Theme 3: Inflammation and Infection (L4-7) Flashcards
1
Q
What are the 2 different branches of the immune system?
A
Innate and adaptive
2
Q
What is inflammation?
A
It is a protective response of vascularised tissues to infections and damaged tissues that brings cells and molecules of host defence from the circulation to the sites where they are needed, in order to eliminate the offending agents
3
Q
How does inflammation act?
A
Serves to destroy, dilute or isolate the injurious agent and the elimination of necrotic cells and tissues
4
Q
What are the 5 R’s of the inflammatory response?
A
Recognition
Recruitment
Removal
Regulation
Repair
5
Q
What happens in acute inflammation?
A
Rapid onset
Short duration
Many neutrophils
Prominent characteristic response
6
Q
What are the cardinal signs of inflammation?
A
Redness
Heat
Swelling
Pain
Loss of function
7
Q
What is the vascular aspect of acute inflammation?
A
Dilation of small vessels - slowing of blood flow
Increased vascular permeability of microvasculature - plasma proteins and leukocytes leave circulation
8
Q
What is the cellular aspect of acute inflammation?
A
Emigration of the leukocytes from micro circulation, accumulate at site of injury before activating to eliminate pathogen
9
Q
What are the key inflammatory mediators?
A
Histamine - mast cell and basophil
Plasma proteins - liver
Prostaglandins - mast cell, basophil and neutrophil
Leukotrienes - mast cell, basophil and neutrophils
Cytokines - mast cell and macrophage
Chemokines - mast cell and macrophage
10
Q
Which inflammatory mediators cause vasodilation?
A
Histamine
Plasma proteins
Prostaglandins
Cytokines
11
Q
Which inflammatory mediators cause increased permeability?
A
Histamine
Plasma proteins
Prostaglandins
Leukotrienes
Cytokines
12
Q
Which inflammatory mediators cause leukocyte recruitment?
A
Histamine
Plasma proteins
Prostaglandins
Leukotrienes
Cytokines
Chemokines
13
Q
What is chronic inflammation?
A
Slow onset
Long duration
Monocytes/macrophages/lymphocytes
Less characteristic response
14
Q
What are the 2 main cells of chronic inflammation?
A
Macrophages and lymphocytes
15
Q
What are the functions of macrophages?
A
Phagocytosis
Initiate tissue repair
Secrete cytokines/chemokines
Activate lymphocytes (using antigen presentation)
16
Q
What are the functions of lymphocytes?
A
T cells secrete cytokines/chemokines leading to chronic inflammation
B cells secrete antibodies leading to chronic inflammation
17
Q
Which types of drugs can reduce inflammation and modulate immune responses?
A
Steroidal anti-inflammatory agents
NSAIDs
Immunosuppressants
Anti-histamines
Anti-cytokine drugs and other biologicals
Disease modifying anti-rheumatoid drugs (DMARD)
18
Q
What happens during signalling pattern recognition receptors?
A
MO pathogen-associated molecular patterns binds toll-like receptor
Activates TXN NfkB & IRF 3/7
Secretion of cytokines
Inflammation which leads to damage-associated molecular patterns
19
Q
What are key inflammatory mediators?
A
Membrane phospholipids
↓ PLA2
Arachidonic acid
↓5-LOX+FLAP or COX
LTA4 or prostaglandins/thromboxanes
↓LTC4 synthase or epoxide hydroxide
LTC4 or LTB4
20
Q
Which mediators do NSAIDs block?
A
COX enzyme
21
Q
Which mediators do LT inhibitors block?
A
5-LOX
22
Q
What does COX-1 regulate?
A
Thromboxane A2 - vasoconstriction and increased platelet aggregation (thrombosis)
Prostaglandins E2 and I2 - gastric protection
23
Q
What does COX-2 regulate?
A
Prostaglandins E2 and I2 - pain and inflammation
Prostacyclin (PGI2) - vasodilation and decreased platelet aggregation
24
Q
Which drugs are used as anti-inflammatories?
A
Strong
Naproxen (HL 14h) - oral administration
Celecoxib (HL 11h) - oral administration
Piroxicam (HL 45h) - oral administration
Moderate
Ibuprofen (HL 1-4h) - oral administration
25
Which drugs are anti-inflammatory in chronic inflammation?
Intial
Ibuprofen (HL 1-4h) - oral administration
Naproxen (HL 14h) - oral administration
Long term
Piroxicam (HL 45h) - oral administration
COX 2 inhibitors like etoricoxib
26
Which drugs are analgesic?
Short term
Ibuprofen, paracetamol (HL 1-4) - oral administration
Naproxen (HL 14h) - oral administration
Long term
Piroxicam (HL 45h) - oral administration
27
What drug is anti-pyretic?
Paracetamol (HL 1-4h) - oral administration
28
What drug is aspirin?
Aspirin (other NSAIDs increase thrombosis) - oral administration
29
What are NSAIDs mechanism of action?
Reversible competitive inhibition - e.g. ibuprofen
Reversible non-competitive inhibition - e.g. paracetamol
Irreversible inhibition - e.g. aspirin acetylates active site
30
What are pyrogens?
Components from MOs to induce fever
31
What are the systemic effects of inflammation?
Secretion cytokines to blood stream (IL-6, IL-1beta, TNF-alpha)
↓
Mitigate to brain
↓
Bind receptors on brain endothelial cells
↓
Activates prostaglandin E2 synthesis
↓
Hypothalamus
↓
Fever
32
What is fever mediated by?
Prostaglandins (E2)
33
What are the gastrointestinal effects of NSAIDs on COX-1?
Dyspepsia, nausea and vomiting (mucosal damage)
Inhibition of synthesis of stomach PGE2
Greatest risk prioxicam
34
What are the skin rash effects of NSAIDs on COX-1?
Common in NSAID Sulindac
Unclear mechanism - to do with the increase in leukotrienes increasing hypersensitivity cutaneously
35
What are the renal effects of NSAIDs on COX-1?
Inhibition of synthesis of PGI2 (COX2) and PGE2 (vasodilation and transport Na+)
Implications for drug clearance
Renal insufficiency treatment continues to damage
36
How do bronchospasms occur in NSAIDs?
Inhibition of COX-1 which leads to an increase in leukotrienes causing bronchoconstriction
Can be caused with aspirin use in people with viral infections
Not caused in selective COX-2 inhibitors
37
What are NSAIDs COXIB's?
Specific COX2 inhibitors
Inc risk of thrombotic effects
Inc heart attack
Inc stroke
With prolonged use
38
What happened to COXIB's?
They were withdrawn due to risk of thrombotic effects
39
What are NSAIDs adverse effects on the cardiovascular system?
COX2 inhibitors decrease platelet aggregation and vasodilation (cardioprotective)
40
What is the function of lipocortin?
Agonist of GR (glucocorticoid receptor) so a phospholipase A2 antagonist
41
How does cortisol cause anti-inflammatory effects?
Induction of lipocortin - inhibits PLA2 (decrease inflammatory mediators)
Dec. capillary permeability
Dec. Phagocytes action of leucocytes
Dec. histamine release
Dec activity of mononuclear cells and proliferation/repair of tissue
Dec. thromboxanes (increase brushing)
42
How do steroid hormones signal?
They bind to intracellular receptor which allows gene expression
43
What are hypersensitivity reactions?
They are exaggerated/inappropriate immunologic responses occurring in response to an antigen or allergen
44
What levels of inflammation does cortisol block?
Acute and chronic
45
What are the 4 main types of hypersensitivity reaction?
Type I: reaction mediated by IgE antibodies
Type II: cytotoxic reaction mediated by IgM or IgG
Type III: reaction mediated by immune complexes
Type IV: delayed reaction mediated by cellular response
46
What is the molecular pathogenesis of atopic asthma?
Environmental stimulus
APC reacts and binds to Th2 cells
Cytokines released activate B cells
IgE antibodies cause sensitisation which leads to degranulation
Airway becomes overthrown with histamine, leukotrienes and prostaglandins
47
What is the process of mast cell degranulation?
1- upon first exposure to allergen, APC processes antigen and presents to Th2
2- Th2 cells release IL-4 and IL-12 activating B cell
3- B cells IgE antibodies proliferates into plasma cells synthesising and secreting IgE antibody
4- IgE binds mast cells via Fc region sensitising mast cells
5- exposure to allergen causes mast cells with IgE to bind to antigen and release inflammatory molecules (allergy symptoms)
48
What happens after antigen exposure in mast cell degranulation?
Histamine is released along with other mediators
49
What can happen during hypersensitivity reactions to blood vessels?
Inc. smooth muscle contraction
Peripheral vasodilation
Inc. vascular permeability
Extravasation of capillary blood
Leads to:
Bronchospasm
Abdominal cramps
Rhinitis
Erythema
50
What can happen during hypersensitivity reactions to histamine?
Histamine is released
Leads to pruritus
51
What can happen during hypersensitivity reactions to fluids?
Fluid shifts into interstitial space
Leads to oedema - pulmonary and cutaneous (eyes/lips)
52
What can happen during hypersensitivity reactions to eosinophils and neutrophils?
Eosinophil and neutrophils chemotaxis
Leads to eosinophilia and raised tryptase
53
What are examples of type I hypersensitivity reactions?
Localised:
Hayfever
Asthma
Angiodema
Hives
Systemic:
Anaphylaxis
54
What are the symptoms of hayfever (allergic rhinitis)?
Red and itchy watery eyes
Sneezing, congestion and runny nose
Itchy/sore throat, cough
Fatigue
55
What is hayfever mediated by?
Binding to H1 receptors
56
Which receptors do antihistamines bind to?
H1 receptors
57
What are first generation antihistamines?
Side effects including drowsiness and cause difficulty urinating or constipation
(chlorphenamine and diphenhydramine)
58
What are second generation antihistamines?
Less likely to give side effects as don’t cross BBB
(cetirizine and loratadine)
59
What is the mechanism of blocking T-cell responses in immunosuppression?
They block the expression and activity of the T cell growth factor and activating cytokines interleukin 2 (IL-2)
60
What are the current immunosupression strategies?
Blocking T-cell mediated immune responses
61
What are examples of immunosuppressants?
Glucocorticoids
Cacineurin inhibitors
Dual calcineurin / mTOR inhibitors
IL-2 receptor antagonists
Nuclei acid synthesis antagonists
T cell receptor antagonists
62
What happens to APC presenting MHC II in the lymph node?
APC binds Th cells and produce cytokines
B cells activated producing plasma cell which opsonises
Then pathogen is neutralised and agglutionised (phagocytosis)
63
What is the pathway of APC binding MHC II to a TCR?
Binding stimulated Ca2+ release and stimulates the calcineurin pathway
IL-2 gene is expressed producing IL-2
IL-2 binds receptors on the cell activating mTOR pathway and the cell cycle
64
How do glucocorticoids interact with NFkB?
They directly bind p65 subunit of NFkB preventing activation of inflammatory genes (e.g. IL-2)
It also promotes IkBa synthesis which prevents p50/p65 nuclear translocation preventing NFkB activation of inflammatory genes
65
What is the mechanism of calcineurin inhibitors?
APC MHC II binds TCR which produces Ca2+
Calmodulin and calcineurin (phosphotase) is produced
NF-AT is activated which binds to DNA in nucleus allowing gene expression of IL-2
Inhibitors block the conversion of calcineurin to NF-AT therefore stopping the production of IL-2 and suppressing the immune system
66
What is the mechanism of Sirolimus?
It is a dual calcineurin / mTOR inhibitor involved in immunosuppression
67
What is FKBP?
FKBP (FK506-binding protein) is a family of intracellular proteins that play a role in protein folding, immunoregulation, and signal transduction.
68
How do IL-2 receptor antagonists work?
Daclizumab - monoclonal antibody to alpha subunit of the IL-2 receptor on T cells
Basiliximab - Chimeric mouse-human monoclonal antibody to IL2-Ralpha of T cells
69
What are the TCR receptor antagonists?
OKT3 - murine monoclonal antibody against ε chain of CD3 complex
Two phases:
Increase T cell depletion from circulation by liver
Removal of important activator domain of T cell receptor
70
What are important concepts of immunosuppressive drugs used in transplantation?
They have a narrow therapeutic window with toxic side effects
Therapeutics drug monitoring is required
71
How does immunotherapy work?
Immune cells are stimulated or inhibited by a range of immune cell checkpoint protein interactions (PDL/PD1 - inhibitory interaction)
72
How can immunotherapy be the future of cancer treatments?
Activating bodies own immune system to recognise and kill cancer cells
Using immune checkpoint inhibitors
PD-1 receptor antagonists
73
What are the important DNA viruses?
Adenovirus - upper respiratory tract + eye infections
Herpesvirus - Genital herpes, varicella, meningoencephalitis and retinitis
Papilomavirus - warts, cancer
74
What are the important RNA viruses?
Paramyxovirus - measles, upper respiratory tract infections
Rhabdovirus - rabies
Togavirus - rubella, yellow fever
Influenza - Influenza
Retrovirus - Leukaemia, AIDS
75
What are the steps of the viral replication cycle?
1- attachment to host cell
2- un-coating of virus
3- control of DNA, RNA and/or protein production
4- production of viral subunits
5- assembly of virions
6- release of virions
76
What are the properties of antiviral drugs?
Must penetrate infected cell
Have high toxicity in healthy cells
77
How do antiviral drugs specifically target infected cells?
It is difficult to achieve distributional selectivity
Target unique enzymes/metabolic pathways
Interfere with nuclei acid synthesis and/or regulation
78
What are examples of antiviral targets?
Viral cell binding
Interrupting virus uncoating
Stimulating host cell immune system
79
What is latency?
Recurrence of infection (persistent, different forms)
80
What are the different reasons for latency?
Non-replicating cells
Joint replication processes
Limited immune detection
81
What form are most antivirals in?
They are mostly virustatic agents (cannot eliminate viral latency)
82
Give examples of viruses that have acute infections
Rhinovirus
Rotavirus
Influenza
83
Give examples of a virus with persistent infection
Lymphocytic choriomeningitis
84
Give an example of a virus that has a latent reactivating infection
Herpes simplex virus
85
Give examples of viruses that have slow infections
Measles SSPE
HIV
86
What is the cause of antiviral resistance?
Rapid replication rate
Spontaneous mutation rate
87
Which enzymes are key in antiviral resistance?
Protease
Reverse transcriptase
88
What are the different forms of herpes virus?
Simplex - cold sores
Varicella zoster - chicken pox
Epstein Barr - glandular fever
89
Where does herpesvirus infect?
Sensory ganglia - becomes latent there
Re-stimulation from external factor
90
What are the symptoms of herpesvirus?
Flu-like
Blister/ulcer stage
91
What is acyclovir?
It is a synthetic guanosine analogue
High specificity to simplex (less with other versions)
High therapeutic index
Requires intracellular phosphorylation to become active
Few side effects
92
What is the metabolic action of acyclovir?
Utilised virus specific thymidine kinase - monophosphate acyclovir
High concentrations of activated form in infected cells
Conversion to di- and triphosphate forms via host cell kinases
93
What is the antiviral action of acyclovir?
Acyclovir-TP is a DNA chain terminator
Inhibitor of vial DNA polymerase
Host significantly less susceptible
Minimal toxicity
94
What is HIV infection and AIDS characterised by?
Opportunistic infections
Rare neoplasms
Death
95
How is HIV transmitted?
Congenitally, parenterally and sexual contact
96
What are the 2 different forms of HIV?
1 - responsible for human AIDS
2 - less virulent form of immune suppression
97
What are the features of primary HIV infection?
Asymptomatic
Following seroconversion
10-15% development febrile illness (influenza-like)
Lined to increasing viral load
Acute retroviral syndrome
98
What are the 4 stages of HIV?
1 - asymptomatic
25-35% development persistent generalised lymphadenopathy (PGL)
2 - progression to severe infection
weight loss <10%
inc. opportunistic infections - ulcer, dermatitis, respiratory, etc.
3 -
weight loss >10%
Oral candidiasis, hairy leukoplakia, mycobacterium tuberculosis
4 -
HIV wasting syndrome, kaposis sarcoma, CNS toxoplasmosis, HIV encephalopathy
AIDS related complex ARC
99
What is the mechanism of action of HIV?
Immune target cells (Th cells and cytotoxic: CD8+, CD4+)
Produce DNA complement of viral RNA (reverse transcriptase)
Attaches to CD4 receptor and protein-coupled receptors (CCR5/CXCR4)
100
What are drugs used to target the HIV life cycle?
Fusion inhibitors
CCR5 inhibitors
NTRIs and NNRTIs
Protease inhibitors
101
What is an example of a fusion inhibitor?
Enfuvirtide
102
What is enfuvirtide?
A fusion inhibitor in HIV (gp41)
Inhibits fusion of cellular and vial membranes
SC injection (rashes + frequent injections)
Most effective as combination
Emergence of resistance (mutation)
103
What is an example of a CCR5 inhibitor?
Maeaviroc
104
What is Maraviroc?
Binds to CCR5 receptor on membrane of CD4 cells
Prevents interaction of HIV-1 GP120 and human CCR5 receptor necessary for entry into cell
(not 1st line!)
105
What is an example of a nucleoside reverse transcriptase inhibitor?
Zidovudine
106
What is zidovudine?
A nucleoside reverse transcriptase inhibitor
In vitro
Active when phosphorylated intracellularly to triphosphate
Inhibits viral reverse transcriptase
107
How does zidovudine work?
Triphosphate competes for pro-viral synthesis
Premature of DNA elongation
Inhibits mammalian γ and β DNA polymerases (toxic)
108
What are the adverse effects of nucleoside reverse transcriptase inhibitors?
Minor: headaches, nausea
Severe: anaemia, leucopenia, neutropenia
109
What are the problems with NRTIs and resistance?
Big problem with zidovudine mono therapy, less so with combined
110
Give examples of non-nucleoside reverse transcriptase inhibitor
Nevirapine
Delaviridine
Efavirenz
111
What are the properties of NNRTIs?
Structurally distinct to NRTIs
Bind reverse transcriptase
Induce CYP450 isoenzymes (drug-drug interaction)
112
Give examples of protease inhibitors
Saquinavir
Ritonovir
113
What is the mechanism of action of protease inhibitors?
Target virus specific protease enzyme
Required for post-translational processing of gag and gag-pol poly proteins into functional proteins
Immature non-infections virions and interruption of viral spread
114
What is the clinical pharmacology of protease inhibitors?
Highly effective in suppressing viral load
Drug-drug interaction (cannot co-administer P450 inhibitors/inducers)
Resistance issues - 47% after treatment saquinavir monotherapy 1 year
Combination therapy most effective (NRTI & NNRTI)
115
What is the most highly active anti-retroviral therapy (HAART)?
NRTI (2x) + NNRTI OR PI (1/2)
116
What is the combination therapy most used?
Atripla (emtricitabine/tenofovir/efavirenz)
Truvada (emtricitabine/tenofovir)
Sustiva (efavirenz)
NOT NEW DRUGS
117
What is an integrate inhibitor?
Raltegravir
Inhibits integration of TXN viral DNA into host cell chromosomes
Only as combination therapy (resistant strains)
Drug-drug interactions
118
What is an antibiotic?
A medicine that inhibits the growth or destroys bacteria
119
What are the different types of antibiotics?
Bacteriostatic: inhibit multiplication
Bactericidal: kill bacteria
120
What do antibiotics target?
Cell wall synthesis
Membrane synthesis
Protein synthesis
Metabolic pathways
Nucleic acid synthesis
121
What are the differences between gram positive and negative bacteria?
Gram negative - smaller peptidoglycan and outer membrane
Gram positive - larger peptidoglycan
122
What is contained in the peptidoglycan unit?
MurNAc and GlcNAc and a chain of amino acids L-ala, D-glu, L-lys, D-ala and D-ala
123
Where are crosslinks formed in the bacterial cell wall?
On lysine residue
124
How does penicillin act?
It stops crosslinking by binding the transpeptidases and binds penicillin binding protein
125
What the β-lactam antibiotics?
Penicillins
Cephalosporins
Monobactams
Carbapenems
126
What does flucloxacillin target?
Gram positive
β-lactamase resistant
127
What does benzylpenicillin target?
Gram positive
128
What does amoxicillin target?
Gram positive
Gram negative
Additional amine for +ive charge - into bacteria
129
What does mecillinam target?
Gram negative (binding protein)
130
What does mezlocillin target?
Gram positive
Gram negative
Pseudomonas aeruginosa
131
What are the properties of cephalosporins?
Broad spectrum antibiotics
Use penicillin binding protein
Oral, IM or IV
Excretion via kidney
132
What are cephalosporins used to treat?
Septicaemia, pneumonia or meningitis
133
What are the adverse effects of cephalosporins?
Nephrotoxicity and diarrhoea
134
What are examples of cephalosporins?
Cefaclor
Cephalexin
Cefotaxime
135
What are the resistance mechanisms of bacteria to penicillin?
Efflux pump
Porins deregulated (how drug enters)
Inactivation of antibiotic
Target site modification
136
How are penicillins inactivated?
β-lactamase enzyme used to hydrolyse ring so cannot bind penicillin binding protein
137
What can be used to stop penicillins being inactivated?
Clavulanic acid (inhibits β-lactamases) - cannot act alone
138
Which bacteria modify penicillin binding proteins?
MRSA - mecA gene
139
What other antibiotics target the cell wall?
Cycloserine - amino acid side chain muramic acid
Bacitracin - de-phosphorylation
Vancomycin - targets amino acid
β-lactam antibiotics - crosslinking
140
Which antibiotics inhibit protein synthesis?
Chloramphenicol - 50S subunit inhibition of peptide bond formation
Erythromycin - 50S subunit, prevents translocation- movement mRNA across ribosome
Tetracyclines - attachment of tRNA to mRNA-ribosome complex
Streptomycin - Changes shape 30S, code on mRNA read incorrectly
141
What are the properties of tetracyclines?
Bacteriostatic
Resistance growing - efflux, ribosomal protection or inactivation
Broad spectrum
Binds to A site
142
What are the properties of aminoglycosides?
Bactericidal
Resistance - amino-glycoside modifying enzyme, modification and efflux
Interferes with mRNA TLN
Activity enhanced by penicillins
Poorly absorbed in gut (IV/IM admin)
143
What are the adverse effects of aminoglycosides?
Ototoxicity
Nephrotoxicity
144
What are the properties of macrolides?
Bacteriostatic - gram positive
Resistance - efflux, methylation ribosomal targets
Binds 50S subunit preventing translocation
Metabolised by demethylation CYP3A4
Oral administration
145
What are the adverse effects of macrolides?
Heart arrhythmias
GI disturbance
146
What are the properties of chloramphenicol?
Bacteriostatic/bactericidal
Resistance - inactivation (acetyltransferase), efflux and ribosomal mutations
Inhibits transpeptidasation reaction
Metabolised in liver
Oral/IV administration
147
What are the side effects of chloramphenicol?
Gray baby syndrome
Bone marrow suppression
148
What is the mechanism of action of sulphonamides?
Bacteriostatic
Inhibit dihydropteroate synthetase (no diffusion of folate into cells)
149
What is the mechanism of action of trimethoprim?
Bacteriostatic
Inhibits dihydrofolate reductase - stops conversion of folate into tetrahydrofolate
150
What are the properties of sulphonamides?
Bacteriostatic
Resistance - low affinity of dihydropteroate synthetase
N-acetylated in liver
Broad spectrum
Well distributed into CSF
Cross BBB
151
What are the properties of trimethoprim?
Bacteriostatic
Resistance - low affinity for dihydrofolate reductase
Specific for bacterial isoform of enzyme
Oral administration
Used in UTI and respiratory tract infections
152
What are the properties of fluoroquinolones?
Inhibit DNA gyrase
broad spectrum
Inhibits CYP1A2
Oral and well absorbed
Does not cross BBB
153
What are the adverse effects of fluoroquinolones?
GI effects
Prolongation of QT interval
154
Why is mycobacterium a problem?
Tuberculosis and leprosy
Nonmotile and slow growing
Thick, waxy, lipid-rich hydrophobic cell walls
Mycolic acids in cell wall (FAs)
Survive in macrophages
155
What are the problems associated with tuberculosis?
13th leading cause of death
MDR resistant TB - health crisis and health security threat
Increased since COVID
Ending TB epidemic by 2030 (goal)
156
What are the properties of rifampicin?
Inhibits prokaryotic DNA dependent RNA polymerase
Semisynthetic derivative of rifamycin
Good against gram +&- and mycobacteria
Potent inducer of CYP3A4 - increase degradation of glucocorticoids and warfarin
Oral administration
Crosses BBB
157
What is the mechanism of daptomycin?
Insert into membrane - cell death
158
What are the properties of daptomycin?
Gram positive: MRSA, vancomycin resistant S.aurus
Poorly absorbed (IV)
Eliminated via renal excretion
159
What are the adverse effects of daptomycin?
Damage mucoskeletal system
Eosinophilic pneumonia
Peripheral neuropathy
