical paradigm is not able to explain these common clinical phenomena.

Provide examples of "puzzling" clinical observations.

Proteases Dust mite faeces Nuts Eggs Fish etc...

Provide examples of allergens.

Indoleamines Phenethylamines NMDA antagonists Indoleamines

Provide examples of hallucinogens.

Cocaine Amphetamines Nicotine Caffeine Ecstasy

Provide examples of stimulants.

Bronchiectasis Cysts Abscesses

Provide examples of the types of airway damage that may result from CF.

Function: Reduce blood coagulation (fibrin formation). Prevent thrombus from forming. Used for patients at an increased thrombotic risk (e.g., acute MI, CABG, prolonged immobility). Examples: LMWH (Enoxaparin) VKAs (Warfarin) NOACs (Dabigatran)

Provide function & examples of anticoagulants.

Function: prevent platelet aggregation. Examples: Low dose aspirin Clopidogrel

Provide function & examples of antiplatelet agents.

Function: Break down the already-formed thrombus by increasing fibrin breakdown (fibrinolysis). Example: rt-PAs (alteplase, tenecteplase)

Provide function & examples of fribrinolytics.

· Normal microbiota overgrow the pathogen on the culture plate. · Previous antimicrobial treatment. · Requirements for bacterial growth not met (nutrients, temperature or atmosphere). · Sample mainly saliva. · Sample not an early morning specimen.

Provide reasons for why a false-negative sputum culture could occur?

*Cowden Syndrome* • PTEN → affects breast, thyroid and endometrial tissues. *Hereditary diffuse gastric cancer (HDGC)* • CDH1 → affects stomach and breast tissues. *Hereditary breast-ovarian cancer* • BRCA1, BRCA2 → affects breast and ovarian tissues. • BRCA genes are DNA repair genes. • There are other risk genes for familial breast cancer.

Provide some examples of highly penetrant inherited cancer syndromes and their corresponding genes.

Gram-negative. Opportunistic rod bacterium. Colonises 3-5% of population.

Pseudomonas aeruginosa → Gram-stain → Opportunistic or Obligate → % Colonised

Can cause life-threatening infection in a susceptible host. Common cause of hospital-acquired infection (HAI). Virulence Factors: - Biofilms - Capssule - Motility - Immune evasion - Adhesions - Enzymes - Toxins

Pseudomonas aeruginosa → Virulence Factors.

Reduce marketing of junk foods. Improve food labelling. Reformulation of processed foods. Taxes and subsidies on unhealthy goods. Only healthy foods available in schools, workplace, hospital, etc. Education and guidelines. Fresh produce available. Minimize frozen desserts. Promote primarily plant-based diet.

Public Health Interventions to Improve Nutrition

Decrease availability Decrease purchase age Pricing and taxation Driving regulations

Public Health Interventions to Reduce Alcohol Consumption

Population screening for carriers. Ethical and social issues → prevent marriages? Reproduction? Prenatal / Genetic screening for affected foetus → termination.

Public health approaches for the prevention of beta-thalassemia

antral region of stomach. (hence, a.k.a antral glands)

Pyloric grands are located in the...

Bacterial skin infections. Example: impetigo, folliculitis, furuncle, carbuncles.

Pyodermas

It is a variation of standard PCR that involves the amplification of specific mRNA obtained from small samples. RNA --> cDNA via reverse transcriptase. Then cDNA is amplified via PCR. Used for detection of HIV nucleic acid (and measurement of HIV RNA levels).

RT-PCR

Road traffic injuries

RTIs

Epidermis: Scalded skin syndrome Follicle: Boils, Carbuncles Dermis: Impetigo, Erysipelas Subcutaneous Fat: Cellulitis Fascia: Necrotising fasciitis Bone: Osteomyelitis

Rank the skin infections from superficial to deep

Membrane permeability Organ perfusion

Rate of drug distribution depends on...

CD4

Receptor for HIV

balanced transfer of material from one chromosome to another

Reciprocal Translocation

SFAs and TFAs should make up >10% of total caloric intake. (Currently in NZ, average is 13%).

Recommendation for Fat Intake

Do not drink alcohol. (If you do, remain within guidelines).

Recommendations for Alcohol Intake

<2000mg sodium (5g salt) per day. (Currently, average is ~3500mg in NZ).

Recommendations for Salt Intake

Added sugar should make up <10% (preferably 5%) of daily total energy intake. This is ~25g (6 tsp) of sugar.

Recommendations for Sugar Intake

Negligible (due to post-zygotic acquirement of the syndrome).

Recurrence Risk of Turner Syndrome

HLA-B27 positive

Recurrence of reactive arthritis is common for those who are...

For example, an incidence of breast cancer must meet certain criteria in order for family members to be screened for a familial form of the disorder. Some of the criteria: · Breast cancer diagnosed <40 years of age · Multiple cases in family history · Male breast cancer at any age · ...etc...

Referral criteria for genetic testing of potentially familial cancers.

Viral rhinitis Sinusitis Pharyngitis Bronchitis / bronchiolitis Pneumonia / ARDs Otitis media

Respiratory Infection Complications