BACTERIAL STRUCTURE, PHYSIOLOGY, AND GENETICSBACTERIAL CELL WALL: From the inside out.   •   GRAM-POSITIVE:         o Plas...
  Endotoxin: LPS coat is the basis for gram-negative bacterial                    endotoxin, which causes anaphylaxis.   ...
BACTERIAL SECRETIONS:  •   Extracellular Proteases are secreted to degrade host ECM, lipid, DNA, and      proteins.  •   E...
•   GROUP TRANSLOCATION: Phosphorylate the sugar as it is brought into the      cell (glucose ------> glucose-1-phosphate)...
•   MICROAEROPHILIC: They are facultative anaerobes, but they prefer low O2-       concentration conditions.PEPTIDOGLYCAN ...
o   METHYL-ACCEPTING CHEMOTAXIS PROTEIN (MCP): It is             activated (autophosphorylation) when an attractant molecu...
    TARGET: Pseudomonas and other gram-negatives, but not                            gram-positives.        o CEPHALOSPOR...
o   TETRACYCLINE: Inhibits 30S Ribosome, but binds to a different site.              Bacteriostatic.                   TA...
•   DNA Polymerase III: The most important bacterial polymerase enzyme.          o DNA Poly I and II are used in repair.  ...
 Intercalating Agents         o PHYSICAL MUTAGENS                 Heat: Causes depurination, removes purine from DNA bac...
•   Mutation Frequency: The number of mutants per total viable population. This       quantity is not a good measure of mu...
•   PHYSIOLOGICAL TRANSFORMATION: Natural uptake of naked DNA,       usually derived from dead bacterial cells in the envi...
  When this phage infects another cell, it makes the other cell                     diploid for the piece of replicated D...
o   F CELL is formed when the F-Factor excises back out of the main              chromosome, and takes a few chromosomal g...
o    OriV: Origination of Vegetative Replication. All Plasmids have an origin            of replication.        o Because ...
Return to top                                  MYCOLOGYBASIC FUNGAL STRUCTURES:  •   STEROLS:         o ERGOSTEROL, rather...
   BUDDING SCAR: Yeast divide by budding, forming septa, and                      then finally separating from one anothe...
•   POLYENES:        o AMPHOTERICIN-B: Attacks ergosterol in the fungal cell wall, causing            cell lysis.         ...
•   MINIMUM INHIBITORY CONCENTRATION (MIC): The minimum       amount of drug necessary to effect stasis or lysis of pathog...
    Demonstrate intracellular parasites inside macrophages in patients                    bone marrow.       o PATHOPHYSI...
o LOCATION: Central / South America. Similar distribution as            Coccidiomyces.         o DIAGNOSIS: Immunodiffusio...
   CONVERSION: Unlike the other dimorphics which convert at                    37C, Sporothrix converts at 35C which is w...
  YEAST: Candida in yeast form is part of our endogenous                  mucocutaneous flora, and exists in healthy peop...
o  AFLATOXIN-B, found in moldy grain, is that awful carcinogen that          comes from Aspergillus.        o DISSEMINATED...
Return to top                                  PARASITOLOGYMALARIA (Plasmodium): A SPOROZOAN. The mosquito is the definiti...
o  PLASMODIUM OVALE               Identification: Infected erythrocyte is pale, enlarged, and contains                   ...
o   CHRONIC: Some immunity has been acquired, but there are still             organisms in the erythrocytic stage.        ...
  The intestinal ulcers result in dysentery, or bloody diarrhea. If they                  ulcerate all the way through, c...
  Death usually from cardiac failure or arrhythmias.        o TRYPANOSOMA BRUCEI (GAMBIENSE, RHODIENSE): The causes      ...
   They develop into adults in small intestine and attach to                  intestinal wall via hooking structures.    ...
o   (S) STRONGYLOIDES STERCORALIS -- THREADWORM                  INFECTION / LIFE-CYCLE: Strongyloidiasis = Penetration o...
o    MORPHOLOGY: Scolex with four suckers.                 It has No Rostellum.                 Uterus proglottid has ar...
o   PATHOGENESIS: It more often infects sheep than humans.                 It forms one fluid-filled cyst that is just ja...
  They can lead to adenomatous hyperplasia, which                              increases the risk for cholangiocarcinoma ...
in the colon                         in the bladder and lower                                                             ...
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Bacterial structure

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Bacterial structure

  1. 1. BACTERIAL STRUCTURE, PHYSIOLOGY, AND GENETICSBACTERIAL CELL WALL: From the inside out. • GRAM-POSITIVE: o Plasma Membrane:  Contains transport enzymes.  In oxidative bacteria, contains proteins for oxidative phosphorylation.  Contains no sterols.  Serves as the attachment site for segregation of DNA (cytokinesis). o Peptidoglycan Cell Wall: MUREIN is the name of the cross-linked substance making up the cell wall.  STRUCTURE:  Alternating chains of N-Acetyl-Glucosamine (NAG) and N-Acetyl-Muramic Acid (NAM), connected together in 1,4-linkages.  Each Muramic Acid has a tetrapeptide of alternating D and L amino acids.  Cross-links are made between adjacent chains, between the third amino acid of one chain and the terminal D-Ala of the other chain.  TEICHOIC ACID is also contained within the Peptidoglycan wall.  STRUCTURE: Polymers of Ribitol Phosphate and Glycerol Phosphate.  Lipotechoic Acid is teichoic acid hooked to a glycolipid in inner membrane.  Teichoic Acids are major antigenic determinants of a cells specificity.  PROTOPLAST forms when a bacterium is insensitive to lysis from Lysozyme which normally lyses the bacterial cell wall.  Forms when the cell is in a medium isotonic with its interior.  This is one form of environmentally-induced bacterial resistance. • GRAM-NEGATIVE o Plasma Membrane o PERIPLASMIC SPACE: That area between plasma membrane and peptidoglycan sheath. o Peptidoglycan Layer: Much thinner than the Gram-Positive Peptidoglycan wall. It has been greatly reduced, with part of it contributing to the periplasmic gel. o LIPOPOLYSACCHARIDE (LPS) COAT: Outer covering of gram- negatives.
  2. 2.  Endotoxin: LPS coat is the basis for gram-negative bacterial endotoxin, which causes anaphylaxis.  STRUCTURE:  Lipid-A: Toxic component.  Oligosaccharide Side Chain: Antigenic determinant  BRAUNS LIPOPROTEIN: Anchors the outer membrane to the peptidoglycan layer. It actually connects to the third amino acid in each peptidoglycan chain.  BAYERS JUNCTIONS: Zones of adhesion between the outer and inner membrane. o SPHEROPLASTS result in gram-negatives if you attempt to kill resistant cells with lysozyme. Part of the periplasmic space remains intact. • ACID-FAST BACTERIA: Mycobacteria. Share similar staining properties as Gram-Positive. o MYCOLIC ACID: They have an outer coat of waxy material made of Mycolic Acid, which is extremely impermeable.CELLULAR STRUCTURES: • CAPSULE: Polysaccharide slime that can evade host defenses and adhere to surfaces. They are virulence factors. o Streptococcus Pneumonia • FLAGELLA: Helical protein made of flagellin o Types of Flagella:  Monotrichous: Single flagellum.  Lophotrichous: Two or several flagella oriented in a bipolar, linear fashion.  Peritrichous: Flagella oriented all about the cell. o Basal Body: Intracellular structure that anchors the flagellum. • PILI: Extensions of cytoplasmic membrane with little openings. Made of pilin. o Common Pili o SEX PILI: Special kind of pili. • CYTOSOL: o Ribosomes: 30S + 50S subunits = 70S ribosomes. • SPORE: Produced by some Gram positive rods. o It is produced in response to poor nutrition. o It is made of a coat that is keratin-like and rich in Cys. o Has special chemical called dipicolinic acid.BACTERIAL GROWTH: • TEMPERATURE o PSYCHROPHILES: Grow best at cold temperature. o MESOPHILES: Grow best at medium temperature. All pathogenic bacteria are mesophiles. o THERMOPHILES: Grow best at hot temperature.
  3. 3. BACTERIAL SECRETIONS: • Extracellular Proteases are secreted to degrade host ECM, lipid, DNA, and proteins. • EXOTOXINS: Secreted substances that exhibit host toxicity. o A-B TOXINS: Examples = Cholera Toxin, Diphtheria Toxin. Exotoxins that ultimately act intracellularly.  STRUCTURE: Two major subunits. The B portion binds to the cell and the A portion is injected into cell to exhibit toxic effect.  A = Activity Subunit.  B = Binding Subunit.  SIMPLE A-B TOXIN:  Monocistronic (encoded by one gene)  Two subunits are covalently connected by disulfide bond.  COMPLEX A-B TOXIN: Multiple subunits of B and only one A subunit.  Polycistronic (encoded by multiple genes)  Subunits also linked by disulfide bonds. o MEMBRANE-DISRUPTING TOXINS: Pore-forming toxins.  No enzymatic activity -- only ability to insert into cell membrane. o SUPERANTIGENS: Toxins of superantigen class that indiscriminately bind to MHC-II and TCR, and thus induce polyclonal activation of T- Cells.  Examples:  Staph Enterotoxin  Strep Exotoxin-A  TSS ToxinBACTERIAL CELL TRANSPORT: • PASSIVE TRANSPORT • ACTIVE TRANSPORT: Active means of transporting molecule (nutrients such as lactose) into the bacterial cell. o PROTON MOTIVE FORCE: Resistant to shock. Transport facilitated by the electron transport chain.  Protons are pumped out of the cytoplasmic membrane into periplasmic space.  Protons spontaneously migrate back in the membrane, with their concentration gradients, through ATP-Synthase channels to generate ATP. o ATP-DEPENDENT TRANSPORT: Sensitive to shock. Direct dependence on ATP for transport.  Binding Protein is also required to get substance in the cell. This protein is in the periplasmic space.  Transporter Protein must also be present in inner cytoplasmic membrane.
  4. 4. • GROUP TRANSLOCATION: Phosphorylate the sugar as it is brought into the cell (glucose ------> glucose-1-phosphate), in order tto maintain concentration gradient. o Phosphotransferase (PTS) System is the name of the group-transport system for glucose. • IRON TRANSPORT: SIDEROPHORES, iron-sequestering proteins, are secreted by bacterial cells. o Siderophore bind the iron and then interact with receptors on bacterial membrane, to bring in the iron. o Siderophore-iron complex is endocytosed into cell. o Iron is an essential mineral for all bacteria.BACTERIAL METABOLISM: • Embden-Meyerhof Glycolysis: Standard pyruvate-forming anaerobic glycolysis o Streptococcus • Mixed-Acid Fermentation: Form formic acid and acetic acid as byproducts. o Escherichia Coli o Enterobacteriaceae • Butanediol Fermentation: Enterobacter • Butyric Acid Fermentation: Clostridium • Aerobes: Mycobacterium TuberculosisOXYGEN NUTRITION: • FREE RADICAL OXYGEN: o SUPEROXIDE DISMUTASE breaks down the Superoxide Anion, O2-2. It is required for bacteria to survive in the presence of oxygen. o CATALASE breaks down Hydrogen Peroxide, H2O2. It is not required, but some bacteria possess it. • OBLIGATE ANAEROBES: Bacteria that undergo anaerobic fermentation and cannot survive in the presence of oxygen. o They do not have Superoxide Dismutase, thus O2 is poisonous as it will yield oxidative radicals that cannot be broken down. • OBLIGATE AEROBES: Bacteria that undergo strictly oxidative respiration and require oxygen for survival. o They do have Superoxide Dismutase and thus can survive in O2 • FACULTATIVE ANAEROBES: Bacteria that can undergo fermentation in the absence of O2, or respiration in its presence. o They do have Superoxide Dismutase and thus can survive in O2. • AEROTOLERANT ANAEROBES: Bacteria that never undergo oxidative respiration but can nonetheless tolerate the presence of oxygen. o They do have Superoxide Dismutase. o Streptococcus Pneumonia is an aerotolerant bacterium that has superoxide dismutase but not catalase.
  5. 5. • MICROAEROPHILIC: They are facultative anaerobes, but they prefer low O2- concentration conditions.PEPTIDOGLYCAN SYNTHESIS: Occurs in three compartments of the cell. • CYTOSOL: UDP-aided N-Acetyl-Muramic Acid is synthesized with a pentapeptide chain hanging off it. o The final product will have only a tetrapeptide. The extra residue is an additional terminal D-Alanine. • CELL MEMBRANE: NAM-Pentapeptide Precursor is attached to Bactoprenol receptor in the plasma membrane. o Inside the cell membrane, N-Acetyl-Glucosamine is added to the NAM- Pentapeptide precursor. • PERIPLASMIC SPACE (or OUTSIDE MEMBRANE): The NAM-NAG Disaccharide is attached to the growing glycan chain. o TRANSPEPTIDASE forms cross-links between the new subunit and the existing chain.  The terminal (fifth) D-Alanine is released as an energy-transducer in order to fuel the transpeptidation reaction. o PENICILLIN-BINDING PROTEINS (PBPs): Several proteins in the periplasmic space, that are required to aid in the cross linking reactions.CELL-SURVIVAL MECHANISMS: • SOS-SYSTEM is invoked in response to damage done to DNA (see DNA repair below) • HEAT-SHOCK proteins are up-regulated in response to heat. Most of the proteins are protein-chaperones that aid in folding proteins. They are needed in higher concentration in presence of heat which threatens denaturation of proteins. • SPORULATION: Formation involves a cascade of sigma-subunits (similar to phosphorylation cascade), culminating in gene-regulation that cause spore- formation.CHEMOTAXIS: A series of "biased random walks" that results in directed movement. • Flagellar Movement o RUN: Counterclockwise rotation of flagella, which produces forward motion. o TUMBLE: Clockwise rotation of flagella, which causes bacteria to stay in place. • REGULATION: Bacteria goes toward attractant by balancing the relative amounts of tumbles -vs- runs. E. Coli example: o When concentration of attractant goes up, tumbles are suppressed and runs take over. o When concentration of attractant subsides, the tumbles take over.
  6. 6. o METHYL-ACCEPTING CHEMOTAXIS PROTEIN (MCP): It is activated (autophosphorylation) when an attractant molecule binds to a membrane receptor. o TUMBLE-RESPONSE REGULATOR PROTEIN (CheY): At end of signal cascade, it binds to a flagellar motor protein and causes the productive (counterclockwise) motion of flagella.  When attractant molecules disengage the receptor, the MCP re- methylates, the CheY lets go, and the default tumble resumes. o ACCOMMODATION: Spontaneous methylation of the MCP leads to deactivation of the MCP.  Accommodation resets the cells sensitivity to the attractants, such that a higher level is required for continued activation. o MOLECULAR MEMORY: The overall basis for chemotaxis. The cell senses its level of activation, and can only continue to be activated if it is in a region of increased level of attractants, compared to where it was a short time ago.PHYSICAL BACTERICIDAL AGENTS: • HEAT: Wet heat is more effective than dry heat. • RADIATION: UV-Light • FILTRATIONANTIBIOTIC DRUGS • beta-LACTAMS: They irreversibly inhibits Penicillin-Binding Proteins in the bacterial periplasmic cell, thereby inhibiting peptidoglycan transpeptidation. All are primarily bactericidal. o PENICILLINS: beta-Lactam.  HYPERSENSITIVITY is possible.  PENICILLIN-G: Natural Penicillin, active against gram-positives  TARGET: Streptococcus Pneumonia, Syphilis.  RESISTANCE is due to beta-Lactamase, which cuts the beta-Lactam ring.  Staph Aureus produces an inducible protein called Penicillinase and is thus resistant to Penicillin.  METHICILLIN, OXACILLIN: Penicillinase-Resistant, Narrow- spectrum Penicillins.  TARGET: Staph Aureus is thus susceptible to these.  AMPICILLIN: Broader-Spectrum Penicillin. It is broader- spectrum because it can traverse the outer membrane of some gram-negatives.  TARGET: Used against gram-negatives.  Not effective against Pseudomonas  PIPERACILLIN: Extended-spectrum Penicillin
  7. 7.  TARGET: Pseudomonas and other gram-negatives, but not gram-positives. o CEPHALOSPORINS: Another class of beta-Lactams.  HYPERSENSITIVITY is possible.  FIRST-GENERATION: Targeted penicillin-resistant Gram- Positive cocci and some gram-negative bacilli.  SECOND-GENERATION: Has an extended spectrum to include more gram-negatives.  It is resistant to some plasmid-encoded beta-lactamases, extending its spectrum.  THIRD-GENERATION: Is even-broader spectrum and is most effective against gram-negatives.  TARGETS: E. COLI and other culprits of UTIs. o CARBEPENAMS: beta-Lactam drug with different synthetic structure than Penicillin (containing Sulfur).  IMIPENEM is the only Carbapenem available in US. o MONOBACTAMS: beta-Lactam drug  AZTREONAM is the only one used in the US.  TARGET: Aerobic gram negatives. Not good for gram- positives. o beta-LACTAMASE INHIBITORS: Drugs that can sometimes be given with beta-Lactams to aid in fighting resistant strains.  CLAVULANIC ACID: beta-Lactam analog that binds irreversibly to beta-Lactamase inhibitors.  SULBACTAM: Another irreversible-binding beta-Lactam analog.  These drugs should not be combined with Penicillinase-Resistant Penicillin (i.e. Methicillin)• VANCOMYCIN: Non-beta-Lactam inhibitor of Peptidoglycan assembly. o TARGET: Multi-resistant gram-positives. o SIDE-EFFECTS: CNS Toxicity. It is only used when necessary. o RESISTANCE is due to modification of target site.• POLYMYXINS: They inhibit cell membrane function. Simple peptides with a cationic detergent effect. o ONLY TOPICAL USE: They interact with host cell membranes and thus are not used systemically.• TRANSLATION INHIBITORS: 30S RIBOSOMAL SUBUNIT o AMINOGLYCOSIDES:  SIDE-EFFECTS: They all exhibit ototoxicity and renal toxicity  STREPTOMYCIN:  TARGET: Must work against Aerobes -- drug is transported into bacterium via oxidative phosphorylation in membrane.  It is not effective against any intracellular pathogens because it cant get into Eukaryotic cells -- no Rickettsiae or Chlamydiae.  GENTAMICIN
  8. 8. o TETRACYCLINE: Inhibits 30S Ribosome, but binds to a different site. Bacteriostatic.  TARGET: Broad Spectrum. Active against Rickettsiae and Chlamydiae.  Affects normal gut flora.  Dont give with milk: It chelates calcium.  RESISTANCE has developed, especially due to overprescription. • TRANSLATION INHIBITORS: 50S RIBOSOMAL SUBUNIT. o CHLORAMPHENICOL: Inhibits Peptidyl Transferase in 50S subunit.  SIDE-EFFECT: Some toxicity.  TARGET: Broad-spectrum antibiotic.  Diffuses across blood-brain barrier, therefore useful for Meningitis.  RESISTANCE: Due to a plasma-encoded Acetyltransferase that acetylates and inactivates the drug. o ERYTHROMYCIN: Binds to the same site as Chloramphenicol.  TARGET: Broad-spectrum. Has both bacteriostatic and bacteriocidal activity.  RESISTANCE: Methylation of the ribosomes, causing the target- site to be blocked. • QUINOLONES: They inhibit DNA replication. Specifically they target DNA Gyrase, which forms or removes supercoils during replication (like a helicase). o NALIDIXIC ACID:  TARGET = Urinary tract infection because it gets into urine well. o FLUOROQUINOLONE: Good body distribution and popular drug.  TARGET = Anaerobics.  RESISTANCE due to alteration of the DNA Gyrase target enzyme. • RIFAMYCIN: Inhibits transcription by binding to RNA-Polymerase. o TARGET = Aerobic bacteria, Mycobacterium Tuberculosis. • METABOLIC INHIBITORS: Inhibits steps in Folate Synthesis, a precursor required for bacterial growth, which bacteria normally make themselves. o SULFONAMIDE: Structural analogue of PABA.  MECH: It inhibits Dihydropteroate Synthetase, preventing formation of Dihydrofolic Acid.  TARGETS: UTIs caused by E. COLI.  RESISTANCE: Plasma-encoded, it modifies the target enzyme, reducing its affinity for the drug.  Resistance can also occur by reduced permeability of the bacterium. o TRIMETHOPRIM: Structural analogue of Dihydrofolate.  MECH: It inhibits Dihydrofolate Reductase, preventing formation of Tetrahydrofolic Acid.  RESISTANCE is by same mechanism as above. o Sulfonamide and Trimethoprim together have a synergistic effect.DNA REPLICATION and TRANSCRIPTION: Bidirectional and Semiconservative.
  9. 9. • DNA Polymerase III: The most important bacterial polymerase enzyme. o DNA Poly I and II are used in repair. • SIGMA FACTOR: A protein that is required for the RNA Polymerase to recognize the promoter site and effect transcription. o Once transcription begins, the sigma factor falls off. • TRANSCRIPTION: o Polycistronic: Multiple genes encoded in one transcript. o Coupled Transcription/Translation: Ribosomal translation begins before transcription is even complete, and there is no post-transcriptional modifications (i.e. splicing).GENETIC MUTATIONS and REPAIR: • Types of Mutations: o TRANSITION: A mutation exchange of purine for purine or pyrimidine for pyrimidine.  CAUSES:  UV-Radiation  Deaminating and alkylating agents  base analogs.  Spontaneous o TRANSVERSION: A mutation exchange of purine for pyrimidine, or pyrimidine for purine.  CAUSES: Strictly spontaneous; no causative agents. o MICRO INSERTIONS / MICRO DELETIONS: They can be frameshift mutations, and they can be offset by a corresponding mutation downstream from the original, to restore the reading frame. o Missense: Change of coded amino acid from one residue to a different residue. o Nonsense: Change of coded amino acid to a stop codon, truncating the protein and rendering it dysfunctional. o CONDITIONAL LETHAL MUTATION: A mutation that is lethal under one condition (usually temperature) but not another. This is most frequent with Temperature-Sensitive Mutants.  Permissive Condition: The condition under which the bacterium survives. (Low temperature)  Non-Permissive Condition: The condition under which the bacterium perishes. (High temperature). • MUTAGENS: o CHEMICAL MUTAGENS  Base Analogs: Compounds that resemble a nucleotide base and cause mispairing when inserted.  5-Bromouracil resembles Thymine and gets in the place of Thymine in a chain, which ultimately can lead to an A--T to G--C transition.  Chemical Compounds
  10. 10.  Intercalating Agents o PHYSICAL MUTAGENS  Heat: Causes depurination, removes purine from DNA backbone, potentially resulting in deletion.  UV-Light: Causes formation of Thymine dimers  X-Ray Radiation: Cause double-stranded breaks in DNA that lead to deletions.  Can also cause radical formation. • ERROR CORRECTION: Briefly, normal correction mechanisms. o EDITING: Transiently incorporated bases are examined to make sure they are paired correctly. If they arent then they dont stick in the first place. o PROOFREADING: 3 ------> 5 exonuclease activity of DNA polymerase, to make sure all bases are paired correctly. A mispair will undergo excision repair by the DNA polymerase. o Post-Replicative Correction o SOS REPAIR SYSTEM: The SOS Repair system is invoked when Thymine dimers are formed from UV damage. It is a "last-resort" repair system, and is error-prone.  Normally, excision-repair occurs which is much more accurate.  Lex-A gene is the gene that expresses a repressor proteins which normally suppresses SOS activity. When LexA is turned off, the SOS system is induced..  REPAIR PROCESS:  Rec A gene is activated by the presence of single-stranded DNA which is indicative of DNA damage.  RecA then interacts with LexA, causing it to autocleave and turning it off ------> SOS System activates.  umuC and umuD are SOS repair proteins, normally suppressed by the Lex-A gene. These proteins make DNA polymerase less base- specific (more error-prone).DIRECTED -VS- UNDIRECTED MUTAGENESIS: Mutation occurs in an undirected,random fashion. • An antibiotic resistance mutation does not occur as the result of introduction of antibiotic. It can occur at any time. • FLUCTUATION TEST: Take two strains, grow them up, introduce Streptomycin into each of them at the same time, and later count how many colonies you have. o RESULT: You will have different numbers of colonies in each strain, because Strep-R mutations occurred at different times in each strain. o CONC: Strep-R mutations occur independently of the introduction of Streptomycin.
  11. 11. • Mutation Frequency: The number of mutants per total viable population. This quantity is not a good measure of mutation, because theres no baseline population to compare to. • Mutation Rate: The probability of a mutation per cell per generation. A much better measure of mutation.AMES TEST: Test for mutagenesis, by measuring the number of backward (reversion)mutations in His- Salmonella cells grown without Histidine. • Introduce Rat-Liver Microsomal Oxidases into the bacterial culture. These enzymes are added in order to metabolize the potential carcinogens (mutagens), as most require metabolic activation before becoming mutagenic. • RESULTS: The more bacterial colonies you get, (bacteria living on the His- bare medium), the greater the mutagenicity of the compound being tested.REVERSIONS: Reversal of a mutation to restore the wild-type. • True Reversion: True backward mutation. Changing the original mutation back to the same way it was. The original mutation is replaced. • SUPPRESSION: A second mutation which in some way restores or partially restores the function of the original mutated protein. The original mutation remains in place. o INTRAGENIC SUPPRESSION: Second mutation within the same gene.  Restore Reading Frame: A micro deletion to suppress a micro insertion, or vice-versa. This often will restore a truncated (nonsense) protein.  Restore Tertiary Structure: Suppression of a point mutation that replaces another residue somewhere else in the protein, which in some way makes the protein once again fold correctly in its tertiary conformation. o INTERGENIC SUPPRESSION: Suppressor mutation alters a tRNA Anticodon so that it recognizes what would otherwise be a stop codon (UAG).  One base-pair of the anti-codon mutates such that the tRNA then codes an amino acid for the stop codon. Depending on the mutation, three surrogate amino acids are possible: Tyr, Ser, Gln.  This might supress the original mutation by eliminating the stop codon and allowing the protein to read past a nonsense mutation. o This process is also called Codon Specific Translational Suppression.TRANSFORMATION: Uptake of naked DNA • ARTIFICIAL TRANSFORMATION: Occurs in labs, to make DNA probes. o Electric Voltage o CaCl2
  12. 12. • PHYSIOLOGICAL TRANSFORMATION: Natural uptake of naked DNA, usually derived from dead bacterial cells in the environment. o GRAM-POSITIVES: The cells must be competent in order to undergo transformation and take up naked DNA.  COMPETENCE: The ability for gram-positives to take up naked DNA.  COMPETENCE-FACTOR: Protein secreted by competent cells, that has autolysin activity (to permeate the membrane), and digests exogenous DNA into absorbable fragments.  Double-stranded DNA is denatured to single-stranded and then taken into the cell indiscriminately.  If it shares homology with any of the host DNA (genome or plasmid), it can be incorporated into genome via generalized recombination.  Any foreign DNA that has no homology will be degraded. o GRAM-NEGATIVES: There is no competence-factor per se.  Only homologous DNA is taken into the cell, and it is taken in as double-stranded.  Transformosomes: Extrusions of outer membrane formed in order to facilitate DNA uptake.TRANSDUCTION: Transfer of host genomic DNA via a bacteriophage virus. • GENERALIZED TRANSDUCTION: Non-specific transfer in which any piece of DNA may be transferred to any cell. o PROCESS: Bacteriophage incorporates a random piece of host-DNA during packaging. This is an error in viral packaging during the lytic cycle, which occurs infrequently. o It occurs in Gram-Positives -- Staph and Strep. o MAPPING: If a single virion incorporates two genes from the host, then you know that those two genes are in close proximity to each other. • SPECIALIZED TRANSDUCTION: Transfer of genes flanking a specific Att attachment region on the host-genome. o Viral genome picks up a couple of genes flanking its attachment site when it excises from the host genome. This is an error in viral replication which occurs infrequently. o Site-Specific Recombination: When phage gets into recipient, it recombines with it replicatively in a site-specific fashion, creating a diploid of whatever genes it contained. o lambda-Phage: It can undergo specialized transduction, creating a DIPLOID cell in the recipient.  It inserts next to the Gal marker in host genome, where it resides as a prophage until it is induced to undergo lytic cycle.  Once in a million times by accident, lambda-phage takes a piece of the host genome with it, forming lambda-D-Gal Phage (D = defective).
  13. 13.  When this phage infects another cell, it makes the other cell diploid for the piece of replicated DNA -- the Gal gene.  The recipient may now have a Gal- and Gal+ copy of the gene. o PHAGE CONVERSION: Imparting genes onto a recipient that were inherently part of the phage genome to start with -- not part of the host genome.  In this case, transduction is not the consequence of a random error. Rather, every infected cell becomes transduced with the gene.Types of Recombination: • SITE-SPECIFIC RECOMBINATION: Replicative recombination in which only a small degree of homology is required, but which occurs at a very specific site. o Recombination is replicative and results in a partially diploid product. • GENERALIZED RECOMBINATION: Non-replicative recombination that requires presence of the Recombinase (Rec) Gene to effect recombination. o A high degree of homology is required. • ILLEGITIMATE RECOMBINATION: Replicative recombination in which no homology is required, such as with R-Plasmids. o Transposable Elements undergo illegitimate recombination.CONJUGATION: Classical conjugation of the F-Plasmid. • EPISOME: A series of genes that can exist as a plasmid or can incorporate themselves into the genome. F-Factor is a plasmid. • F-FACTOR: Plasmid encoding for Pili which allows for sexual conjugation (transfer) of genetic material. o A bacterium that possesses the F-factor is F+ (male). o A bacterium that lacks the F-Factor is F- (female). o STRUCTURE:  Contains a sex pilus gene  Contains an Ori of replication. • Classical Conjugation: Replicative transfer of the F-Factor from F+ cell to F- cell. This induces the F- cell to become F+. • High Frequency Recombination (HFR): When the F-Factor is incorporated into the host genome, the cell becomes known as an HFR Cell. HFR-Cells are F+ but cannot transfer their F-Factor to recipients. o CONJUGATION in this case does not result in converting a cell to F+, because incomplete transfer of the genome occurs, and some of the F- Factor genes are not replicated. o The Ori site of the F-Factor is the origin of replication for the entire genome in this case. Because the genome is too long to be transferred in its entirety, some portion of the F-Factor almost always is not transcribed.
  14. 14. o F CELL is formed when the F-Factor excises back out of the main chromosome, and takes a few chromosomal genes with it. (Imperfect excision).  SEXDUCTION: Transfer of F factor to an F- recipient, making it F+.  The recipient cell is then known as Secondary F Cell because it is diploid for the transferred chromosomal genes.TRANSPOSABLE ELEMENTS: Genes that can transfer themselves from one location toanother by some mechanism. • INSERTION SEQUENCES (IS-ELEMENTS): Basically, just one gene, flanked by inverted repeats on either side. o The single gene on the inside codes for Transposase, the protein that allows the gene to jump around. • TRANSPOSONS: Insertion-sequences that contain more genes on the inside, and are bounded flanked by IS-elements on either side. o TnA-TYPE TRANSPOSONS: They contain genes that code for transposases, which allow for movement. Thus they can move be illegitimate, replicative recombination.  Genetic Contents: May contain various resistance genes.  tnpA: Transposase gene. Required for transposition.  tnpR: Transposon resolvase gene. Required for transposition.  bla: beta-Lactamase (resistance) gene. o COMPOSITE TRANSPOSONS: They do not contain the tnpA and tnpR genes -- only the IS-elements plus any genes that code for resistance.  Recombination with composite transposons requires the Rec-A gene, occurs by generalized recombination, and is non-replicative.  They are still flanked by inverted repeats. • TRANSPOSITION: Process = Donor plasmid recombines with recipient plasmid in a process of illegitimate, replicative recombination. o They form a large composite transposon known as a Cointegrate. o Resolvase then resolves the Cointegrate into two plasmids, both of which contain the transposon and internal (resistance) genes. • MUTATION: Transposons can cause mutation in the genes they donate to. o They can be spliced into the middle of the gene, turning the gene off. o They can take large pieces of DNA with them when they transpose. o They can change regulation of a gene, by moving a gene close to a new promoter.PLASMIDS: Covalently Closed circular DNA, existing independent of the host genome. • SIZE: 1.7kb - 700kb • SELF-REPLICATION: Plasmids can replicate independently, but they depend on host polymerase replication machinery.
  15. 15. o OriV: Origination of Vegetative Replication. All Plasmids have an origin of replication. o Because of self-replication, plasmids can be transferred between phylogenetically unrelated species.• PLASMID SURVIVAL: Plasmids have a set number of copies per cell. Cell can withstand only a certain number of plasmids. This is a mode of selection against plasmids, and, all other things held constant, plasmids are selected against.• CONJUGATIVE PLASMID: A plasmid containing genes for making Pili. This is not an F-Factor, but a different "non-classical" form of conjugation. o GENETIC CONTENTS:  OriV: Origin of replication.  OriT: Origin of Transfer  tra: Transfer Genes that code for Pili.  Resistant-determining gene. o TRANSFER:  Conjugative plasmids can direct the transfer of non-conjugative plasmids. All a host-cell needs to transfer all of its plasmids is a single conjugative cell that can build the pili.  There is no transfer of genomic DNA (as in F-Factor and HRF) -- only transfer of the plasmid itself.• NON-CONJUGATIVE PLASMID: Can only be transferred in the presence of a conjugative plasmid. o GENETIC CONTENTS  OriV: Origin of replication.  nic: A "pre-OriT" site, or nicking site, that becomes OriT once cleaved.  mob: It codes for an endonuclease that cleaves the nic site ------> OriT, enabling the non-conjugative plasmid to transfer to a new cell in the presence of Pili.  Resistance-determining gene.• R-PLASMIDS: Also known as Multi-Resistant Transfer Plasmids (MTRP). Can be either Conjugative or Non-Conjugative. o GENETIC CONTENTS:  r-Region: Contains one or multiple resistance genes.  The resistance region is usually flanked by IS-elements and contained on transposons.  RT Region: Contains gene for transfer. o TRANSFER: The r-Region is usually contained on transposons. Transfer primarily occurs by conjugation and illegitimate recombination.  Conjugation allows transfer of resistance between bacterial species.  Generalized Transduction can also occur within the same species -- for Gram-positives Strep and Staph.
  16. 16. Return to top MYCOLOGYBASIC FUNGAL STRUCTURES: • STEROLS: o ERGOSTEROL, rather than Cholesterol, dominates cytoplasmic membrane. It is a frequent target for anti-fungal drugs. o ZYGOSTEROL, precursor to Ergosterol, is also found in cell wall. • CELL WALL: o It is made of three polysaccharides unique to fungi.  CHITIN: Long unbranched chains of N-Acetylglucosamine  MANNAN  GLUCAN o CHITIN SYNTHASE: The cell wall is located outside of the cell membrane, and there is a periplasmic space in between the wall and cell membrane. Chitin Synthase is located in this space and is thus a potential target for antifungal drugs (but none are developed yet). • Reproductive Structures: o MOLDS:  CONIDIA: Asexual reproductive elements.  The TIPS of the conidia are crucial for growth. They spray digestive enzymes which allow to penetrate through soil as they grow.  GERMINATION: Formation of many hyphae and then a mycelium. The mold is most susceptible to phagocytic attack during the germination stage.  MYCELIUM: Intertwined mass of budding HYPHAE. Because it is too big, mycelia are not easily digested by phagocytes.  SEPTATE: Septate fungi form cell walls, or septa, as they grow up along each hyphae.  NON-SEPTATE: Non-septate fungi form each hyphae as one continuous cell.  FRUITING BODIES are formed off of the mycelium, whenever nutrients become scarce. Those fruiting bodies can leave to form new conidia.  SPORES: Sexual reproductive elements.  ASCOSPORE: Most common spore form, four or eight asci in each spore. o YEAST: Reproduce strictly by budding, where each daughter cell juts out from its parent. Size of 2-60 micron.
  17. 17.  BUDDING SCAR: Yeast divide by budding, forming septa, and then finally separating from one another. A characteristic scar is left on the cell after its daughter cell has separated from it.  PSEUDO HYPHAE are formed when the yeast dont actually separate.  POLARITY: Yeast budding can be BIPOLAR or MULTIPOLAR. Multipolar yeast have budding scars all over it. • DIGESTIVE VACUOLES: Degradative role. These are equivalent to (but not the same as) lysosomes.INFECTION: • Abrasion • Maceration: Skin lacerated and wet. • BurnsIMMUNITY: Immunity against fungal infections is cell-mediated -- not humoral. • We have natural antibodies to fungal galactomannans, except these only are expressed in the mold form. • HYPHAE and YEAST CELLS: Neutrophils are the primary defense. • DIMORPHICS: They are slowed, but not killed, by Activated Macrophages (IL2, IFN-gamma).MYCOTOXINS: Fungal toxins, produced in the environment, but not in-vivo, once thefungus has already infected. No known fungal toxins are produced in-vivo. All chemicaltissue damage is the consequence of host-defenses.FUNGAL CLASSIFICATION: • ZYGOMYCETES: Forming Zygospores, phylogenetically simple and similar to Euglena. • ASCOMYCETES: They create eight ascospores inside each ascus, or sexual reproductive structure. o Many of the fungi previously classified as Fungi Imperfecti may actually fall into this category. It depends on whether or not the have sexual structures, and whether those structures have been discovered. o Thus you could say that most pathogens fall into this class. • BASIDIOMYCETES: No medically important fungi are in this class. They are the most structurally complex. • FUNGI IMPERFECTI: Fungi, mostly Dimorphics, that do not have a sexual stage of reproduction. o There are no sexual spores, and fungi reproduce only by forming conidia.ANTI-FUNGAL DRUGS:
  18. 18. • POLYENES: o AMPHOTERICIN-B: Attacks ergosterol in the fungal cell wall, causing cell lysis.  IV-ADMINISTRATION: Amphotericin-B is not absorbed in the GI-Tract and must be administered IV.  TOXICITY: It is highly toxic because ergosterol is very similar to cholesterol, thus Amphotericin also has cross-reactivity to cholesterol in human cell membranes.  FUNGICIDAL: They cause fungal cell lysis.  SIDE-EFFECTS: Chills, fever, dyspnea can be seen.  RENAL DYSFUNCTION is the most common, virtually inevitable complication. o NYSTATIN: Alternative polyene similar to Amph-B.• AZOLS: They all work by blocking the CYTOCHROME-P450 Synthesis of Ergosterol, thus inhibiting fungal growth. Specifically it interferes with conversion of lanosterol to ergosterol. o FUNGISTATIC: Action is fungistatic. o FLUCONAZOLE: Most popular azol, used for disseminated dimorphic infections.  Fluconazole is often used prophylactically in AIDS patients (indefinite treatment is required after exposure to a systemic pathogen).  Fluconazole is the single best treatment for Cryptococcal Meningitis.  CANDIDIASIS RESISTANCE: It will kill Candida Albicans, but other species of Candida are resistant. Thus treatment with Fluconazole can result in a Candida non Albicans disseminated infection. o ITRACONAZOLE: Also used for systemic infections.• GRISEOFULVIN: Acts on microtubules within fungal cells, inhibiting growth. o Only works on superficial fungi. o It is very slow acting and thus has limited utility.• POTASSIUM IODIDE: Singularly useful against Sporothrix Schenckii. It is only to toxic to the yeast form -- not the mold form.• FLUCYTOSINE: Active against yeasts -- Cryptococcus Neoformans and Candida Albicans. It is an analog of cytosine which can block DNA synthesis or transcription. o RESISTANCE can occur, making the drug impermeable to fungal cells. o SYNERGY: It is most often used in conjunction with Amphotericin-B, where it has synergistic effects.• UK-109,496: Experimental triazole drug with broad spectrum anti-fungal properties. o It fungicidal for Aspergillus o It is the strongest binder to Cytochrome-P450. It binds so strongly that it is classified as Fungicidal.
  19. 19. • MINIMUM INHIBITORY CONCENTRATION (MIC): The minimum amount of drug necessary to effect stasis or lysis of pathogenic cells.LAB DETECTION OF FUNGI: • SABOURAUDS AGAR: The most commonly used agar for culturing fungi for identification. • MORPHOLOGY: Molds are usually identified by the morphology of their conidia. o This process is slow because conidium production may not occur for weeks, similar to waiting for a flower to bloom. • EXOANTIGEN TEST: Most of the dimorphic fungi are identified by an immunodiffusion assay utilizing distinct antigens on their cells.CUTANEOUS FUNGI: DERMATOPHYTES are the names of the fungi that causesuperficial infection.SYSTEMIC FUNGI: Most systemic fungi are thermally dimorphic. • THERMAL DIMORPHISM: Fungi exist as mold at ambient temperature, but convert to Yeast form at body temperature. o CONVERSION:  Converting from mold to yeast form puts new adhesins on their cell membranes, which allows them to invade and makes them pathological.  Cell wall loses disulfide bonds during conversion. o GALACTOMANNANS: Antigenic cell wall component. We have antibodies to these, but they are usually only present in the mold stage. They disappear in the yeast stage, thus the yeast stage is more virulent. • HISTOPLASMA CAPSULATUM: Thermally Dimorphic o STRUCTURE: Shares the same sexual precursor with Blasto: Ajellomyces o INFECTION: Histoplasma conidia range in size, from Macroconidia to Microconidia.  TUBERCULATED MACROCONIDIA are found in mold form and inhaled.  MICROCONIDIA can also be inhaled and reach the lungs.  After conversion, budding yeast are small enough (5micron) that they can get clear down to the alveoli when inhaled. Histoplasma is found in CHICKEN SHIT. o DIAGNOSIS:  Look for H-Antigen on immunodiffusion assay of the URINE. The body concentrates the antigen in the urine, making it the fastest, easiest test (although its expensive).  DNA-Probe for 16s RNA  Demonstrate thermal conversion in culture. Conversion will yield small, single-budding yeast.
  20. 20.  Demonstrate intracellular parasites inside macrophages in patients bone marrow. o PATHOPHYSIOLOGY: Acute Histoplasmosis is most similar to tuberculosis in its histology and pathophysiology.  Pulmonary Infection will leave little calcified granulomas that can be silent in immunocompetent patients.  Histoplasma live intracellular, inside alveolar macrophages. This is their route of dissemination, hence primary sites of dissemination are reticuloendothelial. o DISSEMINATION: Histoplasmosis disseminates primarily to Reticuloendothelial System (liver and spleen). o AIDS: It is common in AIDS, suggesting that CD4+ is essential to host defense.• BLASTOMYCES DERMATITIDES: Thermally Dimorphic o STRUCTURE: Shares the same sexual precursor with Histo: Ajellomyces. Blastomycoses exhibit broad-based budding. o PATHOPHYSIOLOGY: Blasto also has huge conidia, but in yeast form it is primarily extracellular rather than intracellular.  It forms uncalcified granulomas in the lungs in immunocompetent people. These granulomas are similar to the cutaneous ones formed by Sporothrix. o DIAGNOSIS:  Skin lesions will be present, whereas in Histoplasmosis skin lesions are usually absent.  Still must demonstrate conversion in culture.  Enzyme Immunoassay assay for Exo-Antigen-A, which will be found in blood, CSF, or lymph fluid. This is the most sensitive test for Blastomycosis. o DISSEMINATION: It often disseminates to skin, bone. o AIDS: It is NOT seen in AIDS, suggesting that CD4+ is not essential to host defense. They dont know what is, though.• COCCIDIOMYCES IMMITIS: Thermally Dimorphic. It is most similar to Histoplasma in its presentation and involvement with AIDS. o INFECTION: Initial infection is also pulmonary, and calcified granulomas are formed. o MORPHOLOGY: Arthroconidia initially infect. o VALLEY FEVER: It forms valley fever and is found in the desert southwest. o DISSEMINATION: Relatively common. Can be found in skin, bone, meninges, and later, mucocutaneous. o DIAGNOSIS: Immunodiffusion assay for Antigen-C• PARACOCCIDIOMYCES BRASILIENSIS: Thermally Dimorphic. It is most similar to Blastomyces in its presentation and lack of involvement in AIDS. o INFECTION: Initial infection is also pulmonary, and uncalcified granulomas are formed.
  21. 21. o LOCATION: Central / South America. Similar distribution as Coccidiomyces. o DIAGNOSIS: Immunodiffusion assay for Antigen-P. • CRYPTOCOCCUS NEOFORMANS: Dimorphic, but not thermally dimorphic. o MORPHOLOGY: In tissue, it is a yeast with an enormous polysaccharide capsule.  The Capsule is susceptible to attack only by activated macrophages, hence AIDS renders us helpless.  The capsule also inhibits phagolysosome formation -- inhibits phagocytosis.  Size once desiccated is around 5micron, thus it gets into alveoli.  SEXUAL FORM: In its sexual form it is a Basidiomyce. o INFECTION: PIGEON POOP -- Desiccated cryptococcal yeast are found in pigeon poop. Initially it is inhaled. o CRYPTOCOCCAL MENINGITIS is the most common disseminated form of the disease. Very common in AIDS.  Phenol Oxidase: The fungi have this enzyme, which may explain its affinity for the CNS.  CNS needs epinephrine for their immunity, and this enzyme may in someway block this pathway, making the CNS susceptible.  Alternatively, the fungi may be able to subsist on Catecholamines since they can use it for nutrient. o FOUR SEROTYPES: Four different antigen structures found on the capsule.  TYPE A: Found in USA, in AIDS  TYPE B: Found in Australia (Eucalyptus trees), and not found in AIDS strangely.  TYPE C: Found in Australia (Eucalyptus trees), and not found in AIDS strangely.  TYPE D: Found in Europe, in AIDS.SUBCUTANEOUS FUNGI: Infection occurs by a puncturing wound subcutaneously. • SPOROTHRIX SCHENCKII: o MORPHOLOGY: It has a mother-yeast cell once it converts, which gives rise to cigar-shaped yeast daughter cells of about 10micron each. o INFECTION: Get pricked with a rose-form. The mold-form is introduced with infection, and it quickly converts to yeast form. o SYMPTOMS: In immunocompetent people, just ulcerating skin papules and lesions at site of infection, with no systemic symptoms if treated. o DIAGNOSIS:  Must demonstrate thermal conversion.  Identify typical conidia: cigar-shaped yeast daughter cells with mother yeast-cell.
  22. 22.  CONVERSION: Unlike the other dimorphics which convert at 37C, Sporothrix converts at 35C which is why it is a subcutaneous yeast.  Dermatophytes, which are strictly cutaneous molds, exhibit the same behavior -- they are inhibited at 37C. o DISSEMINATION:  In immunocompromised, it can disseminate to skin, eyes, joints, conjunctivae. Chronic arthritis is probably most prevalent disseminated symptom.  Sporothrix disseminates through Lymphatics. o TREATMENT:  Cutaneous Sporotrichosis is treated with oral KI.  Systemic Sporotrichosis must be treated with Amphotericin-B. • SUBCUTANEOUS ZYGOMYCOSES: Both come from insect-vectors and amphibian shit. Both are prevalent with Diabetic Ketoacidosis. o BASIDIOBOLUS RANIERUM: Amphibious excrement.  Dissemination leads to RHINOENTEROMOPHTOROMYCOSES. (See systemic infections)  Swelling of paranasal sinuses and face.  Terrible swelling of the legs.  Can be treated with KI. o CONIDIOBOLUS CORONATUS:  Leads to Subcutaneous MUCORPHYCOMYCOSES. Swelling of legs.  Can also be treated with KI. • CHROMOMYCOSIS: Caused by infection with Phialophora and Cladosporium. o INFECTION: By direct skin-contact with fungus. It is tropical fungus found in soil. o MORPHOLOGY / DIAGNOSIS: Distinctive brown-pigmented hyphae are found in culture. o SYMPTOMS: Cutaneous lesions with no dissemination. o TREATMENT: Difficult to treat. • MYCETOMA: Infection with Petriellidium Boydii. o INFECTION: Direct contact with bare feet. o SYMPTOMS: Massive induration with draining sinuses. The rower who insisted on rowing barefoot got this disease. o TREATMENT: Difficult to treat.OPPORTUNISTIC FUNGI: • CANDIDA ALBICANS: Candida is dimorphic in that it exists in yeast and hyphae form, but it is not thermally dimorphic. o Morphology:
  23. 23.  YEAST: Candida in yeast form is part of our endogenous mucocutaneous flora, and exists in healthy people in small numbers in oral and vaginal mucosa.  Psuedohyphae: This is also called germ-tubes. When Candida is in the form of psuedohyphae, it can escape neutrophilic attack. Other forms of Candida are susceptible to neutrophilic attack.  HYPHAE: Candida only exists in hyphal state when it is disseminated. In immunocompetent people, immunity keeps the Candida in yeast state.  Hyphae have extra and different adhesins which impart virulence onto them.  Hyphae are of the Ascomyces class. o DEFENSE: Neutrophils are the most important defense. They can phagocytose yeast form, and can release oxidative enzymes onto mycelial form to degrade it.  Neutropenia can thus lead to Candidiasis.  Candida can bind iC3b receptors in a manner that inhibits opsonization. o CANDIDIASIS: Mucocutaneous Candida infection, originating from endogenous flora.  THRUSH: Oral Candidiasis on the tongue. White cheesy stuff. Esophageal Candida can also be found.  RISK FACTORS: AIDS, Diabetes o DIAGNOSIS: KOH preparation, look for associated hyphae and the disease is almost certainly Candidiasis. o TREATMENT: Only Candida Albicans is susceptible to Fluconazole -- not other species.  With AIDS, prophylactic use of Fluconazole leads to selection for Non-Albicans species of Candida, and thus promotes disease of other species.• ASPERGILLUS FUMIGATUS: o MORPHOLOGY: Characteristic finger-like conidia, and septate hyphae. Hyphae are narrow and branch at narrow angles. o AIR CONDITIONERS in hospitals can blow their conidia all over the place when they are turned on initially. The Aspergillus can collect in condensations around the air conditioner, and conidia are dispersed when its turned on. o ALLERGY to Aspergillus is very common. Allergy is usually to the galactomannans (against which we have antibodies) or glycoproteins.  The extent of allergy is proportional to the dosage -- the amount of Aspergillus hyphae present.  Allergy is a pulmonary infection and occurs in lungs.  IMMUNOGENICITY: Aspergillus conidia are not immunogenic. It is not until hyphae are formed, and mycelia, that immune response ensues.
  24. 24. o AFLATOXIN-B, found in moldy grain, is that awful carcinogen that comes from Aspergillus. o DISSEMINATED ASPERGILLOSIS: Septate Hyphae can disseminate in immunocompromised host.  Symptoms: Lung is most common site of immunocompetent and immunocompromised infection.  Acute Pneumonia is common in immunocompromised patients.  Bad prognosis with dissemination to other organs common.  Causes  Immunosuppression  Feeding tube  Use of an indwelling catheter  Spread: Hyphae (not conidia) spread to all organ systems. Dissemination is deadly and is often only detected post-mortem.  IMMUNITY:  Neutrophilic attack against the hyphal form is important in initial protection.  Aspergillus possess extracellular factors that inhibit complement fixation by the alternative pathway.• PNEUMOCYSTIS CARINII: Opportunistic organism of unknown origin. It resembles both protozoa and fungi. o It stains similar to fungi and shows evidence of ascus-like structures, but cell walls like ergosterol. o Due to no ergosterol, it is not sensitive to current anti-fungals.• ZYGOMYCOSIS (MUCORMYCOSIS): Deadly infection of Rhino cerebrum in immuno-compromised host. o MORPHOLOGY: They are true molds and exhibit non-septate, broad hyphae that branch approximately at right angles. o PATHOPHYSIOLOGY: They like to grow in acidic environments or immunocompromised hosts. They invade blood vessels, causing massive infarcts.  DIABETICS are especially vulnerable, since Ketoacidosis reduces effectiveness of Neutrophils. o Genera that cause it:  Conidiobolus  Basidiobolus  Rhizopus (parasitic)  Rhizomucor  Absidia  Mucor  Cunninghamella o Symptoms: Headaches ------> Orbital Cellulitis ------> Cranial Nerve Palsy and hemorrhage ------> coma and death in 2 weeks if untreated.• CRYPTOCOCCUS NEOFORMANS: See systemic infections.
  25. 25. Return to top PARASITOLOGYMALARIA (Plasmodium): A SPOROZOAN. The mosquito is the definitive host (inwhich sexual reproduction takes place), and the human is the intermediate host, in whichlarvae are disseminated. • Species: o PLASMODIUM FALCIPARUM: The most virulent of all of them. It will attack all RBCs indiscriminately.  Identification: Small rings on inside of cell; sometimes multiple parasites inside each erythrocyte. Infected and uninfected erythrocytes may or may not be the same size.  The Schizont forms a ring or double-ring inside the erythrocyte.  Erythrocytic Cycle: 48 Hrs. -- infected erythrocytes rupture 48 hours after initial invasion into RBC.  Malignant Tertian Malaria: It is the most virulent because it has the shortest pre-erythrocytic cycle, and it produces the greatest number of merozoites.  PATHOGENESIS: Schizont in the RBC produces adhesins that bind to ICAM-1, CD46, causing endothelial cell adhesion.  RBC LYSIS can also occur. This can result in anemia, and if rapid, hemoglobinuria which is known as BLACK WATER FEVER o PLASMODIUM VIVAX  Identification: Infected erythrocyte is pale, enlarged, and contains dark pigment. This is because it attacks only immature (large reticulocyte) RBCs.  Erythrocytic Cycle: 48 Hrs. -- infected erythrocytes rupture 48 hours after initial invasion into RBC.  14 to 16 merozoites are in each Schizont.  Benign Tertian Malaria: Intermediate in severity. It can give profound anemia after a week to a month. o PLASMODIUM MALARIAE  Identification: Infected erythrocytes are not enlarged and contain no pigment.  Erythrocytic Cycle: 72 Hrs. -- infected erythrocytes rupture 72 hours after initial invasion into RBC.  Quartan Malaria: Slowest acting disease. After immunity is formed, immune complexes can accumulate in the kidney.  Only 8 Merozoites in each Schizont.
  26. 26. o PLASMODIUM OVALE  Identification: Infected erythrocyte is pale, enlarged, and contains dark pigment. This is because it attacks only immature (large reticulocyte) RBCs.  Erythrocytic Cycle: 48 Hrs. -- infected erythrocytes rupture 48 hours after initial invasion into RBC.  Benign Tertian Malaria• LIFE-CYCLE o SEXUAL CYCLE: Sporogony in the mosquito, taking 1 to 3 weeks.  Mosquito bites a malarious human and thereby ingests male and female Plasmodium gametocytes.  Zygote penetrates mosquito gut wall and forms an oocyst, in which thousands of Sporozoites are grown.  Oocyst ruptures, and thousands of SPOROZOITES are released into mosquito, rendering it infectious to humans. o ASEXUAL CYCLE: Schizogony, formation of the Schizont.  Infected mosquito bites another human.  PRE-ERYTHROCYTIC PHASE: It occurs in the liver.  Sporozoites from mosquitos salivary glands make way to human liver.  Mosquito saliva has anti-coagulant properties.  HYPNOZOITES: P. Vivax and P. Ovale: Some sporozoites stay in hepatocytes and reside in a dormant state.  Sporozoites undergo asexual reproduction to make 2000 - 40,000 MEROZOITES.  ERYTHROCYTIC PHASE: Formation of more Merozoites from Merozoites.  Merozoites (larvae) enter erythrocytes by receptor- mediated endocytosis, where they mature to ring-shaped TROPHOZOITES  Erythrocytic Schizogony: The Trophozoite then undergoes nuclear division to make multinucleated SCHIZONT.  Schizont then creates from 8 to 24 MEROZOITE daughter cells.  RBCs ruptures either 48 or 72 (P. Malariae) hours after infection, releasing the merozoites to infect other cells, and effecting the disease process.  Some daughter cells will be transformed to gametocytes, where they can be picked up by mosquitos.• CLINICAL STAGES OF MALARIA: o ACUTE: All organ systems can be involved. Hepatosplenomegaly, renal failure, CNS vascular problems.  P. Falciparum has the worst acute phase. P. Malaria has virtually no acute phase.
  27. 27. o CHRONIC: Some immunity has been acquired, but there are still organisms in the erythrocytic stage. o RELAPSING: Re-activation of Hypnozoites of P. VIVAX and P. OVALE. o RECRUDESCENT: Recurrent malaria due to immunodeficiency, such as from corticosteroids, stress, or chemotherapy. This differs from relapsing because the organisms did not come from the Hypnozoite stage, but rather from an erythrocytic stage.  Malaria is NOT a problem in AIDS.PROTOZOA: • GIARDIA LAMBLIA: FLAGELLATE INTESTINAL PROTOZOAN that lives on the glycocalyx of intestinal enterocytes, causing Giardiasis. o LIFE-CYCLE / MORPHOLOGY:  Trophozoite form has two nuclei.  Cyst form has four nuclei -- each cyst gives rise to two trophozoites. o INFECTION: Fecally contaminated food and water. o PATHOPHYSIOLOGY:  The creatures adhere to the enterocyte glycocalyx epithelium. This leads to malabsorption and facilitates bacterial metabolism, resulting in non-bloody diarrhea and immense foul-smelling flatulence. o TREATMENT: Flagyl (Metronidazole) • CRYPTOSPORIDIUM PARVUM: FLAGELLATE INTESTINAL PROTOZOAN which causes Cryptosporidiosis. o INFECTION: Fecal-oral transmission. o PATHOPHYSIOLOGY: It also affects the glycocalyx, living actually intracellularly, between the apical plasma membrane and terminal web. It never gets all the way into enterocytes though. o CLINICAL: It leads to diarrhea. It is self-limiting in immunocompetent people but is a problem in immunocompromised people. • ENTAMOEBA HISTOLYTICA: RHIZOPOD that causes Amebiasis and is one of the leading causes of DYSENTERY (bloody diarrhea). o INFECTION / LIFE-CYCLE:  Two stages -- Mobile stage, found in diarrheal stools, infects humans, and non-mobile cyst stage that can be found in all stools.  Cyst form has four nuclei.  Can be transmitted as a cyst in food, or via anal / fecal - oral transmission. o PATHOPHYSIOLOGY:  They initially invade in areas of fecal stasis (low peristalsis) -- the cecum and recto-sigmoid colon. Trophozoites invade through the intestinal epithelium where they can form flask-shaped ulcers in the submucosa.
  28. 28.  The intestinal ulcers result in dysentery, or bloody diarrhea. If they ulcerate all the way through, complications are Amebic Peritonitis or Bacterial Peritonitis.  Amoeba like to eat red cells. They get into the blood and go through portal circulation to liver, where they form Liver Abscesses that looks like anchovy paste. o DIAGNOSIS: Take a fresh stool sample and look for motile trophozoites in the stool. This finding is intermittent, and you should check at least three times before ruling out amebiasis.• TRICHOMONAS VAGINALIS: Pear-shaped, flagellate organism causes Trichomoniasis, a sexually transmitted disease. o LIFE-CYCLE: It exists only as a trophozoite -- no spore form. o PATHOPHYSIOLOGY: Inhabits vagina or prostate. o EPIDEMIOLOGY: Very common parasite, most common in sexually active women in 30s. o DIAGNOSIS: Women will have foul-smelling foamy discharge, itching, and burning. Men are usually asymptomatic. Diagnose by wet-mount of vaginal secretions. o TREATMENT: metronidazole (Flagyl).• TOXOPLASMA GONDII: The cause of Toxoplasmosis. o INFECTION: Ingest cysts from undercooked meat or from contact with cats. Person-to-person (horizontal) transmission does not occur, but mother-fetus (vertical) transmission does occur.  Tachyzoites: Organisms that rapidly multiply within macrophages, to lyse the cell and infect other cells.  Bradyzoites: In immunocompetent hosts, these are organisms that slowly multiply within cysts, usually in the brain. o DISEASE: The disease is usually asymptomatic in immunocompetent host. Cell-mediated immunity is required to keep the disease asymptomatic.  Congenital Toxoplasmosis (TORCH): Occurs only when mother is initially infected during pregnancy. If she was previously infected, the disease wont reactivate.  Infected newborns are symptomatic only 10% of the time. Symptoms include encephalitis, chorioretinitis, hepatosplenomegaly.• TRYPANOSOMA: o TRYPANOSOMA CRUZI: The cause of Chagas Disease (American Trypanosomiasis)  INFECTION: Vector is reduviid bug. Mammalian animals and humans are both hosts.  DISEASE: Organisms infects cardiac cells (cardiomyopathy), and it causes neuronal damage leading to megacolon and megaesophagus.  Symptoms: Facial edema, and a nodule called chagoma, fever, lymphadenopathy, hepato-splenomegaly.
  29. 29.  Death usually from cardiac failure or arrhythmias. o TRYPANOSOMA BRUCEI (GAMBIENSE, RHODIENSE): The causes of African Sleeping Sickness (African Trypanosomiasis).  INFECTION: Tsetse fly is the vector. T. Gambiense infects humans as host, while T. Rhodiense infects domestic animals and humans.  DISEASE: High antigenic variation in organisms leads to cyclic, spiking fevers. Progressive demyelinating encephalitis, coma, and death.  Will see trypanosomal chancre at initial site of bite.  T. GAMBIENSE is acute progress of disease (a few months).  T. RHODIENSE is chronic progress of disease (two years). • LEISHMANIA: o LEISHMANIA DONOVANI: Cause of Kala-Azar (Visceral Leishmaniasis)  INFECTION: Dayfly is the vector.  DISEASE: Massive splenomegaly is characteristic finding, from both proliferation of macrophages and sequestration of RBCs. o LEISHMANIA BRAZILIENSIS: Cause of Mucocutaneous Leishmaniasis.  INFECTION: Vector = sandfly.  DISEASE: Cutaneous lesion at site of bite with granulomatous response.NEMATODES (ROUNDWORMS): • INTESTINAL NEMATODES can be remembered by the mnemonic AHEATS o (A) ASCARIS LUMBRICOIDES: They are the largest intestinal nematodes.  INFECTION: Eating food contaminated with the eggs.  LIFE-CYCLE: They subsist on ingested food and lay thousands of eggs which pass through feces back to the soil.  PATHOGENESIS / CLINICAL:  Larval Migration is principle cause of disease -- they goto lungs, inciting an Eosinophilic exudate in lungs. This can lead to pulmonary ascariasis  Intestinal ascariasis may be asymptomatic or may cause pain or obstruction.  DIAGNOSIS: Look for eggs in the feces.  LOCATION: Worldwide, in USA found in the south. o (H) HOOKWORMS -- ANCYLOSTOMA, NECATOR  INFECTION: SKIN PENETRATION from filariform larvae in moist soil. They then migrate to lungs, are coughed up, and then are swallowed.  PATHOGENESIS / CLINICAL:
  30. 30.  They develop into adults in small intestine and attach to intestinal wall via hooking structures.  Necator have cutting plates.  Ancylostoma have teeth.  Biggest clinical problem is BLOOD-LOSS -- Microcytic Hypochromic Anemia, an iron-deficiency (not hemolytic) anemia. The hookworms suck blood in small intestine.  DIAGNOSIS: Look for eggs in the feces.  LIFE-CYCLE: Fecal eggs yield Rhabditiform larvae which feed but are not infectious to humans. They then mature into Filariform Larvae which can penetrate human skin.  LOCATION: Worldwide, in USA found in the south.o (E) ENTEROBIUS VERMICULARIS -- PINWORM  LIFE CYCLE: Strictly confined to humans.  Male and female worms both live in colon.  At night, female migrates to anus and lays eggs on the anus. Reinfection of the eggs can then occur if the patient scratches anus and then brings fingers near mouth (no wash hands ick).  The eggs form an allergenic goo, which is itchy, so the patient scratches.  INFECTION: Ingestion of eggs.  CLINICAL: Perianal itching (pruritus) is most common symptom.  DIAGNOSIS:  SCOTCH TAPE on the ass at night can recover eggs.  The eggs are not found in stools. They are only found in perianal region.  Most commonly affects children.o (A) ANISAKIS  INFECTION: Raw saltwater seafood (sushi -- red snapper, salmon), and dolphins and seals, leads to Anisakiasis.  PATHOGENESIS: They penetrate gastric mucosa and dwell in submucosa in stomach and intestine.  SYMPTOMS: Gastroenteritis, eosinophilias, occult blood in stool.o (T) TRICHURIS TRICHIURA -- WHIPWORM  INFECTION: Eat food contaminated with the eggs.  LIFE-CYCLE:  Worms mate in colon, and thousands of eggs are created daily.  Embryos are formed only in warm, moist soil, after defecation.  CLINICAL: Most infections are asymptomatic. It may cause diarrhea.  TENESMUS is anal dry heaves. It can occur with Whipworm and can lead to rectal prolapse.
  31. 31. o (S) STRONGYLOIDES STERCORALIS -- THREADWORM  INFECTION / LIFE-CYCLE: Strongyloidiasis = Penetration of skin by filariform larvae. They go to lungs, are coughed up and then are swallowed.  Larvae mature in small intestine, enter the mucosa, and lay eggs.  Eggs hatch within mucosa, forming Rhabditiform Larvae  AMPLIFICATION CYCLE: Eggs can also form more filariform larvae which can go back to the lungs to repeat the cycle. This occurs particularly in immunocompromised (AIDS) patients. It can be fatal.  CLINICAL: Can be asymptomatic, depending on worm-burden.  Watery diarrhea  Pneumonitis can occur in lung  DIAGNOSIS: Identify larva in stool sample. • TRICHINELLA is also a Nematode and causes Trichonosis which we get from undercooked pork. o PATHOGENESIS: Eggs develop in striated muscle cells. o SYMPTOMS: Fever, muscle pain, eosinophilia, periorbital edema. • TISSUE NEMATODES o WUCHERERIA: Cause of Filariasis.  INFECTION / LIFE-CYCLE: Female mosquito bites.  Microfilariae are formed in the blood. They circulate in the blood only at night, thus blood tests for the worm should be taken at night.  Microfilariae produce infective larvae which can be picked up by another mosquito bite.  CLINICAL: ELEPHANTIASIS, from lymph channel obstruction. Gross enlargement of legs and genitals.  Lymphangitis, cellulitis.  DIAGNOSIS: Nighttime blood-smear for the microfilariae is diagnostic. o ONCHOCERCA: Cause of Onchocerciasis.  INFECTION: Female blackfly bite. Microfilariae burrow in subcutaneous tissue.  CLINICAL: Subcutaneous pruritic papules and nodules that ultimately migrate to eyes.  Major cause of River Blindness o LOA o DRACUNCULUSPLATYHELMINTHES CESTODES (TAPEWORMS): Has a scolex (head),proglottids (segments), and suckers. • TAENIA SAGINATA (BEEF TAPEWORM): Cause of Taeniasis.
  32. 32. o MORPHOLOGY: Scolex with four suckers.  It has No Rostellum.  Uterus proglottid has around 20 branches on each side. o INFECTION: Ingestion of cysticerci in undercooked beef. Humans are definitive host and cattle intermediate host. o CLINICAL: Unlike pork tapeworm, findings are largely asymptomatic. Proglottids may be found in stool.• TAENIA SOLIUM (PORK TAPEWORM): Cause of Cysticercosis. It is called cysticercosis because the larvae are pathogenic -- not the worm itself. o INFECTION / LIFE-CYCLE: Undercooked pork. In pigs, they reside in skeletal muscle (pig-meat).  Normally, people ingest the larvae, or Cysticerci.  REFLUX, as in vomiting, can expose proglottids to acid which causes them to release tremendous numbers of eggs. Not good! A far more dangerous, disseminated infection occurs once eggs are released. o MORPHOLOGY: It has 4 suckers a circle of hooks. Eggs look the same as T. Saginata.  It does have a Rostellum, hooks, coming out of scolex.  Uterus proglottid has far fewer branches (5-10) on each side than T. Saginata. o PATHOGENESIS: Ingested larvae take 3 months to grow, and worms can be up to 5m long.  Intestinal tapeworm does little damage.  The Cysticerci larvae cause the damage! They can go to brain where they occupy space (non-inflammatory). Once they die, inflammation can ensue.  Neurocysticercosis is the leading cause of Epilepsy in Mexico, where they eat undercooked pork.• DIPHYLLOBOTHRIUM LATUM (FISH TAPEWORM): Cause of Diphyllobothriasis. o MORPHOLOGY: Worm has a sucking groove, and is the longest of tapeworms, up to 13m. o LIFE-CYCLE: Human are definitive hosts  Copepod Crustacea are first intermediate host.  Freshwater fish are second intermediate host. o PATHOGENESIS: Largely asymptomatic.  The worm likes to eat Vit B-12, thus Pernicious (Megaloblastic) Anemia can result from infection.  Abdominal discomfort and diarrhea may occur.• ECHINOCOCCUS GRANULOSUS (DOG TAPEWORM): Cause of Unilocular Hydatid Cyst Disease. o LIFE-CYCLE: Dogs are definitive hosts, and so are sheep. Humans are a dead-end intermediate host. o EPIDEMIOLOGY: The disease is seen in big-game hunters and in shepherds. Very large at-risk population.
  33. 33. o PATHOGENESIS: It more often infects sheep than humans.  It forms one fluid-filled cyst that is just jam-packed with scoleces from the parasite. Embedded daughter cysts can form within the main cyst, etc.  Cyst must be surgically removed. Parasite is antigenic, and if not careful, removal of cyst and exposure to antigen can result in anaphylaxis. o SYMPTOMS: Often asymptomatic, but liver cysts, brain cysts can result. Cyst rupture can cause fatal anaphylactic shock.PLATYHELMINTHES TREMATODES (FLUKES): • MORPHOLOGY: They possess sucking disks that provide them motion. • ENTERIC FLUKES: Restricted to the orient and we will rarely see them. o FASCIOLOPSIS BUSKI: Large enteric fluke -- very large, about size of microscope slide.  SYMPTOM: May cause intestinal obstruction. It will ruin the brush border anywhere it sucks onto in the intestine. o METAGONIMUS YOKOWSKI: Small enteric fluke. • BILIARY (LIVER) FLUKES: They obstruct bile ducts and lay eggs within them, leading to cholelithiasis (Gall stones). o FASCIOLA HEPATICA: Relatively common large fluke.  SYMPTOMS:  Gallstones -- the eggs can be seeds for gallstones.  Biliary obstruction can occur because the flukes are so large. (High blood bilirubin glucuronide), biliary cirrhosis if untreated.  LIFE-CYCLE:  Eggs are excreted in feces of infected host.  Egg hatches and forms a miracidium in water. It penetrates a SNAIL host.  In snail, free-swimming cercariae are released. They collect on watercress plants.  Metacercariae are ingested by humans. o FASCIOLA GIGANTICA: Relatively rare gigantic fluke. o CLONORCHIS SINENSIS: Oriental SMALL BILIARY FLUKE, causing Clonorchiasis.  INFECTION: eating raw or undercooked freshwater fish.  LIFE-CYCLE:  Snails are first intermediate host.  Eggs leave snail as free-swimming cercariae.  Cercariae burrow in fresh-water fish, the second intermediate host.  EPIDEMIOLOGY: China, Japan, and Vietnam  PATHOGENESIS: They get into the small bile ducts but dont cause biliary obstruction except with a huge worm burden.
  34. 34.  They can lead to adenomatous hyperplasia, which increases the risk for cholangiocarcinoma (carcinoma of bile ductal epithelia). o OPISTHORCHIS FELINEUS: SMALL BILIARY FLUKE, causing Opisthorchiasis.  CLINICAL: Very similar to Clonorchis infection.  Infection can lay dormant for several years before presenting clinically. • BLOOD FLUKES: SCHISTOSOMA, which cause SCHISTOSOMIASIS o LIFE-CYCLE / INFECTION: Snails are the intermediate host.  Cercariae penetrate skin of human host, and are known as a Schistosomula once inside.  They immediately travel to liver, where they lay eggs. Male and female mate in portal blood in liver.  Female travels, against the flow of blood, to final destination (see below) where it lays eggs.  Eggs then reach fresh water again through feces, urine. o Species Differentiation:  SCHISTOSOMA MANSONI:  Egg has a large lateral spine.  Infects colon and resides in Inferior Mesenteric Venules.  A cause of Hepatosplenic Schistosomiasis.  SCHISTOSOMA JAPONICA:  Egg has a small lateral spine.  Infect small / large intestine and resides in Superior and Inferior Mesenteric Venules.  A cause of Hepatosplenic Schistosomiasis.  SCHISTOSOMA HAEMATOBIUM:  Egg has a terminal spine.  Cause of Urinary Schistosomiasis.  Reside in Vesicular Venous Plexus. o PATHOLOGY: All pathological findings are due to the presence of the eggs -- not the worms!CLINICAL PRESENTATION of SCHISTOSOMIASIS HEPATOSPLENIC URINARY SCHISTOSOMIASIS SCHISTOSOMIASISSpecies Schistosoma Mancini Schistosoma Haematobium Schistosoma JaponicaPathogenesis Inflammatory granulomatous Inflammatory granulomatous response to allergens from eggs response to allergens from eggs
  35. 35. in the colon in the bladder and lower ureters.ACUTE Eosinophilia EosinophiliaSCHISTOSOMIASIS Granulomatous Polyps in Colon Hematuria Fever, anorexia, weight loss, Terminal Dysuria (pain, anemia difficulty at end of micturition) Portal HypertensionSecondary Sites of Eggs go back through portal Eggs go back through systemicInfection circulation to liver, causing circulation (iliacs) to Lungs, granulomatous inflammation in causing granulomatous liver: Hepatomegaly, Liver inflammation in lungs. tendernessSequelae Portal Hypertension leads to Obstructed urine flow results in Splenomegaly, esophageal Hydroureter andCHRONIC varices, and ascites. Malnutrition HydronephrosisSCHISTOSOMIASIS or concurrent GI infections can result in death.ACTIVE -vs- INACTIVE URINARY SCHISTOSOMIASIS: Inactive Schistosomiasisrefers to the remaining constriction and fibrosis of ureters that persists after infection hassubsided. It has similar symptoms to active Schisto, but it is not contagious. Return to top

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