Necrosis Information and Courses from MediaLab, Inc.

If the atherosclerotic process continues and other risk factors are involved, the lipid core of the plaque grows and pushes the arterial wall out. The myeloperoxidase and metalloproteinases degrade the cellular matrix, thinning the fibrous cap making it capable of tearing. Once there are tears, platelet aggregation and the coagulation cascade begin; thrombi or blood clots become part of the plaque. Further plaque growth and repair leads to occlusion and necrosis of vessels. Varying degrees of pain, cerebral or pulmonary infarction, and/or ischemic heart disease result.

Cardiac troponins are the preferred marker. CK-MB (specified as mass measurement) is an acceptable alternative when cardiac troponins are not available. The 2007 ESC/ACC/AHA guidelines recommend use of cardiac markers to detect myocardial necrosis in the following manner: Elevations of cTnI or cTnT over decision limit on one occasion in the first 24 hours after chest pain. Elevations of CK-MB (specified as mass measurement) over decision limit on two successive samples or one sample that is two times the upper limit of normal during the first hours following chest pain. The CK-MB levels should exhibit a rising or falling pattern to be diagnostic. If the CK-MB levels do not fall, it is likely not an AMI.Healthcare facilities and cardiology staff develop their own criteria for AMI diagnosis and treatment based on these guidelines. Many facilities assay both cardiac troponin and CK-MB biomarkers and may request serial troponin levels to find two elevations similar to guidelines for CK-MB.

CK-isoforms are also markers of myocardial necrosis. Using high voltage electrophoresis, subtypes of CK-MM and CK-MB, CK isoforms, can be isolated. They are released in myocyte necrosis and are not ordinarily in peripheral circulation. CK-MB has 4 isoforms; CK-MB1 and CK-MB2 are released 2-4 hours after chest pain, peak in 6-9 hours and like myoglobin, are early markers of an AMI.CK-isoforms are not widely measured in evaluating chest pain and ACS due to the labor intensive procedure that is required (high voltage electrophoresis). When CK-isoforms are used, most often a ratio of CK-MB2/CK-MB1is reported. A ratio of <1 is negative for myocardial necrosis; a ratio >1.7 is positive for myocardial necrosis.

C-reactive protein (CRP) is a very sensitive acute phase reactant. Serum CRP levels increase following a variety of pro-inflammatory events such as infection, tissue necrosis, trauma, surgery and even malignancy. CRP levels can increase quickly and dramatically (often 100 fold) during inflammation. CRP can activate compliment, bind Fc receptors and can function as an opsonin, enhancing phagocytosis with certain infections. Measurement of CRP is not new, it has been on clinical laboratory testing menus for decades. However, a newer version of the CRP test is now in use to assess cardiovascular risk.High sensitivity-CRP (hs-CRP) assays have been developed that are more sensitive to the more subtle changes that can occur during chronic vascular inflammation. (Recall that atherosclerosis is an inflammatory process.) By measuring hsCRP we can get a glimpse at vascular function. CRP has been shown to be an independent risk factor for atherosclerotic disease and cardiac death. A 2002 prospective study of more than 27,000 patients showed that the CRP concentration is a stronger predictor of cardiovascular events than the LDL-cholesterol level.

This painful event of vaso-occlusive crisis often results in tissue necrosis. Organs affected include the bone marrow, brain, lungs, kidneys, liver, and spleen. Disorders that may result include bone and joint pathology, stroke, acute chest syndrome, nephropathies, and infections. Triggering mechanisms for this crisis include infection, fever, acidosis, dehydration, cold temperatures, anxiety, stress, and depression. Adults may experience acute chest syndrome due to pulmonary infarcts caused by sickling in the pulmonary microvasculature, whereas children with sickle cell disease can experience acute chest syndrome due to infections.

Reticular fibers support body organs like the liver, spleen, and kidney. The Gordon and Sweet's silver staining method is used to demonstrate abnormal reticular fiber patterns that may indicate cirrhosis or necrosis of the liver. This is why reticular stains are often requested on liver biopsies. Abnormal reticular fiber patterns may also indicate the presence of certain tumor types in the liver, spleen, or kidney.

The adipokines that will be discussed on the following pages include: Tumor necrosis factor-alpha (TNF-a) Interleukin 6 (IL-6) Plasminogen activator inhibitor-1 (PAI-1) Adiponectin Angiotensinogen Leptin Resistin

As mentioned in the course introduction, MRSA infections fall into two general types:Healthcare-associated MRSA (HA-MRSA) Infections that occur in people who are, or have recently been, hospitalized. Community-acquired MRSA (CA-MRSA) Infections that are apparently acquired in the community There are a number of factors that distinguish HA-MRSA from CA-MRSA isolates. These factors are summarized in the table below.FactorHA-MRSA CA-MRSAOrigin of strainsNosocomial infectionsFive isolates associated with healthcare settings: USA100, -200, -500, -600, -800USA100 is the predominant isolate while USA 200 is the second most common isolate. USA700 has been isolated in both healthcare and community settings.Evolved from endemic methicillin-susceptible S. aureus (MSSA) strains Two clones, USA300 and USA400, are associated with the majority of CA-MRSA infections in the United States. USA300 has emerged as the most prominent clone and is not found among hospital strains.Genetic lineageIsolates usually carry large SCCmec types I, II or III (34-67 kb)The larger size of SCCmecII and III permits the inclusion of other non-beta-lactam resistance genes so that HA-MRSA strains tend to be multi-drug resistantIsolates carry a smaller SCCmec variant, predominantly type IV (24 kb), less often type V or variant VT. SCCmecIV (except for mecA) does not permit the inclusion of other non-beta lactam resistance genes so that CA-MRSA isolates exhibit resistance to only methicillin and erythromycin and are more often susceptible to other non-beta lactam antibiotics (eg., trimethoprim/sulfamethoxazole (SXT) and clindamycin). Affected populationLargely affects older adults and people with weakened immune systems; those who have undergone surgical procedures are at increased risk. Healthy persons in the general population without established risk factors for MRSA acquisitionClinical syndromesFound at multiple sites, most commonly bloodstream infections, urinary tract infections (UTI) and respiratory tract infectionsPredominantly skin and soft tissue infections (SSTIs), such as abscesses, cellulitis, folliculitis and impetigo and a serious form of pneumoniaGenes for Panton-Valentine leukocidin (PVL) are associated with SCCmecIV; the clinical spectrum of infections caused by CA-MRSA is directly related to the presence of PVL genes, coding for the production of a cytotoxin that causes tissue necrosis and leukocyte destruction.

Toxin Comment Most Likely Means of Dissemination Primary Route of Entry General Signs and Symptoms Laboratory Testing Botulism toxin: Gram stained image of C. botulinum courtesy of CDC Produced by Clostridium botulinum Could be purified and used in a bioterrorist event to contaminate food or aerosolized to cause disease Aerosol Food contamination Inhalation Ingestion Difficulty speaking or swallowing Blurred or double vision Drooping eyelids (ptosis) Dilated pupils Dry mouth, decreased gag reflex Weakening of the reflexes (hyporeflexia) Abnormal sensations such as numbness, tingling, and progressive arm or leg weakness Flaccid paralysis Culture, anaerobic Digoxigen-labeled IgG ELISA to detect A, B, E, and F toxins Mouse Bioassay for all toxin types and to confirm DIG ELISA Ricin toxin: Extracted from Castor beans Inhibits protein synthesis Causes death approximately 72 hours after initial exposure As an aerosol Inhalation Fever Cough Chest tightness Dyspnea Cyanosis Gastroenteritis Necrosis Antibody detection in clinical specimens Clinical testing not performed unless known exposure has occurred

Increased numbers of cuboidal cells are found in renal transplant rejection, acute tubular necrosis (diuretic phase), injuries that interrupt blood flow to the kidney, and acute glomerulonephritis accompanied by tubular damage. Ingestion of various drugs and chemicals may cause significant tubular shedding of these epithelial cells. Cuboidal cells are easily seen in urine in cases of salicylate intoxication.