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Toxic Information and Courses from MediaLab, Inc.

These are the MediaLab courses that cover Toxic and links to relevant pages within the course.

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Chemical Screening of Urine by Reagent Strip
Clinical Significance cont'd

Proteinuria related to kidney impairment may be due to glomerular membrane damage caused by toxic agents, immune complexes found in lupus erythematosus, or streptococcal glomerulonephritis. The amount of protein present in urine samples from patients with glomerular damage usually ranges from 10-40 mg/dl. If the urinary protein is due to a disorder that affects tubular reabsorption, the urine protein quantities will be much greater. In patients with multiple myeloma, proteinuria is due to the excretion of the Bence Jones protein. This low molecular weight protein produced by a malignant clone of plasma cells circulates in the blood and is filtered in the kidneys in quantities exceeding the tubular capacity. This excess protein is excreted in the urine.

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Proteinuria related to kidney impairment may be due to: (Choose ALL of the correct answers)View Page
Clinical Significance

No blood is found in the urine of healthy individuals although samples from menstruating females, frequently, but not always, test positive for blood. Hematuria is associated with renal or genital urinary disorders in which the bleeding is the result of irritation to the involved organs or trauma. Examples include renal calculi, pyelonephritis, glomerulonephritis, tumors, trauma or exposure to toxic chemicals or drugs and/or strenuous exercise. Hemoglobinuria may be due to the lysis of red cells within the urinary tract. If it is caused by intravascular hemolysis, the hemoglobin is then filtered through the glomeruli. In the normal individual, the hemoglobin molecule attaches to haptoglobin and in this way bypasses the kidney filtration system. When the hemoglobin/haptoglobin system is overwhelmed, as in cases of hemolytic anemia, severe burns, transfusion reaction, infection or strenuous exercise, hemoglobin passes into the urine.

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CLIA Chemistry / Urinalysis Review
Which one of the following statements about TSH is true:View Page
Which one of the following statements about acetominophen metabolism is false?View Page

CLIA Hematology / Hemostasis Review
Seen in infections and inflammations the cell indicated by the arrow in this illustration is exhibiting:View Page
Identify the object contained in the cell in this illustration indicated by the arrow:View Page
The WBC anomaly indicated by the arrow in this illustration is:View Page
The cell indicated by the arrow in illustration is indicative of:View Page

Confirmatory and Secondary Urinalysis Screening Tests
Other Causes of Ketonuria

Ketonuria can also be found in conditions associated with a decreased intake of carbohydrates (starvation), digestive disturbances, dietary imbalance (high fat/low carbohydrate diet), eclampsia, prolonged vomiting and diarrhea, glycogen storage diseases, vigorous exercise, fever, and following administration of anesthesia. Ketone bodies are mildly toxic to the body, tending to interfere with the excretion of uric acid, produce mild depression of the central nervous system, and cause acidosis.

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Current Topics in Clinical Microbiology
Review 1

Spencer RC.: Invasive streptococcEuropean Journal of Clinical Microbiology & Infectious Diseases. 14 Suppl. 1:S26-32, 1995.Before the introduction of antibiotics, serious infections caused by Streptococcus pyogenes (Lancefield Group A streptococci) were common. Before World War II, this bacterium was responsible for as many as 50% of postpartum deaths and was the major cause of death in patients with burns. Also common were the sequelae of streptococcal infections-rheumatic fever and post-streptococcal glomerulonephritis.With the use of penicillin, however, Streptococcus pyogenes was believed to be virtually eliminated as a pathogen. The organism was consigned to the history books, but not for long.In the mid-1980s, focal resurgences of rheumatic fever began to be reported from different areas in the USA, such as Salt Lake City, Utah. In such communities, where increases in cases of rheumatic fever had been reported, the serotypes M-1, 3, 5, 6 and 18 were isolated which, on culture, produced characteristic mucoid colonies. At the same time, reports of increases in invasive streptococcal disease began to surface in both the USA and Europe.Two syndromes were described; invasive streptococcal infection, occurring in previously healthy children and adults, commonly associated with septicaemia resulting from a deep focus of infection such as bone or lung; and streptococcal toxic shock syndrome, involving a cutaneous focus, accompanied by necrotizing or bullous soft tissue changes. Septicaemia is rare in streptococcal toxic shock syndrome, but the most characteristic feature is one of rapidly progressing multi-organ failure. A high proportion of the strains of Streptococcus pyogenes associated with this condition are serotype M-1, and fatality rates approaching 50% have been reported.

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A major complication of toxic shock syndrome related to group A streptococci, leading to 50% mortality is:View Page
Review 2

Cunningham MW.: Pathogenesis of group A streptococcal infections. Clinical Microbiology Reviews. 13):470-511, 2000Group A streptococci are model extracellular gram-positive pathogens responsible for pharyngitis, impetigo, rheumatic fever, and acute glomerulonephritis. A resurgence of invasive streptococcal diseases and rheumatic fever has appeared in outbreaks over the past 10 years, with a predominant M1 serotype as well as others identified with the outbreaks.Emm (M protein) gene sequencing has changed serotyping, and new virulence genes and new virulence regulatory networks have been defined. The emm gene superfamily has expanded to include antiphagocytic molecules and immunoglobulin-binding proteins with common structural features.At least nine superantigens have been characterized, all of which may contribute to toxic streptococcal syndrome. An emerging theme is the dichotomy between skin and throat strains in their epidemiology and genetic makeup. Eleven adhesions have been reported, and surface plasmin-binding proteins have been defined.The strong resistance of the group A streptococcus to phagocytosis is related to factor H and fibrinogen binding by M protein and to disarming complement component C5a by the C5a peptidase. Molecular mimicry appears to play a role in autoimmune mechanisms involved in rheumatic fever, while nephritis strain-associated proteins may lead to immune-mediated acute glomerulonephritis. Vaccine strategies have focused on recombinant M protein and C5a peptidase vaccines, and mucosal vaccine delivery systems are under investigation.

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HIV Safety for Florida
Overview

Prevention of HIV exposure is the best line of defense to prevent occupational transmission of HIV as there is no vaccine available to develop specific immunity and the postexposure prophylaxis is toxic. Following appropriate workplace practices in the laboratory focus on preventing needlesticks or other sharps injuries and exposure of mucous membranes and abraded skin to HIV-infected blood or body fluids.

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Introduction to Bioterrorism
Chemical Agents

Chemical warfare agents are poisonous vapors, aerosols, liquids, or solids that have toxic effects on people, animals or plants. They can be released in a number of ways such as by bombs or sprayed from aircraft. Some chemical agents are odorless and tasteless. They can have an immediate effect (such as a few seconds to a few minutes), or a delayed effect (from several hours to several days). Even though chemical agents have the potential to be lethal, they are difficult to deliver in lethal concentrations, particularly in outdoor situations where they tend to dissipate rapidly.

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Laboratory Response - Chemical, Level 2

In addition to the responsibilities listed for Level 3, over 40 laboratories also participate in Level 2 activities. At this level, laboratory personnel are trained to detect exposure to a limited number of toxic chemical agents in human blood or urine, the analysis of cyanide and toxic metals in human samples, for example.

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Laboratory Response - Chemical, Level 1

At present, 5 laboratories participate in Level 1 activities. At this level, technical personnel are trained to detect exposure to an expanded number of chemicals in human blood and urine. This includes all Level 3 and 2 laboratory analyses, plus analyses for mustard agents, nerve agents, and other toxic chemicals.

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Mycology: Yeasts and Dimorphic Pathogens
A hematology technologist observed the intracellular forms seen in the field of view of a Wright-Giemsa-stained peripheral blood smear shown in this photomicrograph. In consultation, the microbiology technologist advised that the form seen most likely represents:View Page

Pharmacology in the Clinical Lab: Therapeutic Drug Monitoring and Pharmacogenomics
Basic Pharmacokinetics

In order to discuss TDM and PGx we need to also introduce the concept of pharmacokinetics. Pharmacokinetics is the study of drug disposition in the body: how and when drugs enter the circulation, how long they remain in the blood, and how they are eliminated. TDM is the clinical assessment of a drug's pharmacokinetic properties. Physicians and pharmacists need to establish that a drug is present at an effective concentration but not at a toxic concentration. The next few pages will describe some of the factors that determine a drug's disposition in the body. These factors ultimately decide the need for therapeutic drug monitoring.

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TDM for all drugs?

Can all drugs benefit from TDM? Not really. For TDM to be effective and useful, one or more of the following should apply: The effective concentration and toxic concentrations must be well-defined. The pharmacokinetics of the drug are known to be variable. The drug is given chronically. There is the potential for drug-to-drug interactions. The drug exhibits high protein binding. The toxicity will mimic the indication for the drug; toxicity may not be visible during an exam but will only be revealed with TDM. The patient is pregnant, very young, or elderly. Compliance or history with the drug is poor.

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A physician needs to prescribe a drug with a narrow therapeutic window. He is concerned about possible toxic effects. To assess the upper concentration of such a drug, which time for drawing the specimen do you think makes the most sense?View Page
Protein Availability and Drug Dosing

Drug-binding proteins in serum can fluctuate in disease states. For example, if albumin levels fall, as can occur in liver failure or nephrotic syndrome, less albumin will be available for drug binding; a subsequent dose may produce a toxic concentration of free drug.The image on the right illustrates the loss of equilibrium between a protein-bound drug and a free drug when drug-binding proteins are diminished.Doses of drugs that are highly protein-bound may need to be adjusted in patients with lower drug-binding protein levels. Examples of some common drugs that are highly protein-bound include thyroxine, warfarin, diazepam, heparin, imipramine and phenytoin. �

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Why TDM?

Every drug has a sub-clinical concentration (a concentration at which effective therapy won't be achieved) and a toxic concentration (a concentration at which the drug will be harmful to the patient.)For some drugs, the range between the minimum effective concentration and the toxic concentration is large. These drugs are thus relatively safe. Other drugs have a very narrow therapeutic window and need closer monitoring. This is the role of TDM.Medications with narrow therapeutic windows, like the anticonvulsant carbamazepine (Tegretol), should be closely monitored since elevated doses can cause serious conditions such as agranulocytosis.

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When is TDM Not Useful?

TDM is not useful for these drugs or in these specific situations: Intracelluar drugs that need to be converted to active forms (like AZT) Drugs in which the effects last much longer than the serum concentrations of the drugs; examples include antineoplastics (cancer chemotherapies) and warfarin Narcotic pain medications where continued use can lead to tolerance such that the levels needed for pain relief in one person would be toxic to another person

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Red Cell Disorders: Peripheral Blood Clues to Nonneoplastic Conditions
The blood study from which this smear was obtained revealed an MCV of 115 femtoliters (fl).Normal MCV values in adults= 80 - 90 fl.Normal MCV values in full-term infants= 98 -108 fl.Which of the following conditions may be indicated by the results seen on this peripheral blood smear?View Page

Semen Analysis
Collection (continued)

Other aspects of specimen collection that must be considered are the temperature of the specimen and the time needed to transport it to the laboratory.Ideally, the specimen should be collected in a room at the testing site.If on-site collection is not possible, the specimen should be kept at body temperature (37°C) from the time of collection until it arrives at the laboratory. This can be facilitated by holding the container close to the body, for example by carrying it in an inside pocket.Semen should arrive at the laboratory as soon as possible after collection, preferably within one hour.Lubricants should not be used for collection unless absolutely necessary as most lubricants are toxic to sperm. If lubricant must be used then non-toxic forms such as KY jelly or cooking oil should be the only options.

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Collection

Accurate semen analysis results require appropriate sample collection. Patients must receive detailed directions for proper specimen collection and transport. Directions should be in writing. Specific instructions should include: The period of abstinence prior to collection should be between 2 and 5 days.The entire specimen must be collected because the different portions have varying concentrations of spermatozoa.An appropriate collection container must be used.Each laboratory should designate an appropriate, wide mouth, collection container.Each lot of collection containers should be tested to ensure that it is non-toxic to sperm.Alternative collection containers should be discouraged because their level of toxicity is unknown.Use of condoms for collection should be discouraged particularly when the purpose of the semen analysis is to test for fertility. Some condoms are toxic to sperm. Collection in condoms often results in inaccurate results for semen volume and other parameters.

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Testing collection containers

In order to test collection containers for sperm collection, the sperm must be held in the container for several hours to ensure that neither the numbers nor motility are adversely affected. Numbers will decline if the sperm adhere to the container. Motility will decline if the container is toxic. One method of testing involves removing sperm from semen. The specimen would be centrifuged and the sperm pellet diluted in a small volume of culture medium containing an energy source and at least 0.5% of a protein, such as serum albumin. The processed sperm specimen would be placed in the container to be tested. Total count and motility of the sperm would be tested at the start of incubation and 24 hours later. The container is non-toxic if the motility at the end of 24 hours is no less than 50% of the original value.

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Variations in White Cell Morphology - Granulocytes
All of the following statements concerning Dohle bodies are true EXCEPT:View Page
What morphological change is present in this slide?View Page
What morphological change is present in this slide?View Page
What morphological change is present in this slide?View Page
What morphological change is present in this slide?View Page
What morphological change is present in this slide?View Page
What morphological change is present in this slide?View Page
Conditions Associated with Hypersegmented Neutrophils

There are a number of conditions in which hypersegmented neutrophils may be seen, such as megaloblastic anemias that include folic acid deficiency and pernicious anemia. Individuals who are receiving chemotherapy or have long-term chronic infections may also have hypersegmented neutrophils.The cells seen in these conditions would be classified as pathological since the body is responding abnormally as a result of either a deficiency of a component needed for DNA production or because of the toxic effect that chemotherapy drugs have on DNA.

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Dohle Bodies and Toxic Granulation

Dohle bodies are frequently seen in conditions such as infection or burns when toxic granulation is also present. The cell in this slide has two Dohle bodies as well as toxic granulation. Vacuoles, although not present in this cell, can frequently appear in a cell containing toxic granulation and Dohle bodies.

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Classification

Vacuoles, toxic granulation and degranulation are classified as reactive since the body is responding normally in an effort to rid itself of infection caused by bacteria. Morphological changes related to aging are also classified as reactive.

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Toxic Granulation

Toxic granulation is present in the neutrophil in this slide. Notice that the granules are much smaller than those seen in the previous slide in a cell from a patient with Chediak-Higashi anomaly.

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Match each of the following. Answers may be used more than once or not at all.View Page
Which morphologic term describes this slide?View Page
Which morphologic term describes this slide?View Page
Which morphologic term describes this slide?View Page
More on Dohle Bodies

Dohle bodies are seen in a number of conditions, including infections, burns, measles, leukemia and chemotherapy. Dohle bodies are classified as pathological in the sense that they are only present when the body is responding to an unusually severe stress or stimulus. This severe stress may cause the cytoplasm of some cells to mature improperly. Their presence does not aid in the diagnosis of the disorders in which they are found, but they are frequently seen along with toxic granulation and/or vacuoles often present in infections and burns. Recognition is important because their appearance is similar to May-Hegglin bodies, which appear in a rare hereditary disorder called May-Hegglin anomaly.

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Toxic Granulation

Toxic granulation is manifested by the presence of large granules in the cytoplasm of segmented and band neutrophils in the peripheral blood. The color of these granules can range from dark purplish blue to an almost red appearance. Toxic granules are azurophilic granules normally present in early myeloid forms, but which are not normally seen at the band and segmented stages of neutrophil maturation. These granules contain peroxidases and hydrolases. Toxic granulation is seen in cases of severe infection, as a result of denatured proteins in rheumatoid arthritis or, less frequently, as a result of autophagocytosis. Infection is the most frequent cause of toxic granulation. This type of granulation may be seen in cells which also contain Dohle bodies and/or vacuoles. Cells containing toxic granules may have decreased numbers of specific granules. Cells containing only a few specific granules, with or without toxic granules, are said to be degranulated. The nucleus in degranulated cells may often be round-bilobed, smooth and pyknotic. This type of nucleus is the result of aging and will disintegrate soon. Increased basophilia of azurophilic granules simulating toxic granules may occur in normal cells with prolonged staining time or decreased pH of the stain.

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Which morphologic term describes this slide?View Page
Band Neutrophil Showing Toxic Granulation

A band neutrophil showing toxic granulation. The granules scattered throughout the cytoplasm are larger, more numerous and darker than those of normal neutrophils.

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Granules in Chediak-Higashi Syndrome versus Toxic Granulation

The neutrophils found in Chediak-Higashi can be differentiated from toxic granulation. In conditions causing toxic granulation, the granules are smaller and more numerous and only the neutrophils are affected. In Chediak-Higashi, eosinophils, basophils, lymphocytes and monocytes are affected. In eosinophils larger than normal eosinophilic granules may be seen, basophils may exhibit larger than normal basophilic granules, lymphocytes, large azurophilic granules. Larger pale granules/bodies may appear in monocytes.

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Alder-Reilly Neutrophil

An example of a normal neutrophil, lower left, and one showing some increased granulation typical of that seen in Alder-Reilly anomaly. Morphologically, it may be difficult to distinguish these granules from toxic granulation, however, the diagnosis is made on the basis of the presence of the many distinctive physical characteristics.

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The inclusions that are frequently seen on the same slide with toxic granulation include: (Choose ALL of the correct answers)View Page
Toxic granulation is seen most frequently in:View Page
Another Example of Toxic Granulation

Another example of toxic granulation. Notice that the granules are larger and redder than those in the previous slide.

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Alder-Reilly Anomaly (Alder's Anomaly)

Alder Reilly Anomaly is a rare autosomal recessive hereditary disorder in which the basic defect involves protein-carbohydrate complexes called mucopolysaccharides. The accumulation of partially degraded (broken down) protein-carbohydrate complexes within the lysosomes account for the larger than normal purple-staining granules seen in the granulocytes, monocytes and/or lymphocytes. The granules may occur in clusters, rather than diffusely, throughout the cytoplasm as in toxic granulation. These inclusions may be seen in the bone marrow more frequently than in peripheral blood. The physical characteristics associated with this disorder include gargoylism and dwarfism. The function of the cells involved is not affected. This morpholical change would be classified as pathological since the body is responding abnormally even though the function is not affected.

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Which morphologic term describes this slide?View Page
Which morphologic term describes this slide?View Page

White Cell and Platelet Disorders: Peripheral Blood Clues to Nonneoplastic Conditions
An increase in peripheral blood monocytes with an appearance similar to the cell in the photograph is highly suggestive of infectious mononucleosis.View Page
Additional comments on this exercise

The following pages in this presentation includes a series of white blood cell abnormalities that may be identified in a peripheral blood smear. Many of the cases will simulate the practice of a peripheral smear review by a hematology morphologist. He/she must asses what responses in patient care may be triggered by the clinician attempting to interpret the reported findings on a peripheral smearObservations of white blood cell abnormalities in the peripheral blood smear should be reported so as to direct the physician to an immediate specific diagnosis, such as: (1) atypical lymphocytes suggesting infectious mononucleosis rather than leukemia, (2) toxic granules in neutrophils as in acute infections, or atypical granules suggesting a genetic disorder, (3) an unusual mix of cells, such as too many or too few neutrophils, monocytes, or other myeloid cells, and (4) the presence of giant platelets, myelocytes, or other cells suggesting a myelodysplastic syndrome.In summary, laboratory data should be presented to clinicians in a user friendly way to promote effective decision making. The design of the data base of information must be directed toward providing clinically helpful information clearly and quickly in order to facilitate appropriate action in terms of optimizing patient care outcomes.d

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The neutrophils illustrated in this photograph are representative of those seen in the smear. The total WBC was 28,500 cells/cumm. The appropriate report to be issued following a morphology consultation would be:View Page
Typical cells on a peripheral blood smear as photographed here were repeatedly encountered as the smear was reviewed. The peripheral white blood cell count was 51,000/ml with an orderly maturation sequence. The comment "leukemoid reaction" may properly be appended to the report.View Page
A peripheral blood smear with many myeloid cells (photograph) was presented for morphology review. Toxic vacuoles in the neutrophil and monocyte most likely represent:View Page
The association of increased platelets accompanying neutrophilia and toxic granululation as illustrated in this photograph is called thrombocythemia.View Page
Toxic granulation noted in the neutrophils' cytoplasm reflects an increase in activity of the: (more than one answer may be correct)View Page
Leukemoid reaction revisited

The term leukemoid reaction is used to describe peripheral white blood cells that on the stained blood smear may have some resemblances to leukemia cells. Quantatively in a leukemoid reaction, the neutrophil count is >50,000 cumm with more immature cells, particularly myelocytes, than are usually present in toxic left shift syndromes. The presence of immature cells in a leukemoid reaction awakens thoughts of leukemia. Great care must be taken to make a distinct differentiation between aberrant white blood cell proliferations and a benign but exaggerated granulocytic proliferative response. Our material is from a 1-month-old girl with Down's syndrome. Her total white blood count was 37,000/mm3 interpreted as leukocytosis with left shift. Leukocytosis with a left shift, and leukemoid reactions with high alkaline phosphatase are conditions to be mindful of in patients with Down's syndrome. The alkaline phosphatase score is high in leukemoid reactions, low in granulocytic leukemia.

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Familial disorders: summary

Several additional familial and congenital disorders associated with atypical inclusions in WBCs are now recorded. These individual syndromes carry the following names: Fechtner, Alport, Epstein, Sebastian, and Paris-Trousseau.Fechtner syndrome( Peterson etal,Blood 65:397-406,1985)was described with 8 family members spanning 4 generations presenting with varying degrees of nephritis, deafness,and congenital cataracts. The syndrome is likely a variant of Alport syndrome with the addition of leukocyte inclusions and macrocytothemia. Several more cases involving other families have been reported. The inclusions resemble toxic Doehle bodies or those of the May-Hegglin anomaly by light microscopy, but are ultrastructurally unique.Alport syndrome in itself is autosomal dominant, X-linked , hereditary and characterized by sensorineural deafness and hereditary nephritis. It is believed to result from abnormal glycopeptide synthesis in renal basement membranes. Recurrent hematuria and slowly progressive renal insufficiency are clinical findings. Cataracts and platelet abnormalities may be added features.Epstein syndrome is essentially Alport syndrome with the addition of macrothrombocytopenia (Seri, et al. Hum Genet 110:182-186, 2002). Neutrophil inclusions are absent in this disorder; neutrophilic inclusions are considered part of the Fechtner syndrome. The Sebastian platelet syndrome is a variant of hereditary macrothrombocytopenia combined with neutrophil inclusions that differ from Doehle bodies, but are similar to those inclusions in Fechtner syndrome. (Greinacher, et al, Blut 61:282-288, 1990).Paris-Trousseau syndrome includes large platelets containing giant alpha granules identifiable in the peripheral blood.(Breton-Gorius, Blood 85:1805,1995)

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Alder- Reilly Anomaly

Large inclusions in leukocyte cytoplasm appear with Alder-Reilly syndrome. Inheritance patterns are not completely clear. The condition is characterized by larger than usual azurophilic and deeply violet staining granules clustered throughout the cytoplasm (even covering the nucleus)in all granulocytes. There are variations in which some lymphocytes and monocytes may be affected. These inclusions represent partially degraded mucopolysaccharides within lysosomes.Alder-Reilly bodies may be found independently of genetic mucopolysaccharidoses as an inherited anomaly (Jordan's anomaly). Cytoplasmic vacuoles of toxic origin are not present in Alder-Reilly cells. The background condition in Alder-Reilly syndrome is mucopolysaccharidosis with various types of bone and cartilage disorders, reported first in gargoylism, then in Hunter and Hurler syndromes. Accompanying conditions are hepatosplenomegaly, corneal opacities, and mental retardation. Reference: Brunning, Richard D. Morphologic Alterations in Nucleated Blood and Marrow Cells in Genetic Disorders. Human Pathol: 99-124, March, 1970

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WBC inclusions: summary

The presence of atypical inclusions within the cytoplasm of neutrophils and other leukocytes should lead to a clinical investigation of the setting for these findings.Atypical neutrophil inclusions may be seen in the following disorders: Chediak-Higashi syndrome, May-Hegglin anomaly, Alder-Reilly anomaly, Fechtner , Sebastian, Epstein and Alport-like syndromes and in infectious and toxic conditions (in the form of Doehle bodies).Although a specific entity may not be evident from examination of the peripheral blood alone, it is important that hematology technologists include a comment reporting on the presence of these inclusions or granules. A clinical investigation with further hematologic and genetic studies may then appropriately be considered.Many of the disorders with atypical neutrophil cytoplasmic granules are also associated with platelet abnormalities, particularly giant platelets (lower photograph).Therefore, when atypical granules are recognized, scanning of the peripheral blood smear for atypical platelets may be revealing. These observations serve as readily identifiable markers for acquired and genetic human maladies, and as a guide for unraveling the reasons for a patient's suffering and impaired health.

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The pale-staining cytoplasmic bodies marked by the arrow in the photograph may be seen in each of the following conditions except:View Page
The May -Hegglin anomaly

Illustrated in the upper photograph is a poorly defined cytoplasmic inclusion somewhat resembling a Doehle body. Note, however, that this inclusion is well defined and there is no evidence of toxic granulation in the cytoplasm.When Doehle-like bodies are identified, May-Hegglin anomaly should be considered in the differential diagnosis even though this entity is rare.The May-Hegglin anomaly is an inherited dominant condition in which large 2 - 5 um, basophilic and pyronophilic inclusions are present in granulocytes, including neutrophils, eosinophils, basophils, and monocytes.Similar to Doehle bodies, the May-Hegglin inclusions also are composed of RNA, probably derived from the rough endoplasmic reticulum. May-Hegglin anomaly includes giant platelets containing few fine granules (lower photograph).Sometimes the platelets have bizarre shapes and variable sizes. Variable degrees of thrombocytopenia complicated by mild bleeding problems and purpura may accompany the aberrant platelets.

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Case History

A 17-year-old young woman was admitted to the hospital with abdominal pain and a tentative diagnosis of appendicitis.The total white blood count was 14,500 cells/cumm with a left shift and neutrophils with changes tagged by the arrow in the photographs (see blue arrow).The bluish-staining, blurred accumulations in the cytoplasm (Doehle bodies), are located at the cell periphery in neutrophils with toxic changes.Doehle bodies are remnants of endocytoplasmic reticulum and are products of cytokine activity in the induction and shortened activity of neutrophil activation.They are often present in conditions with increased neutrophil lysosomal activity, manifest as toxic granulation.In this case, the presence of Doehle bodies serves as markers for infection-induced leukocytosis and supports the diagnosis of acute appendicitis.

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The cytoplasmic inclusion illustrated at the tip of the blue arrow is characteristic of:View Page
Basophils

A basophil and a small lymphocyte are compared in the same field of the upper photograph, A single basophil is shown in the lower photograph.The cytoplasmic granules of the basophil are larger than the granules of toxic granulation.They contain chemical mediators of immediate hypersensitivity, and are found in the cytoplasm and overlying the nucleus (better seen in the lower photograph). Basophilic granules stain metachromatically with toluidine blue indicating the presence of acid mucopolysaccharide or proteoglycans, both thought to be heparin or heparin-like substances.Basophils are related to tissue mast cells, each involved in hypersensitivity responses and following anaphylactic episodes.Under the stimulation of complement components C3a and C5a, many mediators are released from the basophil granules, including histamine, heparin, and eosinophil chemotactic factors of anaphylaxis, or ECF-A.Basophils are the least common neutrophils in the peripheral blood, comprising 2% or less of the differential count.The presence of large granules of irregular size in basophils and the admixture of eosinophilic granules may indicate dysplastic changes associated with myelodysplastic disorders and leukemia.

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A peripheral blood smear is submitted for morphology review. The patient is a 10 year-old boy with symptoms suggesting appendicitis and an appendectomy is being considered. The total WBC is 18.5 X 1000/uL, RBC's = 5.45 X 1M/uL, hemoglobin = 16.0 g/dL, hematocrit 48.2%;wbc differential: Segs = 53%, bands = 42% (two of which are shown in the photograph), monocytes = 2%, and lymphocytes= 2%. These findings support the diagnosis of appendicitis.View Page
Case Follow-up

Illustrated in the upper and lower photographs are two-lobed, eye glass ("pince nez") nuclei of neutrophils typical for patients with Pelger-Huet anomaly. In addition to the characteristic two lobes connected by a delicate bridge, the dense, homogeneous nuclear chromatin helps to define Pelger-Huet anomaly. Since the peripheral blood smear did not support the diagnosis of appendicitis in this patient, and since abdominal pain localized to the right lower quadrant never developed, the boy was hydrated with intravenous fluid and observed. After hydration, his constitutional symptoms improved and the abdominal pain subsided. In fact, the lad was back on the ski slopes the next afternoon. People entering high altitude where the humidity may be very low are susceptible to dehydration and may experience symptoms related to mountain sickness. Therefore, close observation and hydration may be the best practice in monitoring patients with stories and findings similar to this one. A further lesson here is that technologists must be alert to the possibility of Pelger-Huet anomaly if a high white blood cell count with a high percentage of band neutrophils with strikingly uniform morphology and without toxic granulation are found. Inappropriate therapy or an invasive procedure as was contemplated here may be avoided by a proper smear assessment and clinical corroboration.

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Case History 2

An 80 year old man was seen in the emergency room with sudden onset of right sided chest pain accentuated on inspiration. His cough was productive of yellow sputum, and he was short of breath.His temperature was 101.2F. A chest X-ray revealed right middle lobe pneumonia. His hemoglobin was 15.2 gm/dl, HCT 44%, and RBC 4.5 m/ml. The white blood count was 35,000/cuml, with 45% neutrophils, 20% bands, 5% lymphocytes, 3% eosinophils, 2% basophils, and 25% atypical monocytes as noted in the photograph.The atypical monocytes had abundant blue-grey cytoplasm with a few scattered vacuoles, which, in company with toxic neutrophils appeared to be a response to infection.The patient had a past history of tuberculosis which may account for the monocytosis.

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Multiple myeloma

Plasma cells are uncommonly observed in the peripheral blood smear.They are normal constituents of lymph nodes, spleen, connective tissue and bone marrow. The presence of plasma cells in the peripheral blood is indicative of a large number of conditions mostly related to infections , immune disorders, malignancies, toxic exposures, hypersensitivity reactions and their responses.Although mature plasma cells have a distinct appearance, they still may be confused morphologically with immature plasma cells and other cells with inclusions, reactive changes or nucleated red bloods cell with altered identities.In the upper and lower photographs are plasma cells with features mindful of myeloma cellsThe large myeloma cell in the upper photograph has an eccentric immature nucleus with a muddy chromatin pattern.Note also clumping and stacking of the erythrocytes, bordering on rouleaux formation ,implicating an increase in plasma gamma globulin.The plasma cell with the double nucleus in the lower photograph is particularly suggestive of myeloma.Further studies are in order including a bone marrow examination where at least 30% of bone marrow cells should be variations of mature and immature plasma cells.Serum electrophoresis will reveal a monoclonal globulin spike, and light chains in excess of 1.0 gm/24 hours may be seen in the urine.The presence of lytic bone lesions is a convincing clinical clue.With these findings in combination, a diagnosis of myeloma can be made with assurance.

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