Antiviral AgentsVirustatic Antiviral drugs are only effective against actively replicating viruses, they cannot kill the latent viruses present in the body.Virus life cycle: • Adhesion • Entry • Uncoating • Synthesis and Assembly • Virion release Antiviral Agents & MechanismsDisrupt the viral envelope or surface proteins; prevent viral transmission:Lipids, detergents, acids, and other anti-viral molecules can disrupt the surfaces of some viruses. For example, citric acids disrupt the surface proteins of rhinoviruses.Prevent Attachment:Antibodies can neutralize viral attachment proteins on most viruses.Peptide analogues can block host attachment protein; ex: drugs that block the HIV co-receptor necessary for entry. Peptides can bind heparan sulfate (and other similar sites) on host cells, blocking the attachment of HIV and Herpes Simplex Viruses.Prevent Penetration & Uncoating:Inhibition of viral fusion proteins; Enfuvirtide blocks HIV fusion.Inhibition of envelope fusion; Docosanol blocks envelope fusion of HSV and other virusesNeutralize vesicle pH which inhibits viral uncoating; amantadine and rimantadine use this mechanism against Influenza APrevent penetration; Tromantadine is a drug that prevents HSV penetration.Block receptors to sprevent uncoating; arilidone, disoxaril, and pleconaril prevent picornavirusesInhibit RNA or DNA synthesis; Block viral replication:Nucleoside analogs: – Acyclovir is active against Herpesviruses and Varicella-zoster virus (VZV); Valayclovir is a prodrug of acyclovir. – Penciclovir is used to treat Herpes simplex viruses (specifically, cold sores), Varicella-zoster virus, Epstein-Barr infections, and Cytomegalovirus (CMV) infections; Famciclovir is a prodrug of penciclovir. – Azidothymidine (aka, AZT), Dideoxyinosine, Stavudine, and Lamivudine are used to treat HIV infectionsNucleotide analogs: – Cidofovir is used to treat Cytomegalovirus infections, especially in patients with AIDS, as well as Polyomavirus, Papillomavirus, and Herpes Simplex Virus infections. – Adefovir is used to treat Hepatitis B (HBV) infectionsNon-nucleoside polymerase inhibitors: – Foscarnet is used to treat infections caused by Herpes virus, HIV, and Cytomegalovirus retinitis in AIDS patients. – Nevirapine, Delvaridine, and, Efavirenze are used to treat Herpes virus and HIV. Block Assembly and Release:Protease inhibitors: Saquinavir, ritonavir, and indinavir, which are active against HIV.Neuraminidase inhibitors: Zanamivir, and oseltamivir, which are active against Influenza A and B.
Macrophage Activation Pro-inflammatory effects: • Stimulation by specific cytokines, such as interferon gamma (aka, type II interferon) and/or by microbes activate macrophages to produce inducible nitric oxide, reactive oxygen species, and lysosomal enzymes, which are antimicrobial. • These activated macrophages also produce inflammatory cytokines and chemokines: – Tumor necrosis factor and chemokines activate lymphocytes. • Activated T lymphocytes produce interferon gamma, which, as we've indicated, triggers pro-inflammatory macrophage activation. Thus, T lymphocytes can act as part of a positive feedback loop with pro-inflammatory activated macrophages. Anti-inflammatory effects: • Anti-inflammatory stimuli include interleukins 13 and 4 (IL-13, IL-4). – In response to these stimuli, activated macrophages produce cytokines, such as interleukin-10 (IL-10), that inhibit inflammatory activity of T lymphocytes, natural killer cells, and macrophages; thus, interleukin 10 prevents excessive inflammation and damage to host cells. – These "alternatively activated" macrophages also produce growth factors that promote tissue repair, including vascular endothelial growth factor (VEGF), which facilitates angiogenesis, and transforming growth factor beta (TGF-ß), which facilitates deposition of extracellular matrix proteins for fibrosis. • Interleukins 13 and 4 (IL-13 and IL-4) are produced by T lymphocytes; thus, T lymphocytes can also promote anti-inflammatory macrophage activation.Be aware that some texts describe two distinct types of macrophage activation, classical and alternative, and the resulting macrophages as either Type 1 (aka, classical type) or Type 2 (aka, alternative type); however, research now suggests that these should not be thought of as dichotomous types, but, rather, as potential phenotypes that macrophages express in response to environmental stimuli. • Upon activation, macrophages engage in various activities: – Presentation of antigens to T lymphocytes. – Production of cytokines, which mediate inflammatory responses. – Production of growth factors and enzymes that promote tissue repair and inhibit inflammation. • To accomplish these goals, macrophages have dynamic phenotypes reflective of their microenvironments.
Hepatitis E • Aka, “Non-A, Non-B Enteric/Epidemic” hepatitis. • Positive-sense RNA Hepevirus with an enveloped icosahedral capsid. • Transmitted via the fecal-oral route. – Epidemics are associated with contaminated water supply. • Acute hepatitis with resolution. Exception: Mortality is high among pregnant (“Expecting”) women* – Especially during the third trimester, when fulminant hepatitis is most likely to develop. • Many authors state that HEV only causes acute hepatitis; however, some evidence suggests that Genotype 3 causes chronic hepatitis in immunosuppressed individuals. • No vaccine • Prevention includes thorough sanitation, particularly of water supplies • Treatment = supportive care. Hepatitis A Hepatitis B Hepatitis C Hepatitis D References Cullen, John M., and Stanley M. Lemon. “Comparative Pathology of Hepatitis A Virus and Hepatitis E Virus Infection.” Cold Spring Harbor Perspectives in Medicine, April 30, 2018, a033456. https://doi.org/10.1101/cshperspect.a033456.Drebber, Uta, Margarete Odenthal, Stephan W. Aberle, Nadine Winkel, Inga Wedemeyer, Jutta Hemberger, Heidemarie Holzmann, and Hans-Peter Dienes. “Hepatitis E in Liver Biopsies from Patients with Acute Hepatitis of Clinically Unexplained Origin.” Frontiers in Physiology 4 (December 13, 2013). https://doi.org/10.3389/fphys.2013.00351.Kasper, Dennis L., Stephen Hauser L., Larry Jameson J., Anthony S. Fauci, Dan Longo L., and Joseph Loscalzo. Harrison’s Principles of Internal Medicine. 19th ed. McGraw-Hill Education, 2015.Levinson, W. Review of Medical Microbiology & Immunology. 14th ed. McGraw-Hill Education, 2016. Lo Re, Vincent. “Extrahepatic Complications of Hepatitis C Virus Infection in HIV and the Impact of Successful Antiviral Treatment.” Clinical Infectious Diseases 64, no. 4 (February 15, 2017): 498–500. https://doi.org/10.1093/cid/ciw814.“WHO | What Is Hepatitis?” WHO. Accessed August 29, 2018. http://www.who.int/features/qa/76/en/.
The immune system is the body’s defense system that protects us from foreign (non-self) substances. The immune system assumes foreign things are dangerous as they are usually pathogens like bacteri…
A comic book on immunology.
The immune system is the body’s defense system that protects us from foreign (non-self) substances. The immune system assumes foreign things are dangerous as they are usually pathogens like bacteri…
Examples of Hypersensitivity reactions #ABIM #MedEd
The immune system is the body’s defense system that protects us from foreign (non-self) substances. The immune system assumes foreign things are dangerous as they are usually pathogens like bacteri…
Helicobacter pylori - GI Infections Gastric helicobacter because it colonizes the stomach.Transmission is human to human; exact mechanisms uncertain.Life-long colonization; infection typically occurs during childhood and produces symptoms during adulthood.Gatalase, oxidase, and urease positive.Spiral, Gram-negative rods that can appear as coccoid in older cultures.Microaerobic: Grow in conditions of reduced oxygen and increased carbon dioxide. Virulence FactorsHelicobacter pylori has several adaptations that allow it to survive the acidic environment of the human stomach and persist for decades. Urease converts urea to ammonia and bicarbonate to neutralize gastric acids.Multiple flagella provide corkscrew motility.Mucinase production allows the bacteria migrate through the viscous mucus that covers the surface of the stomach. Infection triggers host production of IL-8, which is a pro-inflammatory cytokine that recruits neutrophils that release harmful molecules and damage host tissues.The bacteria protect themselves from these harmful molecules by producing superoxide dismutase and catalase, which detoxify reactive oxygen species.Lipopolysaccharide endotoxin; however, as compared with many other Gram-negative bacteria, its endotoxin has low toxicity. Vacuolating cytotoxin A promotes pore formation, disrupts cell signaling, and induces apoptosis and necrosis of host cells.Cytotoxin-associated gene A (cagA) product promotes proliferation and morphological changes in host tissues, and induces T-cell apoptosis. Type IV secretion systems inject the cagA effector protein into host cells. InfectionsGastritis is inflammation of the stomach lining with infiltration of neutrophils and mononuclear cells; T-1 helper cells are also implicated. Some individuals are asymptomatic, and others experience an acute phase of nausea, bloating, and vomiting. Inflammation can be localized to one area, usually the pyloric antrum, or widespreadIn a subset of patients, gastritis progresses to more serious conditions.Peptic ulcers 10-20% of patients with gastritis will develop peptic ulcers, in which inflammation erodes the stomach tissues.Ulcers can be located in the stomach, or they can be in the duodenum, which is the first portion of the small intestine.Gastric adenocarcinoma In approximately 1-2%, chronic inflammation will lead to gastric adenocarcinoma.This occurs when inflammation leads to metaplasia; over time, the gastric mucosa is replaced by fibrotic tissue, and can become neoplastic.Reduced gastric acid secretion is associated with a higher risk of adenocarcinoma.Gastric-associated lymphoid tissue B-cell lymphomasIn response to Helicobacter pylori infection, lymphoid tissues infiltrate the stomach; in some cases, monoclonal B cells proliferate and form MALT lymphomas (MALT = Mucosa-Associated Lymphoid Tissue). Summary Illustration:We draw the stomach, esophagus, and duodenum. Gastritis can be localized in the pyloric antrum, and indicate that this is associated with increased acid production and formation of duodenal ulcers.Multifocal inflammation, as in pangastritis, is associated with atrophy and reduced acid production; this is associated with gastric metaplasia and cancer. Helicobacter pylori infection causes destruction of the mucosa, which allows acids and toxins, as well as the microbes themselves, access to deeper tissues. • Ulceration leads to bleeding, perforation, and, in severe cases, metaplasia. Treatment:Because chronic gastritis can lead to severe consequences, treatment is important.Macrolides, Beta-lactams, and proton-pump inhibitors. Enterohepatic helicobacters:Helicobacter cinaedi and Helicobacter fenneliae Invade the intestines and liver, and can cause gastroenteritis and bacteremia, particularly in immunocompromised individuals.
The immune system is the body’s defense system that protects us from foreign (non-self) substances. The immune system assumes foreign things are dangerous as they are usually pathogens like bacteri…
Myocardial Infarctions: PathophysiologyMyocardial Infarctions Occur when there is evidence of: Myocardial injury is defined as elevated levels of cardiac troponin values. Ischemia occurs when there is an imbalance between oxygen supply and demand. Infarctions usually occur in the left ventricle, and damage may extend to the right ventricle or even the atria.The evolution of myocardial infarctions comprises processes of inflammation and repair in response to myocardial injury and ischemia. Sustained ischemia leads to the death of cardiomyocytes and the release of their contents into the extracellular matrix. The release of cell contents into the ECM triggers the inflammatory response, which is dominated by neutrophils. Eventually, the necrotic cell debris is removed. Collagen deposition and scar formation occurs.The healing process requires a balance between the processes of inflammation and tissue repair. When these processes are out of balance, adverse remodeling can lead to heart failure, arrhythmias, and other complications. Review complicationsA common site of blockage is in the left anterior descending coronary artery. The "zone of perfusion" for this artery, which, due to the blockage, is now also the "area at risk" of ischemia and infarction. Blockage in other coronary arteries puts different areas at risk. When blockage leads to significant ischemia, the area at risk becomes the area of infarction, which is characterized by a necrotic core and a surrounding border zone Myocardial Infarctions: Timeline and Progression First, we illustrate some normal, healthy cardiac cells: Branching, striated cells with intercalated discs and nuclei. First 12 hours of myocardial infarction: cell death occurs. Coagulation necrosis begins, and cells spill their contents into the surrounding ECM. Microscopic changes include the appearance of "wavy fibers," which are elongated myocardiocytes; their striations and nuclei become less apparent. The sarcolemma begins to malfunction,...
Organ Transplantation is the replacement of dysfunctional tissue with healthy tissue from “somewhere” else. An individual can receive an organ donation from an animal (such as a pig heart valve) or…
Prepare for the pediatrics board exam with our board review questions and practice exams. Browse your options to find which is right for you!
Effector cells of the CD4 lineage are characterized by their ability to express surface molecules and to secrete cytokines that activate other cells B
Fungal infections of the nervous system, called neuromycoses, are rare in healthy individuals. However, neuromycoses can be devastating in immunocompromised or elderly patients. Several eukaryotic parasites are also capable of infecting the nervous system of human hosts. Although relatively uncommon, these infections can also be life-threatening in immunocompromised individuals. In this section, we will first discuss neuromycoses, followed by parasitic infections of the nervous system.
Apoptosis is a form of cell death characterized by energy-dependent biochemical mechanisms and morphological changes.
Quantal Response Curves • Quantal: Binary ("either-or" or "all-or-none") responses. Specify 50% and 100%, which we'll see are important - Let's imagine we want to know the minimum dose required to achieve a systolic blood pressure of less than 120
There are a groups of inflammatory signals that play key roles in the early phases of acute inflammation. These signals cause the Cardinal Signs of Inflammation and are involved in the inflammatory…
Reversible Cellular Injury is harm done to a cell that can be undone once the stress on the cell is removed. Severe or prolonger reversible cellular injury will eventually lead to irreversible cell…
When acute inflammation is not sufficient to deal with a pathogen, chronic inflammation takes over. Chronic inflammation is mediated by B-Cell and T-Cell leukocytes/lymphocytes. These white blood c…
Reversible Cellular Injury is harm done to a cell that can be undone once the stress on the cell is removed. Severe or prolonger reversible cellular injury will eventually lead to irreversible cell…
When acute inflammation is not sufficient to deal with a pathogen, chronic inflammation takes over. Chronic inflammation is mediated by B-Cell and T-Cell leukocytes/lymphocytes. These white blood c…
Reversible Cellular Injury is harm done to a cell that can be undone once the stress on the cell is removed. Severe or prolonger reversible cellular injury will eventually lead to irreversible cell…
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1000's of PANCE and PANRE Board Review Questions and Practice Exams. The Daily PANCE Email Series, Flashcard Sets, Audio Guides and Much Much More!
Primary Immunopathogenic mechanism: Initiator of the disease process by: Antibody mediated injury: immune complex deposition or cytotoxic antibodies T-cell mediated immune injury: non-immune complex…
