Introduction to Laboratory Medicine PDF

Introduction to Laboratory Medicine Know the purposes for ordering laboratory tests Screening ◦Identify risk factors ◦Detect occult disease in ASYMPTOMATIC patients Diagnosis ◦Establish or exclude disease in SYMPTOMATIC patients Patient Management Know what is meant by test accur...

Introduction to Laboratory Medicine Know the purposes for ordering laboratory tests Screening ◦Identify risk factors ◦Detect occult disease in ASYMPTOMATIC patients Diagnosis ◦Establish or exclude disease in SYMPTOMATIC patients Patient Management Know what is meant by test accuracy and precision and what factors affect these Test accuracy: ◦Ability to distinguish patients with a disease from those who are disease free ◦Test accuracy not fixed, may vary among patient populations and with different clinical conditions Test precision: ◦Reproducibility of a test measurement when the same specimen is rechecked under the same circumstances ◦Sources of imprecision include: ‣ Biologic variability: variation in test results in same person at different types due to physiologic processes (like biologic rhythms), constitutional factors & extrinsic factors ‣ Analytic variability: variation in repeated tests on the same specimen due to analytic technique or specimen processing/handling (ex. blood glucose testing) Know what the problems are related to establishing a normal range for a test Results of laboratory tests are compared with a reference standard (which indicates values seen in healthy persons) Reference range- results between chosen percentiles in a healthy reference population ◦Normal includes 95% of tests results, thus 5% of healthy population will be outside reference range even if them neat ◦Reference population is not representative of persons being tested ‣ There are differences in gender, age distribution, race, ethnicity setting (hospital vs ambulatory patients) physiologic conditions (fasting, sitting, resting) ◦When more than one test is ordered, the probability increases that at least one result will be outside the reference range Know the diagnostic test performance characteristics Definitions and formulas for: ◦Sensitivity: % of persons with disease correctly identified by the test ‣ Sensitivity (disease present) = True Positive / (True Positive + False Negative) ◦Specificity: % of persons disease-free correctly excluded by the test ‣ Specificity (disease absent) = True Negative / (True Negative + False Positive) ◦Positive Predictive Value: % of persons with a positive test who actually have the disease ‣ Positive Predictive Value = True Positive / (True Positive + False Positive) ◦Negative Predictive Value: % of persons with a negative test who do not have the disease ‣ Negative Predictive Value = True Negative / (True Negative + False Negative)  Sensitivity & Specificity: ◦Inherent technical aspects of test ◦Independent of disease prevalence Predictive Value ◦Influence by sensitivity & specificity ◦Dependent on disease prevalence (% of persons in a population who at a given time have the disease) r a.ae Selecting Cut off Values for ‘Normal” neerkt awent can unnoticed a rather ◦Disease detection- want to maximize sensitivity (fewer false negatives) at the expense of decreasing specificity (more false positives) i dont it have ‣ Decrease in false negatives = increased sensitivity & increase in negative predictive value think they it nave that ‣ Increase in false positives = decreased specificity man miss people ◦Disease confirmation- want to maximize specificity (fewer false positives) & positive predictive value ‣ Want to make sure that positive results are true positives, not false positives ‣ Do not want to misidentify healthy persons so that they do not undergo unnecessary to disease treatment ‣ Decrease in false positives = increased specificity ‣ Increase in false negatives = decreased sensitivity ◦Disease exclusion- want to maximize sensitivity (fewer false negatives) & negative predictive value sure make t ‣ Want to make sure that negative results are true negatives, not false negatives no one wi ‣ Want to correctly exclude that and individual has the disease disease ismissed ‣ Decrease in false negatives = increased sensitivity ‣ Increase in false positives = decreased specificity ◦False negatives inversely related to sensitivity ◦False positives inversely related to specificity Know the criteria for use of screening tests and the use of multiple tests atest least If two tests are available for diagnosis of disease, three combinations can lead to affirmative ustbe positivediagnosis ◦If one of two tests is positive —> diagnosis made potties ◦Positive result for both test —> confirmed diagnosis ◦Second test performed IF first is positive, —> labeled disease ONLY if second is also positive Criteria for Use of Screening Tests ◦Characteristic of population ‣ Sufficiently high disease prevalence ‣ Likely compliant with subsequent tests & treatments ◦Characteristics of disease ‣ Significant morbidity & mortality ‣ Effective & acceptable treatment available ‣ Pre-symptomatic period detectable ‣ Improve outcome from early treatment Reading Lab reports Important to confirm patient Name & DOB, important to record Date & Time of Collection (this is biologically significant) Hematopathology I – Learning Objectives Understand the definition, detection,symptoms, and classifications of anemia o Anemia is a common disorder of the red blood cells in which there is: Reduction in the oxygen-carrying capacity of the blood A decrease in tissue O2 triggers erythropoietin secretion by renal cells. It leads to: o Compensatory hyperplasia of erythroid precursors in bone marrow Extramedullary hematopoiesis occurs in severe cases o Release of immature cells into circulation (reticulocytosis) Reduction of total circulating red cell mass of red blood cells o Red blood cell morphology on a peripheral blood smear provides clues to detect anemia Red blood cells are evaluated by: Size (normocytic, microcytic, macrocytic) Hb content (normochromic, hypochromic) Shape o Anemia is classified by one of the three ways there is to lose oxygen carrying capacity Bleeding (hemorrhage) Acute blood loss o Is typically noticed Severe blood loss can result in shock o Normochromic, normocytic anemia o With adequate iron stores, replacement begins quickly Chronic blood loss o May go unnoticed o Often caused by GI ulcers, IBD, menstrual irregularities GI tract is the main source for small bleeds o Causes a gradual depletion of iron stores (iron deficiency anemia) Hemolysis (intravascular or extravascular) All hemolytic anemias are characterized by: o Increased rate of RBC destruction Decreased lifespan of RBC due to inherent defect in RBC or acquired disease o Increased rate of erythropoiesis – increased reticulocytes in blood Young RBCs that still contain nucleic acid remnants o Retention of RBC breakdown product (i.e., bilirubin) Hyperbilirubinemia o Extramedullary hematopoiesis may occur Spleen is the most common site for extramedullary hematopoiesis Diminished erythropoiesis (production) o Symptoms generally include pallor, fatigue, and pallor, but additional symptoms may arise depending on the type of anemia Hemolytic anemias: Hyperbilirubinemia, jaundice, pigmented gallstones Ineffective production of red blood cells: Iron overload with time Define and describe the various kinds of hemolytic anemia discussed in lecture Hematopathology I Anemia Etiology Description Signs & Symptoms Treatment/Diagnosis Hereditary Autosomal dominant Decreased membrane stability Splenomegaly (spheres cannot No cure Spherocytosis Mutations in various proteins Loss of membrane – RBCs become transit from spleen and are removed Anemia is helped forming intracellular skeletal spherical in shape (hold less blood) by macrophages) by splenectomy meshwork just beneath surface of RBC plasma membrane (ankyrin that connects spectrin meshwork to intrinsic membrane proteins,(band 3 & band 4.2) Sickle Cell Anemia Autosomal recessive Most prevalent hemaglobinopathy Cells sickle with deoxygenation: HbS Homozygotes – Point mutation at #6 codon – structurally abnormal Hb ‘polymerizes.’ Sickling increased in sickle cell anemia on B-chain (valine glutamic Sickling is influenced by the other tissues with low oxygen (spleen, Heterozygotes acid), producing HbS type of Hb present bone marrow, areas of (60 HbA: 40 HbS) 8% of African Americans in US (a) HbA doesn’t aggregate well with inflammation) – sickle cell trait are heterozygotes HbS so patient has trait Sickled cells cannot transit spleen Reversible with (b) HbC aggregates with HbS so and are removed by macrophages oxygen, but patients have symptoms lifespan of RBCs down to 20 days; becomes q (c) HbF aggregates poorly with HbS extensive erythropoiesis with permanent when so newborn with SCA only apposition of new bone to expand repetitive manifests disease after 4-5 months the marrow, causing “hair end” of age, when HbF declines in RBCs appearance on x-rays to adult levels and cells mainly HbS Sickled cells obstruct peripheral capillaries causing painful microinfarcts (autosplenectomy over time, prone to infarcts) Immunohemolytic Autoimmune disease or Caused by antibodies binding to IgG acts as opsonin so RBCs Coombs test anemias induced by drugs/chemicals normal or altered RBC membrane phagocytosed by macrophages in evaluates as haptens antigens spleen (extravascular) presence of free IgM activates complement or bound to RBCs intravascular hemolysis or anti-RBC opsonization via C3b antibodies Anemia variable in severity (most mild/chronic) Glucose 6- X-linked (males) More common in African American No symptoms unless RBCs are Acute onset of Phosphate Many mutations identified males subjected to oxidants (certain drugs, symptoms, but Dehydrogenase Most common mutation RBCs are susceptible to damage by bacterial toxins, reversible with Deficiency causes G6PD to denature oxidants infection/inflammatory free radicals, new RBCs with rapidly once synthesized – Oxidants are normally neutralized fava beans) functioning older RBCs lack the enzyme by glutathione (GSH) Denatured Hb precipitates enzyme and become inadequate in Deficiencies in enzymes that intravascular hemolysis or RBC GSH maintain adequate levels of GSH removed by spleen macrophages increase risk of oxidizing (denaturing) Hb Thalassemia Heterogenous group of B-Thalassemia B-Thalassemia B-Thalassemia genetic disorders with Single base changes (there are Cells are microcytic, hypochromic becomes decreased rate of Hb many possible) in beta gene Thalassemia major – alpha chain apartment when no synthesis Mutations – stop codons, dysfunctional promoters, B0 allele – no production; B+ allele – minimal production One abnormal B allele – aggregates and alter RBC shape so they are removed by macrophages in spleen/bone marrow HbF levels decline Thalassemia aberrant mRNA processing Thalassemia minor Secondary hemochromatosis (Fe major sustained Two abnormal B alleles – overload); could be fatal treated by blood Thalassemia major with Fe chelators or bone marrow transfusions A-Thalassemia transplant A-Thalassemia Hb alpha chains produced by 2 Marrow expansion HbH disease may genes/ 4 alleles Hepatosplenomegaly not require A-thalassemia results from Massive attempt by body to replace transfusions deletions of the alleles RBCs Loss of 1 allele – silent carrier state Thalassemia minor – hypochromic, Loss of 2 alleles – A-thalassemia microcytic anemia but normal trait; asymptomatic or mild lifespan Loss of 3 alleles – B-globin chains form tetramers (HbH), which bind O2 tightly, will not release it peripherally (HbH disease); less severe than Thalassemia major Loss of 4 alleles – hydrops fetalis (incompatible with life) Hemolytic anemia Cardiac valve prosthesis Damaged RBCs lose parts of cell Causes intravascular hemolysis Not mentioned due to Narrowing, partial membrane and are removed by mechanical obstruction of small blood splenic macrophages (seen as trauma to RBCs vessels due to damage to foreign by spleen) vessel wall or formation of firbin clots (SLE, hypertension, cancers, disseminated intravascular coagulation, etc) Malaria Protozoa (4 types) – One of most widespread infections Merezoites are released from RBCs Humans are only Plasmodium spp. in humans every 48-72 hrs causing extensive natural reservoir Plasmodium falciparum causes the hemolysis, cyclic fevers, chills, Look at travel more serious types with a high shaking history mortality rate. All forms Hemolysis results in hemogloinemia, Ring forms transmitted via female Anopheles jaundice, & hemoglobinuria Schizont mosquito (blackwater fever) Complex life cycle: infects liver Splenomegaly (splenic macrophages cells, multiplies & in short time increase in number to deal with the showers merozoites (baby version parasitized RBCs) of parasite) into blood stream Cerebral vessels engorged with parasitized RBCs, create microthrombi (parasitized RBCs tend to clump together, adhere to endothelium), brain damage, convulsions, death Higher degree of parasitemia increases risk of symptoms  Hematopathology Part II Anemias of Diminished Erythropoiesis Iron deficiency anemia o It is the result of a negative iron balance. This can be caused by a variety of things, but the most common cause is loss of RBC from bleeding (commonly in the GI tract, but can also be caused by cancers, infections, or menorrhagia) ▪ It can also be caused by low dietary iron intake (which is uncommon in the US), malabsorption syndromes, and excessive demand for iron from pregnancy or during infancy. o The onset is insidious from a gradual decrease in Fe-containing proteins such as hemoglobin and myoglobin ▪ Results in hypochromic, microcytic anemia that is usually mild The pallor center of the RBC is usually about 1/3 of its size, but in this type of anemia, it is about 2/3 the size of the RBC o There is minimal bone marrow hyperplasia, which is limited by iron availability o Symptoms include atrophic glossitis, weakness, and pallor Anemia of chronic disease o Typically occurs in chronic disease that are associated with long-term systemic inflammation. This type of anemia is associated with increased amounts of cytokines ▪ Common chronic diseases that can lead to anemia are osteomyelitis, bacterial endocarditis, Crohn’s disease, rheumatoid arthritis, Hodgkin lymphoma, etc. ▪ IL-1 and TNF are proinflammatory cytokines, which are upregulated in these diseases They induce the sequestration of iron in macrophages, therefore the iron is not available for RBCs ▪ Effective treatment is to treat the underlying disease causing the anemia ▪ Normochromic, normocytic/hypochromic, microcytic as it gets worse Megaloblastic anemia o Results in a deficiency of dietary folate or vitamin B12 ▪ Both folate and vitamin B12 are involved in the DNA synthesis of purines, and they have a similar effect erythropoiesis This results in a delay of DNA synthesis, which causes a delay in nuclear maturation and cell division o Cytoplasmic components mature normally an continue to accumulate during the delay, which results in enlarged RBC precursors (megaloblasts) and enlarged RBCs, as well as other cells in the body o RBCs are macrocytic and neutrophils are hyper segmented o Anemia is due to slow production of RBCs, which reduces the total output. Some fail to divide at all, in which they undergo apoptosis o Results in pancytopenia, which is a reduction in all cell lines ▪ Deficiency in either vitamin results in a slow turnover of cells in parts of the body that normally have a fast cellular turnover rate, such as the GI tract epithelium. This can result in severe symptoms of the alimentary tract such as a sore tongue and cheilosis ▪ B12 deficiency also results in a demyelinating disease of the peripheral nerves and spinal cord, which results in nervous system issues ▪ B12 deficiency can also be due to inadequate synthesis or the defective function of intrinsic factor, which results in pernicious anemia  Intrinsic factor is needed for absorption of B12 in the gut This anemia is the result of autoantibodies, which attack either the cells that make intrinsic factor (parietal cells) or the intrinsic factor itself This can be caused by gastric atrophy or gastrectomy, resection of the distal ileum, malabsorption diseases, or Crohn’s disease (which results in decreased area for B12 to be absorbed) Aplastic anemia o Disorder due to the suppression of multipotent myeloid stem cells, which results in marrow failure and pancytopenia ▪ Myeloid stem cells are stem cells committed to the myeloid lineage, and they are the precursors for RBCs, platelets, and all WBCs except lymphocytes o The most common causes are idiopathic, but some may be caused by myelotoxic drugs, radiation, or following a viral infection o This is the result of T cells attacking the myeloid stem cells ▪ Treated with immunosuppressive drugs in 80% of cases o Symptoms include anemia, petechiae, ecchymosis due to thrombocytopenia and persistent infections from neutropenia o Progression is unpredictable, because the cause may be fleeting or persistent ▪ Treatment can include discontinuing the drug, or a bone marrow transplant if the patient cannot recover Myelophthisic anemia (very general term) o Anemia caused by extensive replacement of bone marrow with fibrosis, tumor cells, etc. that crowd out normal hematopoietic elements ▪ The bone marrow is being replaced with something else that results in a space modifying lesion of the bone marrow o Causes of this include: leukemia, multiple myeloma, metastatic cancers, infections (TB), progressive fibrosis of marrow, and osteosclerosis o Symptoms include anemia and thrombocytopenia Polycythemia Characterized by an increase in RBC with increased hemoglobin. It is broken down into 2 types: o Relative polycythemia = due to decreased plasma volume as it occurs with dehydration ▪ It can be treated by administering fluids o Absolute polycythemia = increase in total RBC mass. This can be further broken down into 2 types: ▪ Primary form (polycythemia vera) is a neoplastic proliferation of progenitor cells. It is the result of a problem with the myeloid stem cells ▪ Secondary form is a response to increased erythropoietin due to high altitude, lung diseases, cyanotic heart disease, and renal cell carcinomas synthesizing excess erythropoietin White Blood Cells Leukopenia o Characterized by a decrease in circulating WBC o The most common form involves neutrophils (neutropenia), because they are the most abundant WBC o It can be caused by:  ▪ Inadequate/ineffective production of WBC from chemotherapy, aplastic anemia, or leukemia m ▪ Accelerated destruction/utilization of neutrophils from severe infection, immunological attack, or an enlarged spleen o Agranulocytosis is a subset of this. It is characterized by the virtual absence of neutrophils due to a depletion of the blood and marrow storage pools ▪ The most common cause is drug toxicity (extrinsic cause) ▪ ANC < 500/μL Low ANC results in an increased risk of infections, which becomes a major problem o Treat by controlling infections and removing drugs that cause this. It can also be treated with G- CSF, which stimulate bone marrow production of neutrophils ▪ It is important to determine the cause before starting treatment Leukocytosis o Mechanisms of leukocytosis include: ▪ Increased production in the bone marrow This can be the result of chronic infections or inflammation, paraneoplastic, or myeloproliferative disorders ▪ Increased release from bone marrow stores This can be the result of endotoxemia, infection, or hypoxia ▪ Decreased margination This can be caused by of exercise or catecholamines ▪ Decreased extravasation into tissues This can be caused by glucocorticoids o Reactive leukocytosis is the reactive increase in circulating WBCs. It is important to determine if it is involving myeloid or lymphoid cells, because this does not differentiate between the types of WBCs. Different types of reactive leukocytosis include: ▪ Neutrophilic leukocytosis is caused by acute bacterial infections, sterile necrosis ▪ Eosinophilia is caused by allergies, drug reactions, or parasites This accounts for about 95% of reactive leukocytosis ▪ Monocytosis is caused by chronic infections such as Crohn’s disease or ulcerative colitis ▪ Lymphocytosis is caused by viral infections such as hepatitis Lymphoid Hyperplasia Reactive lymphoid hyperplasia o Caused by antigenic stimulation of lymphoid tissue, which often results in lymph node enlargement. This is usually the result of a bacterial or viral infection ▪ Inflammation can also occur within the lymph node and then have a lymphadenitis. The inflammation will begin at a locally and then spread to other lymph nodes. There are 2 types of lymphadenitis Acute lymphadenitis is involved with neutrophils, and can result in possible abscess and necrosis Chronic lymphadenitis is involved with reactive follicular hyperplasia or paracortical lymphoid hyperplasia o In chronic nonspecific lymphadenitis, the lymph nodes are nontender. This is because the nodal enlargement occurs slowly overtime o This is particularly common in inguinal and axillary lymph nodes  o Microscopically results in follicular hyperplasia, paracortical expansions, and sinus histiocytosis Intro to Neoplastic Proliferation of WBC It is important to first assign the lineage that the neoplasm involves: o Lymphoid neoplasms are usually the result of a block at a particular stage in B or T cell differentiation, with subsequent proliferation of immature cells ▪ These include Non-Hodgkin/Hodgkin’s lymphoma, lymphocytic leukemia, and plasma cell dyscrasia o Myeloid neoplasms arise from stem cells that normally give rise to RBCs, platelets, and granulocytes o Histiocytic neoplasms are uncommon, and they include Langerhans Cells Histiocytosis Neoplastic Disorders of Hematopoietic System Lymphoid Neoplasms ◦Some arise in bone marrow and circulate in blood as a leukemia ‣ No tissue masses in leukemia ◦Lymphomas typically appear as tumor masses in lymph nodes or lymphoid aggregates in organs ‣ GI is often involved in lymphomas ‣ But no organ is immune ◦Tumors of plasma cells (e.g. multiple myeloma) usually present as masses in bone with systemic symptoms related to production of large amounts of Ig chains ‣ Multiple myeloma- higher degree of malignancy ◦All lymphoid neoplasms tend to spread to lymph nodes and other tissues, spleen, liver, bone marrow ‣ Lymphomas, myelomas can spill over into blood giving a leukemia picture, and leukemias can form masses ◦After determining that neoplasm is of lymphoid lineage, determine further lineage: ‣ Most T and B lymphomas composed of cells that have stopped at a particular stage of differentiation Diagnosis depends heavily on maturation markers ‣ Most common lymphomas in adults are B cell origin 85-90% of lymphomas Derived from follicle where cells usually undergo regulated somatic hypermutation that places cells at risk of mutations Common chromosomal translocations involve the Ig gene loci ◦This is the driving force ‣ T cells are more genetically stable, fewer lymphomas T cells do not make Ig to the extent of B cells, so this may be why these lymphomas are less common than those of B cell origin ◦Lymphoid neoplasms are clonal ‣ Clonal evolution: phenomenon that these diseases can become more aggressive, acquiring additional mutations & abnormalities ◦Lymphoid neoplasms disrupt normally immunity ‣ Immunodeficiencies, autoimmunity accompanies them ◦Non-Hodgkin lymphomas are often widely disseminated at time of diagnosis, requiring systemic therapy ◦Hodgkin lymphomas often present at a single site and spread from node to node in a chain ‣ May be cured with local therapy early in course of disease Early diagnosis —> favorable outcomes ◦CD34: marker for immature somatic cells = blasts (marrow contains up to 3% of blasts) ◦Lymphoid stem cell —> B or T cell = loss of CD34 ◦As B cell matures —> gaining of CD19 and CD20 —> surface Ig molecule is present —> terminal differentiation of B cells into plasma cells (whose purpose is antibody production) ◦As T cells mature —> gaining of CD3 and CD2 + cytotoxic T cells gain CD8 and helper T cells gain CD4  Background/ Affected Population Symptoms Prognosis/ Images Pathophysiology (I.e. age, race, etc.) Outcomes Precursor (Acute) Aggressive, immature Pre-B form occurs In Abrupt onset, Certain B/T cell immunoblasts young kids symptoms related to karyotypic lymphoblastic Pre-B lymphoblastic Pre-T mainly in marrow failure, bone changes relate to leukemia/lymphoma tumors arise in bone teens pain, a better marrow and pre-T Assign lineage by hepatosplenomegaly, prognosis lymphoblastic tumors markers enlarged lymph Chemotherapy arise in thymus as nodes has resulted in mediastinal mass regression/cure Both rapidly progress to in many cases a leukemic phase as (due to targeting acute lymphoblastic the rapidly leukemia (ALL) due to dividing cells) rapid division Small lymphocytic B-cell Most are diagnosed Can be Course is variable lymphoma/chronic Same disease, differing at CLL stage, asymptomatic, but Some die with lymphocytic in extent of peripheral common in adults symptoms can reflect the disease, while leukemia blood content bone marrow failure, in other cases a enlarged organs, new, more (SLL/CLL) bone pain aggressive clone emerges dropping survival duration Lymph node has no Richter architecture transformation: transformation to Monomorphic population = large B cell everything is same, one type lymphoma of cell has taken over Expectant observation: sometimes these PTs are monitored and not treated Smudge cells: smearing artifact, usually referring to CLL Follicular B-Cell Older patients, 40% Painless Long natural Back to back follicles lymphomas Uncommon in extranodal of adult NHLs in US lymphadenopathy, history, indolent (follicles are lined up) sites, uncommon to be often generalized and generally leukemic including bone incurable Most have a t(14:18) About 40% translocation with develop a new, overexpression of BCL-2 more aggressive gene (anti-apoptosis) clone giving rise to diffuse lymphoma and worse prognosis Diffuse large B cell Typically present with Aggressive, account Fatal, if not Diffuse sheets of large cells lymphomas rapidly enlarging single for about 50% of treated CD20 would be used as mass at nodal or adult NHLs Combination marker extranodal site Must occur in older chemotherapy Liver, spleen and bone adults, but wide age puts about 60- marrow not usually range 80% into involved at time of EBV implicated in complete diagnosis and leukemic those occurring in remission component is rare immunosuppressed Burkitt Lymphoma Endemic Endemic Both types are Starry sky appearance o Translocation of o Parts of Africa, high grade, (lighter macrophages MYC gene strongly aggressive Other darker purple cells o Malaria, other associated with tumors are neoplastic cells infections reduce EBV infection Aggressive immunocompetence o Children/young chemotherapy allowing EBV to adults permits cure in cause B cell most proliferation o Maxilla or mandible is most common presentation in FISH: fusion from African form translocation t(8;14) Non-endemic: N. American form (sporadic) o MYC translocation, but only 20% have EBV o Presents as an abdominal tumor Multiple Myeloma One of the plasma cell Multifocal lytic Bone pain, fractures, No cure, median High Ig production shown in neoplasms (spectrum of lesions in skeleton, hypercalcemia, survival is 4-6 plasma cell diseases/disorders) mainly in older myelophthisic years o Originate from clone adults anemia, infections, of B cells that Highly unlikely in amyloidosis differentials into patients 0.5 cm in prepubertal individuals or > 1.5 cm in postpubertal individuals -2 or more neurofibromas of any type of 1 plexiform neurofibroma -Axillary or inguinal freckles  -2 or more Lisch nodules -Optic glioma -Sphenoid dysplasia or thinning of long bone cortex with or without pseudoarthrosis -First degree relative diagnosed with neurofibromatosis type 1 TUMORS OF UNCERTAIN ORIGIN - Synovial sarcoma ○ 20-40 yrs old ○ 10-20% of sarcomas ○ Microscopically: Monophasic or biphasic cells - Monophasic synovial sarcoma consists of uniform spindle cells with scant cytoplasm + dense chromatin growing in short, tightly packed fascicles - Biphasic SS has epithelioid/granular like component + spindled component ○ Misnomer (NOT from synovial): First described cases arose in the soft tissues near the knee joint + a morphologic relationship to synovium was postulated ○ Characteristic chromosomal translocation t(x;18)(p11;q11) producing fusion genes composed of portions of the SS18 gene and one of three SSX genes - Undifferentiated pleomorphic sarcoma ○ Malignant mesenchymal tumors w high-grade pleomorphic cells that cannot be classified into another category ○ Usually large, grey-white fleshy masses that can grow quite large (10-20 cm) depending on the anatomic compartment ○ Necrosis + hemorrhage are common - Ugly looking, don’t know cell of origin, doesn’t stain, no genetic marker, etc. PATHOGENESIS OF SARCOMAS - Most are sporadic + have no known predisposing cause - Germline mutations in tumor suppressor genes - Environmental factors + radiation - Host immune surveillance - Autoimmune disease - Simple karyotypes: mutation sarcomas = uniform - Complex karyotypes: high variability Medical Management of Rheumatologic and Connective Tissue Disorders Dental Management of Rheumatologic/CT Diseases Arthritis Dental management ◦Same for rheumatoid and osteoarthritis EXCEPT there are more problem related to the medications for rheumatoid arthritis ◦Short dental appointment ◦Frequent position changes and physical supports to keep the patient comfortable ◦If there are no physical disabilities present —> NO need to treatment plan modifications ‣ Assess the physical disabilities and dexterity Oral complications ◦TMJ pain/dysfunction ‣ Sudden occlusal changes may indicate erosion of the condole ‣ Manage with a soft diet, moist heat or ice, occlusal appliances, and surgery if there is difficultly with normal functions ◦Bilateral condyle resorption ‣ Sudden anterior open bite Rheumatoid Disorders and SLE Drugs *KNOW ORAL/DENTAL CONSIDERATION FOR EACH CLASS OF DRUGS Systemic Lupus Erythematous (SLE) No specific dental treatment plan modifications are needed ◦May have an increased risk of infection, prolonged bleeding, stomatitis, and oral ulcers Gold compounds, sulfasalazine, or immunosuppressives can lead to bone marrow suppression Additional corticosteroids are usually not needed Leukoplakia is common in SLE patients ◦Not associated with increased risk of infection unless patient is taking corticosteroids Platelet count < 50000 will result in severe bleeding Elevated PTT associated with lupus anticoagulant but usually does not cause increased bleeding ◦Surgery is OK Oral manifestations ◦Nonspecific lesions on lips and mucus membranes ‣ Resemble lichen planus or leukoplakia ‣ Frequently notes after sun exposure ◦Xerostomia  ◦Dysgeusia ◦Glossodynia (burning tongue/mouth) Prosthetic Joints 2015 guidelines (KNOW) ◦Antibiotic prophylaxis is NOT recommended for patients with prosthetic joint implants prior to dental procedures to prevent dental infections ◦Practitioner and patient should consider: ‣ Individual circumstances may suggest the presence of a significant risk in providing dental care without antibiotic prophylaxis ‣ Known risks of frequent or widespread antibiotic use Evidence for 2015 guideline (KNOW) ◦Dental procedures are NOT associated with prosthetic joint implant infections ◦Antibiotics provided before oral care do not prevent prosthetic joint implant infections ◦Potential harms of antibiotics include risk for anaphylactic, antibiotic resistance, and opportunistic infections ◦Benefits of antibiotic prophylaxis now not exceed harms for most patients Sjogren’s Syndrome Eye and mouth dryness, hyposalivation, and enlargement of parotid glands ◦Secondary outcomes ‣ Increased dental caries ‣ Oral candidiasis ‣ Dysgeusia ‣ Angular cheilosis Xerostomia/dry mouth leads to INCREASED ROOT and DENTINAL CARIES Measure flow rate by having patient drool into graduated container for 5 minutes ◦Normal unstimulated (resting) whole flow = 1 mL/5 min ◦Normal stimulated whole flow = 5 mL/5min ◦Sjogren’s unstimulated whole flow = 0.5 mL/5 min Management of salivary dysfunction ◦Provide moisture and lubrication as needed ◦Soft tissue lesions and soreness should be treated with topical glucocorticoids as they appear ◦Oral candidiasis with anti fungals ◦Prevention of caries and periodontal disease by keeping the mouth clean and increasing fluoride Parasympathetic mimetics such as pilocarpine and cevimeline can increase salivary flow ◦Dose related side effects include salivation and then sweating ◦Contraindications ‣ Uncontrolled asthma ‣ Acute iritis ‣ Narrow angle glaucoma Viral lnfection of Skin & Joints – Learning Objectives Learn about the basic anatomy and normal microbiota of the skin o The skin structure is composed of the skin surface, the epidermis, and the dermis: The normal human skin microbiota (all the organisms living in the skin) is comprised of bacteria, viruses, fungi, and mites It has been established via sequencing methods that there is a high diversity of DNA viruses identified on the human skin o Viruses are associated with skin infection may cause rashes: Maculo-papular rashes Flat to slightly raised colored bump o May or may not contain pus Vesicular or pustular rashes Elevated lesions filled with fluid or pus Other rashes The skin exhibits natural defenses, which help, in part, defend against viral infection: Keratin Skin sloughing Sebum (low pH, high lipid) Sweat (low pH, high salt) o Contains lysozyme, which digests peptidoglycan o Contains RNase, which digests RNA Cells of the epidermis include keratinocytes, melanocytes, and Langerhans’ cells: Keratinocytes o Produce keratin, which gives the skin a protective capacity from: Water/heat loss Penetration of microbial agents Physical trauma Melanocytes o Produce melanin, which gives the skin a protective capacity from: UV rays Langerhans’ cells o Are antigen-presenting cells, which: Transport antigens to regional lymph nodes, where they present the antigens to naïve T lymphocytes There are a variety of physiological functions of the skin: Display o Enables us to assume our identify & to recognize among ourselves Protection o Protects the body from many environmentally unfavorable factors and unnecessary entry or egress of fluids into and from the body Thermoregulation o Conveys sensory input to the CNS & modulates temperature via sweating, vasodilation, & shivering Immunologic o Bears lymphocytes, Langerhans’ cells, & mast cells Synthetic o Synthesizes vitamin D, hormones, melanin, & other substance  Lean about viral infections of skin and the joints that are characterized by maculo-papular (maculo-pustular) rashes Virus/Disease Epidemiology Symptoms Pathogenesis Diagnosis Transmission Prevention/Treatment Measles Virus Leading Initial infection of oro-pharynx MeV is a single Histology Viral Effective (Rubeola) cause of Local infection of lymph node(s) stranded negative- shows that infection childhood vaccine vaccine (neck) sense RNA virus many of the through (MMR, 2-3 doses) preventable Lymphocyte associated viremia Caused by Measles infiltrating aerosol Primary reason death among (cold & fever) virus (MeV) infection mononuclear droplet for ongoing high children Macular rash with raised spots (due MeV is enveloped & cells are T Spreads childhood deaths Disease still to immune response) contains 6 proteins lymphocytes throughout is failure to exists Rash begins on face & affects trunk ELISA for the body (via deliver at least worldwide & & extremities IgM, T cells) one dose of millions still Koplik’s spots in oral mucosa acute/conval measles vaccine at risk May cause other health escent IgG to all infants Death rate complications (pneumonia, higher in diarrhea, encephalitis, corneal malnourishe scarring) d children Rubella Virus First Mild rash (milder than Measles) Togavirus that is ELISA for Viral Vaccine highly st (German described by If contracted during 1 trimester of enveloped & has IgM, infection effective (MMR) Measles) German pregnancy, disrupts fetus single stranded acute/conval through Currently used physicians in development of CNS & other positive-sense RNA escent IgG aerosol vaccination mid 18th organs (Congenital Rubella droplet (RA27/3 strain) century Syndrome) Once causes post- o Low birth weight , infected, vaccination joint blindness, hearing loss, transmits symptoms in 15% mental retardation, heart systemically of recipients problems o Infection lasts mos-yrs in the newborn Natural infection associated with arthritis both children & adults o Sudden onset, polyarticular (in fingers, knees, wrist), brief, & symmetrical Human Ranked as Progresses in stages Small, non-enveloped Not Exclusively Vaccine is Parvovirus B19 fifth disease Stage 1 (immediate): Single stranded DNA mentioned infects currently being (Fifth Disease/ in a 1905 list o Mild illness with fever, GI virus humans developed for Erythema of skin rashes symptoms, & headache Lack of lipid PVB19 Infectiosum) Most widely Stage 2 (3-7 days after): membrane gives the Vaccine consists known o Malar erythema (‘slapped virus stability and of 25% VP1 cutaneous cheek’ appearance which resistance to heat, (capsid) & 75% finding spares nasal bridge & cold, and detergants VP2 (capsid) with Mostly seen periorbital area) that an adjuvant in children 4- becomes more pronounced 11 y/o upon exposure to sunlight or heat, pallor near mouth Varied spectrum of manifestations, ranging from subclinical infection to skin & joint symptoms o Arthralgia (joint pain) mainly seen in female adult o Arthralgia symmetric in adult & affects small joints o Arthralgia asymmetric in kid & affects larger joints o Arthralgia in kid tends to occur later in course of infection & is self-limiting but may recur o Small number of kid & adults develop chronic polyarthritis (similar to rheumatoid arthritis)  Learn about viral infections of skin and the joints that are characterized by vesicular or pustular rashes Virus/Disease Epidemiology Symptoms Pathogenesis Diagnosis Transmission Prevention/Treatment Herpes Human HHSV-1 HSV-1 usually causes oral herpes Core of double stranded Not Ubiquitous & Acyclovir may Simplex Virus affects ½ of (cold sores, fever blisters) but can DNA surrounded by mentioned contagious lessen symptoms 1,2 (Cold population infect genitals icosahedral protein coat but does not Sores) HSV-2 usually causes genital Nucleocapsid surrounded eliminate virus lesions, but can also infect the by envelope mouth HHV-1 can remain latent Leading cause of blindness in US (1) in trigeminal ganglia Rare complication of herpes encephalitis Herpetic Whitlow o Primary lesion on finger/thumb w/ herpetic stomatitis due to autoinoculation Eczema Herpeticum o Severe form of cutaneous herpes o May occur in children & adults with atopic eczema Varicella- Common Causes varicella (chickenpox) in Human alpha herpesvirus Clinical Recuperation Decreasing Zoster virus children and zoster (shingles – skin Infects human when appearance can result in disease in US due Virus/Human Benign but lesion) when reactivated in adults particles reach mucosal life long to effective Herpes Virus 3 life- With a decline in VZV-specific cell epithelial sites of entry. benign VZV childhood vaccine (Chickenpox) threatening mediated immunity in elderly Local replication followed latency (in for immune- individuals, as well as in AIDS and by spread to tonsils & sensory compromised other immunocompromised other regional lymphoid ganglia via patients, VZV reactives from one tissues, where VZV gains neuronal or more ganglia to cause herpes access to T cells transport or zoster (shingles) Infected T cells deliver viremia) virus to cutaneous sites of Life-long replication immunity Human Pox Was one of All infected individuals have Orthopoxvirus (OPV) Clinical A strictly Live vaccinia virus Virus /variola the most symptoms variola virus caused 1- appearance human vaccine (VACV) (Smallpox) deadly Was categorized by systemic aches 30% case fatality rates of disease – no contributed to viruses & fever that peaked in ~1 wk. As smallpox animal eradication Eradicated the fever broke, oropharyngeal reservoir Utilized pre & enanthema (eruption on a mucous Droplet, post exposure surface) developed, followed by indirect Isolation exanthema (skin rash with contact centrifugal virus filled pustules) Learn about other viral infections of skin and the joints Virus/Disease Epidemiology Symptoms Pathogenesis Diagnosis Transmission Prevention/Treatment Molluscum Kid, sick, Skin lesions or pustules (2-5 mm, Caused by DNA virus of Not Contagious, Not mentioned Contagiosum sexually flesh colored, dome-shaped, w/ Poxviridae family mentioned human- Virus active central depression) human Dengue Virus Not Petechia, purpura, fever, headache, Four serotypes; sequential Not Mosquito Recovery confers (Dengue mentioned muscle/joint pain, dehydration, infection increases risk for mentioned (Aedes immunity to that Fever) epistaxis, haematuria, pain more serious disease (DHF) aegypti) serotype Zika Virus Emerging Asymptomatic or mild (~ 1 wk) Primary human fibroblasts Morpholog Yellow fever Not mentioned (Zika) arbovirus Incubation period of 2-7 days are susceptible to ZIKV ical mosquito Outbreaks Rash (maculopapular & pruritic), ZIKV infects human changes in (Aedes in South self-limiting acute fever, arthralgia, keratinocytes human skin aegypti) & America myalgia, headache, conjunctivitis Infection inhibited by late biopsy Asian tiger Targets neural progenitor cells stage pregnancy (IGN1 & specimens mosquito (A. during 1st trimester (microcephaly) ISGs) albopictus) Chikungunya Found for 3-7 days after being bitten Not mentioned Not Mosquitoes Risk virus will be 1st time in Fever, joint pain (may persist for mentioned imported to new Americas in months), headache, muscle pain, areas by infected Caribbean joint swelling, rash travelers (2013) Severe & debilitating (but no death) No vaccine to Newborns, elderly, people with prevent and no medical conditions (high BP, medicine to treat diabetes, heart disease) at risk for more severe disease Clinical Correlation: Alveolar Bone Homeostasis Discern the anatomy and functions of the attachment of teeth and dental implants to the alveolar bone The attachment of epithelium to a tooth is similar to the attachment of epithelium of a dental implant ◦In both, the oral epithelium is continuous with sulcular epithelium that lines the inner surface of the gingival sulcus ◦Apical part of the gingival sulcus is lined with the long junctional epithelium ‣ The epithelial cells of the long junctional epithelial attachment adjacent to the implant attach with a basal lamina and hemidesmosomes ‣ Connects soft tissue to the root of teeth and connects soft tissue around the implants ◦The intercellular spaces of sulcular epithelium are tightly sealed by many spot desmosomes ‣ Contributes to the low permeability of the peri-implant mucosa ◦Alignments of connective tissue fiber are circular and horizontal around implants ‣ This helps to seal the underlying tissue ◦The zone of supracrestal CT has an important function in the maintenance of a stable soft tissue-implant interface as a seal (barrier) to the outside oral environment ‣ Supracrestal tissues cover the alveolar bone ‣ Protects the tissue and bone under it from insults that could cause damage Major differences between natural teeth and implants ◦Implants LACK root cementum, PDL, and alveolar bone proper (the dense bone lining the tooth socket) ‣ Because implants lack cementum, the collagen fibers do not anchor the implant to the bone ◦Dentoalveolar and dentogingival fiber bundles connect the soft tissues with the tooth (root cementum) ‣ NO fibers are seen in peri-implant tissues ◦Natural tooth is mobile within its socket ‣ Implant is rigidly anchored (ankylosed) to the surrounding bone ◦Natural teeth are NOT in direct contact to bone. There is PDL fibers that anchor the tooth to the bone ‣ Implants are in direct contact with the bone (= osseointegration) because there is no PDL ◦CT surrounding teeth has more of a blood supply, because it supplies the PDL ‣ CT surrounding implants has less of a blood supply, because it does not have a PDL In the areas beyond the tissue adjacent to implant, the blood supply is normal Describe the details of wound healing following periodontal surgical procedures Wound healing following periodontal treatment is similar to skin, and it occurs in 4 phases ◦Hemostasis (blood coagulation) ◦Inflammation (formation of granulation tissue) ◦Proliferation (new tissue formation) ◦Maturation (remodeling) ‣ The goal is to obtain the same form of tissue before the damage occurred Early healing events at the tooth-gingival flap interface ◦10 minutes: RBC adhering to dentin ‣ Seals wound and provides scaffold for cells to migrate ◦1 hour: RBC in a fibrin network ‣ Forms a mesh guided by fibrin ◦6 hours: early phase of inflammation ◦3 days: late phase of inflammation ‣ Macrophages cleanse the area of debris and dead cells ◦5 days: granulation tissue formation ‣ Fibroblasts are producing collagen ◦7 days: connective tissue formation ‣ More cells and CT formation ◦Complete epithelialization of the wound occurs after a few weeks of healing The cells that contribute to wound healing after periodontal treatment can arise from different sources: ◦Oral epithelium ◦Connective tissue ◦PDL ◦Alveolar bone  There are 2 possible healing outcomes that can follow periodontal treatment ◦New periodontal attachment can form ‣ New fibers form that connect the bone to the teeth ‣ More desirable! ◦Long junctional epithelium can form ‣ No new PDL fibers form, only new bone Describe the biological events leading to osseointegration following the placement of dental implants Osseointegration = direct functional and structural connection between the living bone and surface of the load carrying implant ◦Indicates successful healing of the implant There are 4 stages involved in wound healing and osseointegration of dental implants ◦Homeostasis and formation of a coagulum ◦Granulation tissue formation ◦Bone formation ◦Bone remodeling ‣ Involves the resorption and apposition of new bone in a coordinated, continuous process Hematopoietic stem cells differentiate into osteoclasts which resorb bone Mesenchymal stem cells differentiate into osteoblasts which form new bone ‣ Remodeling is important for the normal function and maintenance of alveolar bone. It is important for: Growth Calcium ion balance Eruption and migration of teeth Orthodontic tooth movement Wound healing Temporal sequence of osseointegration ◦Day 1-4 ‣ Day 1 = coagulation formation ‣ Day 4 = coagulum is replaced with granulation tissue that contains inflammatory cells, mesenchymal cells, and newly formed vessels and innervations This is the beginning of new tissue formation ◦Week 1-2 ‣ Week 1 = Finger like projections of woven bone occur around the vascular structures in the center of the bone chambers and also in direct contact with small areas of the implant The projection extend towards the implant surface to increase the stability of the implant ‣ Week 2= woven bone is deposited on the bony wall of the tissue chamber and on the implant surface A scaffold of tiny trabeculae of woven bone connects the old bone and implant surface (bone becomes more trabeculated) ‣ NOTE: at 1-2 weeks at sites with old compact bone in contact with the implant surface, and the process of new-bone formation is delayed because the old bone needs to be resorbed first (remodeling) When old bone is present in the space, it needs to be resorbed before it can be replaced with new bone ◦Week 4 ‣ Chambers are filled with woven bone extending from the old bone to reach the surface of the titanium device ‣ The volume density of the scaffold is increased by the formation of new trabeculae and by the deposition of more mature, parallel-fibered bone onto the primary scaffold ‣ There is new tissue formation and bone maturation ◦Week 6-12 ‣ Bone remodeling occurs, in which primary bone is replaced with secondary osteons Woven bone is replaced by lamellar bone and bone marrow ‣ Bone to implant contact is established ◦ Describe the type of alveolar bone that covers successfully osseointegrated dental implants The implant surface may be covered by trabecular bone, compact bone, or a combination of both Factors that influence osseointegration ◦Initial mechanical stability is a prerequisite for osseointegration ‣ There should be NO mobility after implant placement ‣ Initial/primary stability is achieved by mechanism factors Direct contact between the surface of the bony walls of the implant bed and the surface of the dental  implant ◦There should be old bone supporting the stability of the implant No biological bonding Factors that determine primary stability (mechanical) ◦Percentage of bone to implant contact ◦Macro-design of the implant in relation to the implant site preparation ‣ Including implant diameter, length, cylindrical vs tapered, thread architecture Increasing the surface area of the implant surface increases the stability of the implant ◦Vertical position of the implant relative to the bone crest (sink depth) ‣ Amount of bone structure (height and width of bone) is critical for success of the implant ◦Surface morphology or roughness of the implant ◦Local bone quality ‣ Compact bone contributes more than trabecular bone to primary stability Secondary stability of implants is biological ◦Established by the apposition of new bone onto the implant surface ◦Bonding between the new bone and implant is biological in nature ◦New bone apposition begins earlier in regions of trabecular bone than in compact bone ◦Surface morphology or roughness of the implant Relationship of primary and secondary stability ◦Primary decreases over time ◦Secondary increases over time ◦The sum of primary and secondary stability accounts for the total implant stability ‣ Represent a balance between primary and secondary stability ◦A transient decrease in implant stability occurs 3-4 weeks after implant placement ‣ Higher total implant stability and less pronounced subsequent stability dip can be achieved by having both cortical and trabecular bone surround the freshly placed implant What are the factors that determine alveolar bone regeneration around teeth and dental implants? Factors that determine the alveolar regeneration ◦Space and stability are required for healing ‣ It’s important for the blood clot to be stable after injury ◦Bone formation is correlated with the width of bone originally present ‣ The greater the width of bone present at the time of implantation, the more bone formation around the implant will occur Key factors for alveolar bone regeneration ◦Elimination of infection ◦Hemostasis and clot stabilization ‣ There should be NO mobility in the clot Mobility will prevent bone formation ◦Space provision ◦Wound closure (compartmentalization) ◦Surgical technique ◦Innate wound healing potential ‣ Availability of cell types needed to regenerate tissue ‣ Cell signals for the recruitment and stimulation of the progenitor cells Additional Information Anatomy of the supporting tissues of teeth and dental implants Alveolar process ◦The part of the jaw bone that contains the teeth, where the teeth are suspended in the bone ◦Rests on the basal bone ◦Parts of alveolar process ‣ External plate is the part of the alveolar process that is composed of thick, compact bone ‣ Alveolar bone proper is the part of the alveolar process that lines the alveoli Inner compact bone Consists mainly of lamellated and bundle bone ◦Lamellated is arranged parallel to the surface of the bone ◦Bundle bone is hard and compact and provides attachment of the prinicple fibers to the PDL ‣ Appears are lamina dura on radiographs Cribriform plate provides perforations that allow the passage of vessels and innervation to the PDL ‣ Trabecular bone is in between the external plate and alveolar bone proper  ◦Portion of jaw that undergoes bone remodeling ‣ Morphology of the alveolar bone is determined by the size, shape, location, and function of teeth The alveolar process will decrease in size over time after the teeth are lost ◦Implants preserve the alveolar process and prevent its degradation overtime Periodontium ◦Provides support and stability to maintain teeth and their function ◦Consists of 4 components that work together as a single unit ‣ Gingiva ‣ Cementum ‣ Alveolar bone ‣ PDL Composed of vascular and cellular tissue surrounding the tooth root ◦Connect the inner wall of the alveolar bone to the root Continuous with CT of the gingiva Communicates with bone marrow through the vascular channels of the bone Width of PDL space will reduced with no function ◦Width of PDL space will increase with hyper function ◦There are 4 types of cells in the periodontium ‣ Connective tissue cells Fibroblasts are most common ◦Regulates collagen turnover Cementoblasts are found on the surface of both cellular and acellular cementum ◦Produce collagen fibers ‣ Epithelial cells Mainly consist of epithelial rests of Malassez ◦Clusters of residual cells which are remnants of Hertwig’s root sheath ◦Appear as clusters of cells or interlacing strands of cells ‣ Immune cells (similar to other types of CT) ‣ Cells related to the vascular supply Functions of the PDL ◦Physical functions ‣ Attachment of the teeth to the bone ‣ Resistance to the impact of occlusal forces Tensions theory: the principal fibers are the major factor in supporting the tooth and transmitting forces to the bone ◦Principal fibers unfold and straighten, and then transmit the force to the alveolar bone ◦Transmitted force causes an elastic deformations the bone socket ◦When the alveolar bone reaches its limit, the force load is transmitted to the basal bone Viscoelastic system theory describes the dissipation of forces via 2 factors: ◦Major factor = fluid movement ‣ Forces applied to the tooth cause the extracellular fluid to pass from the PDL into the marrow spaces of the bone through the foramina into the cribriform plate ◦Secondary factor = PDL fibers tighten to absorb some of the load (elasticity of fibers) ‣ Transmission of occlusal forces to the bone ‣ Provision of a soft tissue “casing” to protect the vessels and nerves from injury by mechanical forces ‣ Maintenance of the gingival tissues in their proper relationship to the teeth ◦Formative and remodeling functions ‣ PDL is constantly undergoing remodeling ‣ Cells of PDL participate in the formation and resorption of cementum and bone Cells involved in synthesis = osteoblasts, cementoblasts, and fibroblasts Cells involved in resorption = odontoclasts and osteoclasts ‣ Allows for physical tooth movement ‣ Accommodation of the periodontium to occlusal forces Excessive occlusal forces will cause remodeling Axial forces are better controlled for implants ◦Lateral forces are more damaging ‣ Repairs injuries to cementum and alveolar bone ◦Sensory functions ‣ Can sense pain and force of the tooth via mechanoreceptors There are no mechanoreceptors in implants, therefore they cannot feel excessive forces and are more likely to get damaged Workshop - Answers Case 1 Case 2 Case 3 Case 4 Exam 2 I Smooth Muscle – Learning Objectives Compare and contrast the similarities and differences between smooth and striated muscle o Smooth muscle morphology Smooth muscle doesn’t have a true sarcomere like cardiac and skeletal muscle Smooth muscle cells have a rudimentary sarcoplasmic reticulum but lack T- tubules (difference between smooth muscle and other muscle types) Thin filaments of smooth muscle will have tropomyosin but lack troponin Thin, actin filaments attach to dense bodies located at the cell membrane and within the cytosol The dense bodies contain alpha-actinin for thin-filament attachment. They are also sites where intermediate filaments can also bind o Smooth muscle function Smooth muscle is specialized for slow, steady contraction and is under the influence of the ANS and hormones Smooth muscle produces a wave of contraction in the GI tract termed peristalsis o Cells are connected via gap junctions o Smooth muscle contraction Smooth muscle contraction is slow and will not consume as much ATP as striated muscle Contraction mechanisms achieve nearly 100% of maximal tension using about 40% of bonds to be phosphorylated smooth o Skeletal and cardiac muscle contraction require nearly 100% of muscle bonds to be phosphorylated to achieve 100% maximal tension requireless When normalized for cross-sectional area, skeletal, cardiac, energy and smooth muscle have nearly equal tension development Contracted smooth muscle reflects a cork-screw shape, reflecting cell twisting with contraction Single, unitary visceral smooth muscle (SUVSM) is about 20 times slower than that of skeletal muscle and about 15 times slower than cardiac muscle Identify the two types of smooth muscle and unique properties of each type o There are two types of smooth muscle based upon innervation: multi-unit and single unit Multi-unit each muscle Few gap junctions (most cells in bundle are innervated) is individual activated Examples include ciliary muscle of eye and erector pili muscle of skin Single unit Many gap junctions (very few cells in a bundle are innervated) 1,1 aus work o Varicosities are present here so that the smooth muscle can behave as a syncytium Examples include GI, uterine, tunica media of blood vessels, urinary bladder Describe excitation-contraction coupling in smooth muscle and the signaling pathways that can increase or decrease smooth muscle contraction o General principles of excitation-contraction coupling in smooth muscle are as follows: Intracellular calcium ca be increased via three pathways: Voltage-gated Ca2+ channels Receptor activated channels (ligand gated) Receptor activated release of calcium from sarcoplasmic reticulum (IP 3)  Membrane potential must exceed threshold for an action potential to occur In order to lower intracellular calcium levels, SUVSM must: Inhibit voltage-gated calcium channels (close off) Pump calcium into SR by SERCA (Ca2+-ATPase) pumps o These are never turned off - always pumping calcium out of cytosol o Calcium must be pumped back into the SR by Ca2+-ATPases so that cross bridge cycling can be decreaed Use exchangers (H+/Ca2+, Na+/Ca2+) o Sequence of excitation-contraction coupling in smooth muscle is as follows: (1) Calcium enters cytosol of smooth muscle cell, where it binds to calmodulin (CaM) Depolarization of smooth muscle opens voltage-gated calcium channels (or another mechanism that causes release of calcium as well) Causes calcium induced calcium release from sarcoplasmic reticulum o Amount of tension generated is proportional to calcium release Rise in intracellular calcium will bind CaM (2) Calcium-CaM activates myosin light chain kinase (MLCK) Ca2+-CaM complex will activate MLCK, which will phosphorylate myosin light chains (3) MLCK phosphorylates myosin light chain, which increases myosin ATPase activity Unique compared to striated muscle (4) In the presence of actin, cross-bridges can form and filament sliding proceeds (5) Myosin light chain phosphatase (MLCP) will remove phosphate groups from myosin light chains to cause relaxation of prohibit continued contraction If there is activation of MLCP, this will produce fewer cross-bridges and less tension will be produced There are also calcium-independent mechanisms to limit MLC phosphorylation o NO can induce relaxation of smooth muscle through increased Iiia cGMP o Rho kinase can inhibit MCLP, increasing smooth muscle contraction  Gastrointestinal Control Systems – Learning Objectives Be able to describe the main functions and general anatomy of the GI system o The GI system is composed of the GI tract and also its associated major accessory glands The GI tract is composed of the mouth, esophagus, stomach, small intestines, and large intestines Mucosal layer will contain epithelial cells, lamina propria (connective tissue with blood/lymph vessels) and muscularis mucosae o Muscularis contains circular & longitudinal muscle (“tube within in a tube”) Circular muscle is thick and densely innervated Longitudinal muscle is thin and contains few nerve fibers Beneath the mucosal layer is a submucosa that contains collagen, elastin, glands, and more blood vessels Major accessory glands associated with the GI system include salivary glands, liver (bile), gallbladder, and pancreas o The main functions of the GI tract include: Provides appropriate environment for physical and chemical breakdown of food (e.g. stomach acid, activation of pepsinogen) Provides appropriate environment for absorption of the products of digestion Provides a way to assimilate nutrients and excrete waste products Contributes to the development of the immune system Provides a symbiotic relationship for commensal bacteria (e.g. microbiota) Describe the neural mechanisms from both the extrinsic (ANS) and intrinsic neural control (ENS) o The GI tract contains innervation for both parasympathetic (e.g. vagus, pelvic nerves) and sympathetic systems The GI tract also contains intrinsic innervation from enteric nervous system susman (submucosal and myenteric plexus) Myenteric (Auerbach) plexus modifies motility Submucosal (Meissner) plexus modifies secretions/blood flow o The autonomic nervous system (ANS) is the extrinsic nervous system Note that both the parasympathetic and sympathetic innervate the submucosal and myenteric plexus. Communicates with enteric nervous system (ENS) Parasympathetic innervation has long preganglionic fibers and short postganglionic fibers. Postganglionic fibers are classified as cholinergic or peptidergic (e.g. VIP) 2 o Parasympathetic innervation supplied by: Vagus nerve (CN X), which innervates upper GI Pelvic nerve, which innervates lower GI Sympathetic has short preganglionic fibers and long postganglionic fibers. Preganglionic fibers release Ach or NE o The enteric nervous system (ENS) is the instrinsic nervous system ENS can function in the absence of extrinsic innervation Receive stimuli from mechano- and chemoreceptors within the mucosa Can also send signals to circular and longitudinal smooth muscle to regulate smooth muscle contraction o Responsible for the moment-to-moment control of gut motility and secretion  Located within the submucosal and myenteric plexus Identify the differences between tonic and phasic smooth muscle contractions o Smooth muscle contractions can be either phasic or tonic. GI motility is a general term that refers to contraction and relaxation of GI tract Phasic contractions are rhythmic contractions followed by relaxation onion Found in esophagus, distal stomach, and small/large intestines Involved in mixing and propulsion Requires a pacemaker Requires action potentials to initiate Ca2+ influx Tonic contractions maintain a constant level of contraction without regular periods of relaxation always on Found in upper stomach, lower esophagus, ileocecal, and internal/external sphincters Does not require a pacemaker Does not require action potentials to initiate Ca2+ influ