NUR55: Pathophysiology - Study Guide
NUR55: Pathophysiology - Study Guide NUR55
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This 51 page Study Guide was uploaded by Marysol Uribe on Thursday October 16, 2014. The Study Guide belongs to NUR55 at Azusa Pacific University taught by Suarez in Fall. Since its upload, it has received 107 views. For similar materials see Pathophysiology in Nursing and Health Sciences at Azusa Pacific University.
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Date Created: 10/16/14
CHAPTER 8 NEOPLASIA Concepts of Cell Di erentiation and Growth cancer is a disorder of altered cell differentiation and growth gt the resulting process is called rzeoplasia new growth gt neoplasm refers to an abnormal mass of tissue in which the growth exceeds and is uncoordinated with that of the normal tissue growth of neoplasm tends to be uncoordinated and relatively autonomous lacks normal regulatory controls over cell growthdivision neoplasms tend to increase in size and continue to grow after the stimulus that evoked the change has ceased or the needs of the organism have been met proliferation process of cell division a i quotererztiation39 process whereby cells become increasingly more specialized with each mitotic division Cell Cycle G1 gap 1 postmitotic phase 0 DNA synthesis ceases while RNA and protein synthesis and cell growth take place S phase 0 DNA synthesis occurs gt two separate sets of chromosomes one for each daughter cell G2 gap 2 premitotic phase 0 similar to G1 DNA synthesis ceases while RNA and protein synthesis continue G1 S G2 interphase M phase 0 phase of nuclear division mitosis gt formation of two daughter cells G0 0 special resting state cyclins family of proteins that control the entry and progression of cells through the cell cycle Cell Proliferation process of increasing cell numbers by mitotic cell division is an inherent adaptive mechanism for cell replacement when old cells die or additional cells are needed number of dying cellsnumber of dividing cells Cell Di erentiation process by which proliferating cells become progressively more specialized cell types 0 results in a fully differentiated adult cell that has a specific set of structural functional and life expectancy characteristics ex red blood cell programmed to function as a vehicle for oxygen transport progenitor parent cells 0 early descendents of stem cells that can differentiate to form one or more kinds of cells but cannot divide or reproduce indefinitely stem cells remain incompletely differentiated throughout life remain quiescent until there is a need for cell replenishment in which case they divide producing other stem cells and cells that can carry out the functions of the differentiated cell selfrenewal o the stem cell can undergo numerous mitotic divisions while maintaining an undifferentiated state potency o differentiation potential of stem cells totipotent stem cells 0 those produced by fertilization of the egg 0 can differentiate into embryonic and extraembryonic pluripotent stem cells 0 rise from totipotent stem cells 0 can divide into three germ layers of the embryo multipotent stem cells 0 cells such as hematopoietic stem cells that give rise to only a few cell types unipotent stem cells 0 produce only one cell type but remain the property of selfrenewal embryonic stem cells 0 pluripotent cells derived from the inner cell mass of the blastocyst stage of the embryo adult stem cells 0 reside in specialized microenvironments that differ depending on tissue type 0 contribute to tissue regeneration and replacement of cells lost to cell death gt play an important role in homeostasis Apoptosis form of programmed cell death that eliminates senescent cells cells with damaged DNA or unwanted cells Ch aracteristics of Benign and Malignant Neoplasms benign neoplasms welldifferentiated tumors that resemble the tissues of origin but have lost the ability to control cell proliferation o grow by expansion enclosed in a brous capsule do not cause death unless their location is such that it interrupts vital body functions malignant neoplasms less differentiated tumors that have lost the ability to control both cell proliferation and differentiation 0 grow in a disorganized and uncontrolled manner to invade surrounding tissues have cells that break loose and travel to distant sites inevitably cause suffering and death tum0rs swelling that can be caused by a number of conditions including in ammation and trauma 0 term has been used more recently to define a mass of cells that arises because of overgrowth benign vs malignant 0 Cell Characteristics welldifferentiated cells that resemble cells in the tissue of organ cells are undifferentiated with anaplasia and atypical structure that often bears little resemblance to cells in the tissue of organ 0 Rate of Growth usually progressive and slow may come to a standstill or regress variable and depends on level of differentiation the more undifferentiated the cells the more rapid the rate of growth 0 Mode of Growth grows by expansion without invading the surrounding tissues usually encapsulated grows by invasion sending out processes that infiltrate the surrounding tissues 0 Metastasis does not grow by metastasis gaines access to blood and lymph channels to metastasize to other areas of the body Cancer Cell Characteristics two main features 0 abnormal and rapid proliferation 0 loss of differentiation so that they do not exhibit normal features and properties of differentiated cells anaplasia the loss of cell differentiation in cancerous tissue pleomorphism cell variations in size and shape on a scale ranging from grades I to IV I neoplasms are well differentiated and grade IV are poorly differentiated cancer cells have the ability to proliferate even in the absence of growth factors contact inhibition cells often stop growing when they come into contact with each other 0 in wound healing contact inhibition causes tissue growth to cease at the point where the edges of the wound come together the reduced tendency of cancer cells to stick together permits shedding of the tumor s surface cells cancer cells remain viable and multiply without normal attachments to other cells and the extracellular matrix cancer cells have faulty celltocell communication gt impaired celltocell communication may interfere with formation of intercellular connections and responsiveness to membrane derived signals cancer cells may produce substances that normal cells of the tissue of origin either do not produce or secrete in lesser amounts Invasion and Metastasis cancer spreads by direct invasion and extension seeding of cancer cells in body cavities and metastatic spread through the blood or lymph pathways 0 seeding of cancer cells into body cavities occurs when a tumor sheds cells into these spaces metastasis used to describe the development of a secondary tumor in a location distant from the primary tumor Tumor Growth Rate of tissue growth in normal and cancerous tissue depends on three factors 0 the number of cells that are actively dividing or moving through the cell cycle the duration of the cell cycle the number of cells that are being lost relative to the number of new cells being produced growth fraction ratio of dividing cells to resting cells in a tissue mass Two types of tumors 0 solid tumor the primary tumor is initially confined to a speci c organ or tissue 0 hematologic tumor disseminated from the onset Etiology of Cancer the category associated with gene overactivity involves proto oncogenes normal genes that become cancercausing oncogenes if mutated the category associated with fene underactivity comprises the tumor suppressor genes less active create an environment in which cancer is promoted Epigenetic Mechanisms molecular and cellular mechanisms that involve changes in the pattems of gene expression without a change in the DNA Carcinogenesis three stages 0 initiation involves the exposure of cells to appropriate doses of a carcinogenic agent that makes them susceptible to malignant transformation 0 promotion involves the induction of unregulated accelerated growth in already initiated cells by various chemicals and growth factors promotion is reversible if the promoter substance is removed 0 progression process whereby tumor cells acquire malignant phenotypic changes that promote invasiveness metastatic competence autonomous growth tendencies and increased karyotypic instability Host and Environmental Factors heredity 0 ex breast cancer 0 several cancers exhibit an autosomal dominant inheritance pattem that greatly increases the risk of developing a tumor gt point mutation occurring in a single allele of a tumor suppressor gene hormones 0 have the ability to drive the cell division of a malignant phenotype immunologic mechanisms o immune surveillance hypothesis postulates that the immune system plays a central role in resistance against the development of tumors 0 provide a means for detection classification and prognostic evaluation of cancers and as a potential method of treatment 0 immunotherapy a cancer treatment modality designed to heighten the patient s general immune responses to increase tumor destruction 0 tumor antigens molecular configurations that can be specifically recognized by immune T cells or by antibodies unique tumorspeci c antigens found only on tumor cells tumorassociated antigens found on tumor cells and normal cells Chemical Carcinogens agent capable of causing cancer 0 direct reacting agents procarcinogensinitiators do not require activation in the body to become carcinogenic o indirect reacting agents procarcinogensinitiators become active only after metabolic conversion direct and indirect acting initiators form highly reactive species electrophiles and free radicals that bind with neutrophilic residues on DNA RNA or cellular proteins 0 reactive species causes cell mutation or alteration in synthesis of cell enzymes amp structural proteins that mess with regulatory control promoters augment carcinogenicity of some chemicals but not cancer causing by themselves risk factors associated with chemical carcinogens 0 smoking 0 dietary factors most occur naturally in plants or produced in food prep 0 alcohol consumption associated with variety of cancers complex mechanisms has toxic metabolites like acetaldehyde amp speeds up developing cancers of smokers Radiation Ionizing radiation in carcinogenesis affect atomic bomb survivors diagnostically exposed patients and in physicians industrial workers scientists exposed during employment 0 type of ionization cancer developed depends on dose age person was exposed and sex usually causes leukemia and malignant epithelioma of skin ultraviolet radiation consists of relatively low energy rays that do not deeply penetrate the skin 0 depends on frequency of exposure light v dark skin complexion light lack melanin to filter radiation intensity of exposure at the time of childhood v episodic exposure usually causes skin cancers melanoma Oncogenic Viruses virus that can induce cancer suspected to play imp role most esp in leukemia and lymphoma Four DNA viruses have been implicated in human cancers 0 HPV human papillomavirus over 60 kind that can cause benign squamous papilloma aka warts and squamous cell carcinoma 0 EBV EpsteinBarr virus implicated in pathogenesis of four human cancers Burkitt lymphoma nasopharyngeal cancer Bcell lymphomas in pple w AIDS and Hodgkins lymphoma 0 HBV Hepatitis B virus etiologic agent in Hep B cirrhosis and hepatocellular carcinoma 0 HHV8 human herpesvirus8 causes Kaposi sarcoma in people with AIDS Only retrovirus that can cause cancer in humans HTLVl T cell leukemia virus 1 0 mode of transmission SEX infected blood and breast milk Cancer causes fatigue anorexia and cachexia anemia decreased resistance to infections and symptoms unrelated to the tumor siteparaneoplastic syndromes pain TISSUE INTEGRITY cancer disrupts tissue integrity cancer compresses erodes blood vessels causes ulceration necrosis frank bleeding hemorrhage waming signs blood in stool enzymemetabolic toxin production damaging surrounding tissues sores that don t heal bowel obstruction etc can develop effusion uid in pleural pericardial or peritoneal spaces presenting sign of tumors SYSTEMIC MANIFESTATIONS usually due to altered metabolic pathways presence of cytokines and other mediators circulating Anorexia and Cachexia cachexia cancer anorexia get it common manifestation of solid tumors and high morbidity rate people with cachexia respond less well to chemotherapy and more prone to toxic side effects anorexia gt loss of fat cachexia gt loss of fat and skeletal muscle anorexia gt protein loss that occurs divided equally between skeletal and visceral proteins cachemia gt protein loss does not affect visceral proteins anorexia gt reversed by refeeding cachexia gt cannot be reversed w food supplements cancer cachexia alters metabolic rates and states to accommodate tumor increasing glucose consumption depletion of muscle mass due to amino acid insuf ciency o syndrome shows similarity to acute phase response seen w tissue injury in ammation or infection Fatigue and Sleep Disorders Most frequent side effect of cancer 0 causes tiredness weakness lack of energy and is NOT relieved by rest or sleep two categories of mechanisms of fatigue o peripheral occurs in neuromuscular junctions and muscles results in the inability of the peripheral neuromuscular apparatus to perform function in response to CNS 0 central arises in CNS difficulty in initiating or maintaining voluntary activities ANEMIA related to blood loss hemolysis impaired RBC production or treatment effects such as the cytotoxic drugs administered cancerrelated anemia associated with reduced treatment effectiveness increased mortality increased transfusion requirements and reduced performancequality of life usually treated w recombinant human erythropoietin rHuEPO PARANEOPLASTIC SYNDROMES manifestations that are produced in sites not directly affected by the disease 0 caused by elaboration of hormones by cancer cells production of circulating factors that produce hematopoietic neurologic and dermatologic syndromes 0 most commonly ass w lung breast and hematologic malignancies 3 most common endocrine syndromes ass w cancer Inappropriate ADH secretion cushing syndrome due to ectopic ACTH production and hypercalcemia symptomatic paraneoplastic neurologic disorders are rare with exception of LambertEaton myasthenic syndrome which weakens muscle in limbs most commonly seen in small cell lung cancer acanthosis nigricans paraneoplastic dermatologic disorder characterized by pigmented hyperkeratoses consisting of symmetric verrucous and papillary lesions that occur in skin exures particularly the axillary and perineal areas these syndromes earliest indicators of cancer SCREENING secondary prevention measure for early recognition achieved through observation palpation and lab tests amp procedures improves outcomes most for cancers of breast cervix colon and rectum prostate and malignant melanoma DIAGNOSTIC METHODS include blood tests for tumor markers cytologic studies tissue biopsy endoscopic exams ultrasounds xrays MRI computed tomography CT positron emission tomography PET Tumor Markers antigens expressed on surface of tumor cells or substances released from normal cells in response to the presence of a tumor markers used for screening establishing prognosis monitoring treatment and detecting recurrent disease 0 hCG hormone used for diagnosing high risk gestational trophoblastic tumors 0 cluster of differentiation CD antigens markers for leukemia and lymphomas o AFP fetal antigen synthesized by liver and detects primary liver cancers testicular ovarian pancreatic and stomach cancers 0 CEA fetal antigen produced by embryonic tissues in gut pancreas and liver detects number of different cancers Cytologic and Histologic Methods Papanicolaou Test cytologic method used for detecting cancer cells consists of microscopic examination of a properly prepared slide by a cytotechnologist or pathologist for the purpose of detecting abnormal cells primarily for cervical cancer Tissue Biopsyinvolves the removal of a tissue specimen for microscopic study vital if cancer cells found in determining treatment plan 0 excisional biopsies whole tumor removed 0 to properly store specimen prompt immersion in a xative solution ie formalin with other portion in special xative for electron microscopy or prompt refrigeration is imp o fineneedle aspiration widely used immunohistochemistry involves the use of antibodies to facilitate the identification of cell products or surface markers microarray technology uses gene chips that can simultaneously perform miniature assays to detect and quantify the expression of large numbers of genes used to study overall pattem of cancer cells Staging and Grading of Tumors grading according to histologic or cellular characteristics of the tumor staging according to the clinical spread of the day both used to determine their choice of treatment CANCER TREATMENT goal categories curative control and palliative Surgery oldest treatment of cancer was previously only method for curing patients used for diagnosis staging of cancer tumor removal and palliative relief of symptoms when a cure cannot be achieved techniques now include cryosurgery chemosurgery laser surgery and laparoscopic surgery Radiation Therapy one of most commonly used treatments used to treat oncologic emergencies such as superior vena cava syndrome spinal cord compression or bronchial obstruction uses high energy particles or waves to destroy or damage cancer cells rapidly proliferating and poorly differentiated cells of a cancerous tumor are more likely to be injured than are the more slowly proliferating cells of normal tissue radiosensitivity inherent properties of tumor that determine its responsiveness to radiation radiation responsiveness the manner in which a radiosensitive tumor response to irradiation oxygen major component of responsiveness can be administered in 3 diff ways 0 external beam teletherapy beams generated at distance and aimed at tumor usually using linear accelerator or cobalt 60 machine 0 brachytherapy sealed radioactive source is placed close to or directly in the tumor site via body cavity intracavity or via body tissues interstitial can be subdivided into HDR high dose or LDR low dose 0 systemic therapy radioisotopes with short halflife are given by mouth or injected into tumor site unsealed intemal radiation sources are injected intravenously or administered by mouth adverse effects include damage to normal cells esp skin mucosal lining of GI and bone marrow fatigue decreases in leukocytes anorexia nausea emesis and diarrhea Chemotherapy major systemic treatment modalities for cancer allows drugs to reach site of tumor as well as other distant sites primary treatment for most hematologic and solid tumors including choriocarcinoma testicular cancer acute and chronic leukemia nonhodgkin and hodgkin lymphomas and multiple myelomas problems presented gt cellular resistance major classifications of chemotherapy drugs 0 Direct DNA Interacting Agents include alkylating agents antitumor antibiotics substances produced by bacteria that in nature appear to provide protection against hostile microorganisms and topoisomerase inhibitors block cell division by interfering w action of topoisomerase enzymes that break and rejoin phosphodiester bonds in the DNA strands to prevent them from tangling during separation and unwinding from double helix 0 Indirect DNA Interacting Agents antimetabolites interrupt the biochemical pathways relating to nucleotide and nucleic acid synthesis and mitotic spindle inhibitors combination chemotherapy more effective than single drug creates more hostile environment for tumor cell growth 0 must be individually effective and may be synergistic with each other usually administered intravenously but can use VAD venous access devices if difficult adverse effects suppress bone marrow function and formation of blood cells anemia neutropenia thrombocytopenia anorexia nausea vomiting alopecia hair loss cell toxicity decreased sperm count and menstrual deviations Hormonal Therapy administration of drugs meant to disrupt hormonal environment of cancer cells used for cancers that are responsive or dependent on hormones for growth Hormone environment therapeutic actions for females w breast cancer and males w prostate are surgery and pharmacological measures resistance eventually builds in patients and must seek altemative therapies Biotherapy use of immunotherapy and biologic response modi ers as a means of changing their persons own response to cancer active immunotherapy nonspecific treatments such as bacille Calmette Guerin BCG passive adaptive immunotherapy transfer of cultured immune cells into tumor bearing host biologic response modi ers cytokines monoclonal antibodies and hematopoietic growth factors interferons type of cytokine endogenous polypeptides that are synthesized by number of cells in response to variety of cellular or viral stimuli monoclonal antibodies are highly specific antibodies MoAbs derived from cloned cells or hybridomas Targeted Therapy uses drugs that selectively attack malignant cells while leaving normal ones unharmed first target MoAbs then small molecules that block speci c growth factors involved in cancer cell growth Cancer is the second leading cause of death in children 114 INCIDENCE AND TYPES childhood cancers usually involve hematopoietic sys nervous sys soft tissues bones and kidneys most tend to have embryonal rather than pleomorphic anaplastic microscopic appearance neuroblastoma arise from primordial neural crest tissue of sympathetic ganglia and adrenal medulla manifestations fever abdominal mass possible weight loss BIOLOGY OF CHILDHOOD CANCERS most notable hereditary down syndrome neurofibromatosis type 1 amp 2 Xeroderrna pigmentosum and Beckwith Wiedemann syndrome some of biology of these tumors reveals aspects of neoplasms such as twohit theory of recessive tumor suppressor genes DIAGNOSIS AND TREATMENT early detection key but more difficult to detect due to lack of screenings and symptom similarities with other childhood diseases Most common therapies chemotherapy surgery radiation therapy and biologic agent theory ADULT SURVIVORS OF CHILDHOOD AND ADOLESCENT CANCER higher survival rates but w impaired growth neurologic dysfunction hormonal dysfunction cardiomyopathy pulmonary fibrosis and risk for second malignancies highest at risk bone tumor survivors CNS tumor and Hodgkin lymphoma Radiation Therapy risks and possible consequences musculoskeletal changes if treated with cranial radiation therapy CDT then diminished intellectual function endocrine disorders growth deficiency if treated w mantle field radiation to chest possibly develop breast cancer heart diseases reduction in pulmonary function and thyroid disease with abdominal treatment risk GI liver spleen kidney genitourinary tract diseases Chemotherapy risks and possible consequences gonadal injury infertility early menopause acute myelogenous leukemia pulmonary fibrosis kidney disease and bladder disorders Chapter 12 Mechanisms of Infectious Disease Two basic objectives survival and reproduction Terminology Q any organism capable of supporting the nutritional and physical growth requirements of another usually a human Infections presence and multiplication within a host of another living organism with subsequent injury to the host Colonization the act of establishing a presence a step require in the multifaceted process of infection Not all interactions between microbes and humans are detrimental Normal micro ora intemal and extemal exposed surfaces of the body are normally harmless and inhabit by bacteria Commensalism commensal ora when the host isn t affected Mutualisms microbe and host both derive benefits from their interaction Parasitic relationship only the infecting organism benefits and the host is injured or gains nothing if host sustains injury the process is called infectious disease severity of disease depends on health of the host and virulencedisease producing potential of microbe Pathogens so virulent that they are rarely found in absence of a disease Saproph es harmless free living organisms obtaining their growth from dead or decaying organic material in the environment Opportunistic pathogens saprophytes and members of the normal ora can be capable of producing an infectious disease when the health and immunity of the host have been weakened by illness malnutrition or medical therapy Agents of Infectious Disease Prions protein particles that lack any kind of demonstrable genome are able to transmit infection diseases Creutz feldt Jakob disease and kuru in humans scrapie in sheep chronic wasting disease in deer and elk and bovine spongiform encephalopathy in cattle Transmissible neurodegenerative diseases slow progression nonin ammatory neuronal degeneration leading to the loss of coordinationataXia dementia and death over a period of months or years PrPquotSCscrapie prion protein is an altered form of PrPquotC normal PrPquotSC resistant to action of proteases enzyme that degrades excessdeformed proteins and aggregates in the cytoplasm of affected neurons as amyloid fibrils resistant to antibodies PrPquotSC binds to PrquotC on cell surface which is then processed to PrquotSC then released from cell and aggregates into amyloidlike plaques in the brain cycle continues with PrPquotC is replenished Prions lack reproductive and metabolic functions Current antimicrobial agents are useless against them Viruses smallest obligate intracellular pathogen no organized cellular structure have protein coat capsid surrounding a nucleic acid core of RNA or DNA never both some viruses are enclosed with a lipoprotein envelope from the cytoplasmic membrane of the parasitized host cell herpesvirus group and paramyxoviruses in uenza and poxviruses lncapable of replicating outside of a living cell must use biosynthesis structure of the cell to produce viral progeny not every viral agent causes lysis and death of the host cell during the course of replication some viruses insert their genome into the host cell chromosome remains in latent nonreplicating state for a long period of time not causing disease under appropriate stimulation the virus undergoes active replication and produces symptoms of disease months or years later examples herpsviruses and adenovirus certain viruses have the ability to transform normal host cells into malignant cells during the replication cycle examples oncogenic viruses retroviruses and DNA viruses Bacteria autonomously replicating unicellular organisms prokaryotes lack an organized nucleus contain both DNA and RNA smallest of all living cells no organized intracellular organelles single chromosome of DNA contain plasmids smaller extrachromosomal pieces of circular DNA sometimes contain genetic info Prokaryotic cell organized in the cytoplasm in cytoplasm reproductive and metabolic machinery of the cell surrounded by a cytoplasmic membrane cell wall is made of peptidoglycan reproduce asexually Cocci can be streptococci chains Staphylococci clusters and diplococci pairs Biofilms colonized structured communities permit access to available nutrients and elimination of metabolic waste chemical signaling for intracellular communication 80 of all chronic infections are due to the presence of biofilms bacteria are adaptive life forms fastidious bacteria with strict growth requirements aerobes require oxygen anaerobic no oxygen needed facultatively anaerobic either 02 or no 02 gram positive purple streptococcus pyogenes Gram negative red Legionella pneumophila acid fast acid alcohol mycobacterium tuberculosis Spirochetes bacteria gram negative rods helical in cell wall and propel organisms three genera Leptospiramucous membranes uids Borrellabite and Treponemadirect contact person to person Mycoplasmas also bacteria unicellular prokaryote independent replication do not produce peptidoglycan cell wall resistant to cell wall inhibiting antibiotics three genera Mycoplams require cholesterol Ureaplasma require cholosterol and Acholeplama mostly commensals but some do cause serious illness Rickettsiaceae Anaplasmataceae Chlamydiaceae and Coxiella combines characteristics of viral and bacterial agents all obligate intracellular pathogens produce a rigid peptidoglycan cell well produce assexually by cellular division contain RNA and DNA Rickettsiaceae depend on host cell for essential vitamins and nutrients Chlamydiaceae appear to scavenge intermediates of energy metabolism such as ATP Fungi free living eukaryotic saprophytes found in every habitat on earth two groups yeasts and molds yeasts single celled organisms reproduce by the budding process molds cottony or powdery Both produce cell wall that is not susceptible to antibiotics asexual or sexual Parasites protozoa helminths and arthropods unicellular sexual or assexual prokaryotes direct host to host indirectly food and water arthropod vector bite helminths worm like parasites sexual reproduction Epidemiology of Infectious Diseases Portal of Entry Penetration Direct Contact Ingestion Inhalation Source exogenous extemal environment endogenous acquired from host s own normal micro ora human animal arthropod inanimate object nosocomial hospital acquired Symptomatology signs and symptoms Disease course Incubation period pathogen replication no symptoms in uenced by the health of the host portal of entry and degree of infectious dose of the pathogen Prodromal period symptoms appear Acute period symptom of host are pronounced and more specific than the prodromal period Convalescent period process to become resolved Resolution total elimination of a pathogen from the body Site of Infection suffix itis in ammation suffix emia in blood Pathogen portal of entry and the host s immune system determine the site of infection the book provides examples of infections and where their site is atsince is was a lot i didn t put it here but be aware of it abscess localized pocket of infectious composed of devitalized tissue microbes and host s phagocytic white blood cells must be surgically removed biomedical implants catheter heart valves bone implants are seldom cured by the host s immune response and antimicrobial therapy Virulence Factors factors that enhance their ability to cause disease Toxins alter destroy normal function of the host or host s cell bacterial toxins exotoxins and endotoxins Adhesions site specific cell specific or nonspecific receptors and ligands ligands that bind to carbohydrateslectins bacterial agents become embedded in a gelatinous matrix of polysaccharidesmucous layer to anchor and protect Hemagglutinins filamentous appendages or spikes Evasions invading host s immune system Invasive products produced by infectious agents that facilitate the penetration of anatomic barriers and host tissue mostly enzymes connective tissue intercellular matrices structural protein complexes Diagnosis require recovery of a probable pathogen or evidence of its presence from the infected sites of a disease host and accurate documentation of clinical signs and symptoms compatible with an infectious process Culture microbe on a growth media agar plates or broth Serology measuring serum antibodies in the diseased host DNA and RNA sequencing DNA probe hybridization polymerase chain reaction Treatments Antimicrobial agents 1 antibacterial agents against prokaryotes 2 antiviral agents 3 antifungal 4 antiparasitic Immunotherapy supplementing or stimulating the host s immune response so that the spread of pathogen is limited intravenous immunoglobulin and cytokines Surgical Interventions surgical removal of infected tissues organs or limbs Bioterrorism do we even need this Category A plague tularemia smallpox hemorrhagic fever virus Category B agents of food and water bome disease agents of zoonotic infections viral encephalitides and toxins from castor bean Category C mycobacterium tuberculosis nipah virus and hantavirus tickbome and yellow fever virus and Cryptosporidium parvum Chapter 13 Innate and Adaptive Immunity Immunity and the Immune System mmunity The protection from an infectious disease Immune Response The coordinated collective response of the cells and molecules of the immune system Innate and Adaptive Immunity Innate Immunity First line of defense consists of the physical chemical molecular and cellular defenses that are in place before infection and can function immediately as an effective barrier to microbes Major Components Skin and Mucous Membranes phagocytic cells neutrophils and macrophages specialized lymphocytes N K cells several plasma proteins proteins of the complement system Rapid Response within minutes hours Prevents the establishment of infection and deeper tissue penetration of microorganisms Effector responses used by the innate immune system to eliminate microbes are similar for different classes of microorganisms Microorganisms not controlled by innate immunity are usually controlled by the more speci c approaches of adaptive immunity what you are bom with Adaptive Immunity second major immune defense responding less rapidly but more effectively Uses focused recognition of each unique type of foreign agent followed in days by an amplified and effective response Maj or Components Lymphocytes and their products antibodies Recognize a vast array of substances produced by microorganisms as well as non infectious substances and developing a speci c immune response that differs with each substance what is acquired Antigens substances that elicit adaptive immune responses 2 Types of adaptive immune responses Humoral immunity generated by B lymphocytes mediated by antibodies and is the principal defense against extracellular microbes and toxins Cellmediated immunity mediated by speci c T lymphocytes T helper and T cytotoxic lymphocytes and defends against intracellular microbes EX Viruses Cells of the Immune System Phagocytic leukocytes lymphocytes and antigen presenting cells Key cells of Innate Immunity phagocytic leukocytes neutrophils and macrophages and NK cells Key cells of Adaptive Immunity lymphocytes lifelong immunity after exposure to disease producing microbes or environmental agents Thelper memory cells Dendritic cells and macrophages antigen present cells for adaptive immunity Phagocytic Leukocytes Granulocytes cells containing granule Neutrophils early responding cells of innate immunity eosinophils and basophils Agranulocytes cells that lack granules Lymphocytes monocytes Macrophages monocytic phagocyte system initiate adaptive immunity Lymphocytes T and B Lymphocytes 25 35 blood leukocytes Only cells in the body capable of speci cally recognizing different antigenic determinants of microbial agents and other pathogens Adaptive immunity speci city and memory Generated from hematopoietic stem cells in the bone marrow B lymphocytes humoral immunity T lymphocytes cell mediated immunity and antibody production B lymphocytes produce antibodies Lymphocyte Markers and the CD Nomenclature System standard nomenclature for these proteins is CD delineate surface proteins that de ne a particular cell type or stage of cell differentiation and are recognized by a cluster of antibodies Natural Killer Cells 10 15 peripheral blood lymphocytes and don t bear T cell receptors or cell surface immunoglobulins Innate immune system First line of defense against Viral infections Ability to recognize and kill tumor cells abnormal body cells and cells infected with intracellular pathogens EX Viruses intracellular bacteria Dendritic Cells Specialized bone marrow derived leukocytes in lymphoid tissue Intermediaries btwn innate and adaptive systems Found as immature cells under epithelial tissue and in most organs Cytokines that Mediate and Regulate Immunity General Properties of Cytokines produced by cells of the innate and adaptive immune systems and that mediate many of the actions of these cells all are secreted in a brief self limited manner Pleiotropic able to act on different cell types and Redundant ability of different cytokines to stimulate the same or overlapping biologic functions Often in uence the synthesis and actions of other cytokines Serve as antagonists inhibit the action of another cytokine Local or systemic Generate responses by binding to speci c receptors on their target cells Chemokines Cytokines that stimulate the migration and activation of immune and in ammatory cells 2 major subclasses CC chemokines or CXC chemokines determined by position of first 2 cysteines being located adjacent to each other CC or separated by an amino acid CXC Colony Stimulating Factors cytokines that stimulate bone marrow pluripotent stem and progenitor or precursor cells to produce large numbers of platelets erythrocytes lymphocytes neutrophils monocytes eosinophils basophils and dendritic cells Availability of recombinant CSFs and cytokines offers the possibility of several clinical therapies where stimulation or inhibition of the immune response or cell production is desirable Innate Immunity Consists of epithelial barriers phagocytic cells NK cells and several plasma proteins Epithelial Barriers Physical and chemical barriers against infection are found in all common portals of entry Ex Intact skin closely packed cells multiple layering continuous shedding of cells keratin protective protein EX Mucous membrane linings of GI respiratory and urogenital tracts Mucus traps and washes away potential invaders Cilia moves many microbes trapped in the mucus toward the throat Cells of Innate Immunity Neutrophils and Macrophages Recruited during an in ammatory response are innate immune cells that recognize and kill infectious invaders Early responding innate immune cell is the neutrophil followed by more ef cient multifunctional macrophage phagocytic killing of microorganisms helps to contain infectious agents until adaptive immunity can be marshaled Natural Killer Cells and Intraepithelial Lymphocytes Innate immunity Neither express the speci c highly diverse receptors or antibodies associated with adaptive immunity Can recognize only broad patterns associated with classes of microbes Pathogen Recognition The ability of any of the leukocytes to participate in innate immunity depends on rst recognizing the invader Pathogen associated molecular pattems PAMPs recognized by host pathogen sensors are composed of combinations of sugars lipid molecules proteins or pattems of modi ed nucleic acids PRRs The binding of pathogens to the PRS on leukocytes initiates the signaling events that lead to innate immunity and the tissue changes associated with acute in ammation Ampli es the initial in ammatory response by inducing antimicrobial genes and secreting in ammatory cytokines TollLike Receptors main pathogen sensors important in innate immunity Soluble Mediators of Innate Immunity Opsonins important in innate immunity and acute in ammation include acute phase proteins lectins and complement IgG and IgM antibodies can coat microbes and act as an opsonin by binding to Fc receptors on neutrophils and macrophages In ammatory Cytokines in uence the events of in ammation and innate immunity by producing chemotaxis of leukocytes stimulating acute phase protein production inhibiting virus replication and affecting the development of cells of the innate and adaptive immune systems Acute Phase Proteins mannose binding ligand and C reactive protein The Complement System Enables the body to localize and destroy infective agents 1 Initiation or activation 2 Ampli cation of in ammation 3 Membrane attack response Adaptive Immunity able to recognize and react to a large number of microbes and non microbial substances Humoral Immunity mediated by secreted molecules and is the principal defense against extracellular microbes and toxins Cell mediated immunity mediated by speci c T lymphocytes and defends against intracellular microbes EX viruses Antigens Substances foreign to the host that can stimulate an immune response Foreign molecules are recognized by receptors on immune cells and by secreted proteins antibodies or immunoglobulins Ex Bacteria fungi viruses protozoa and parasites Cells of Adaptive Immunity Lymphocytes Cells that speci cally recognize and respond to foreign antigens T and B lymphocytes Maj or Histocompatibility Complex Molecules Essential feature of adaptive immunity its ability to discriminate btwn the body s own molecules and foreign antigens Chapter 14 In ammation Tissue Repair and Wound Healing In ammation response aimed at eliminating the cause of cell injury removing the damaged tissue and then generating new tissue In ammation response destroys harmful agents toxins infectious organisms and foreign agents In ammatory conditions are commonly named by adding the suffix itis to the affected organ or system ex pericarditis appendicitis Cardinal Signs terms to describe in ammation l Rubor Redness 2 Tumor Swelling 3 Calor heat 4 Dolor Pain 5 Functio Laesa Loss of function Besides cardinal signs systemicconstitutional manifestations may occur as chemical mediators ex Fever In ammation can be divided into 2 categories 1 Acute in ammation in ammation that is relatively short duration lasting from a few minutes to several days and is characterized by the emigration of predominantly neutrophils into the extravascular tissues 2 Chronic in ammation in ammation that is of a longer duration lasting for days to years and is characterized with the presence of lymphocytes macrophages proliferation of blood vessels fibrosis and tissue necrosis Acute In ammation Is the immediate reaction of local tissues and their blood vessels to injury and typically occurs before adaptive immunity becomes established Triggers l Infections 2 Immune reactions 3 Trauma 4 Physical agents 5 Chemical agents 6 Tissue necrosis 2 major components of acute in ammation 1 Vascular stage 2 Cellular stage the cells involved endothelial cells white blood cells mast cells broblasts tissue macrophages lymphocytes and components of the extracellular matrix collagen elastin adhesive glycoproteins and proteoglycans Vascular phase causes changes in the small blood vessels at the site of injury It begins with momentary vasoconstriction and is then followed by rapid vasodilation Vasodilation increases capillary blood ow that causes lg and redness This is accompanied by an increase in vascular permeability that leads to an outpour of protein rich uid into the extravascular spaces The loss of E1 results in an increase concentration of blood constituents red cells leukocytes platelets and clotting factors and clotting of blood at the site of injury The loss of proteins reduces capillary osmotic pressure and increases the interstitial osmotic pressure that causes uids to move into the tissues The accumulation of uid in the tissue spaces produces swelling peg and impaired function Increased permeability characteristic results from formation of endothelial gaps in the venules of the microcirculation This leads to the separation of intercellular junctions Vascular Response Patterns 1 Immediate transient response occurs with minor injury and has a short duration of 15 to 30 minutes 2 Immediate sustained response occurs with more serious types of injuries and continues for several days In addition it affects arterioles capillaries and venules due to direct damage of the endothelium 3 Delayed hemodynamic response often accompanies injuries due to radiation such as sunbum and causes an increase permeability in the venules and capillaries Cellular Phase involves the delivery of leukocytes mainly neutrophils to the site of injury where they can perform their normal functions of host defense and changes in the endothelial cells lining the vasculature The delivery of leukocytes follows the following steps 1 Adhesion and Margination 2 Transmigration 3 Chemotaxis 4 Activation and phagocytosis Once the leukocytes arrive at the site of injury the products that are generated by tissue injury trigger a number of leukocyte responses including phagoc osis and cell killing Phagocytosis involves 3 distinct steps 1 Recognition and adherence 2 Engulfment 3 Intracellular killing Recognition is made easier through opsonization which is the coating of an antigen with antibody or complement in order to enhance binding Leukocytes attach to the endothelium by adhering strongly to intercellular adhesion molecules ICAMs Chemokines small proteins that direct the trafficking of leukocytes during the early stages of in ammationinjury these ensure the directed movement of leukocytes to the site of infection Endothelial cells make up the single cellthick lining of blood vessels and produce antiplatelet and antithrombotic agents that maintain vessel patency Endothelial cells also contribute to the regulation and modulation of immune responses through synthesis and release of in ammatory mediators In addition endothelial cells participate in the repair process that accompanies in ammation through the production of growth factors and stimulate angiogenesis formulation of new blood vessel and ECM synthesis Platelets activated platelets release many potent in ammatory mediators These increase vascular permeability and altering the chemotactic adhesive and proteolytic properties of endothelial cells Neutrophils and monocytesmacrophages neutrophils are the primary phagocytes that arrive early at the site of in ammation usually within 90 minutes of injury They are able to produce oxygen hydrogen peroxide and nitrogen products nitric oxide that assist in destroying the engulfed debris Neutrophils have a lifespan of about 10 hours which is why they are constantly replaced Monocytes and macrophages arrive after neutrophils to perform their phagocytic functions produce potent vasoactive mediators and promote regeneration of tissues Macrophages engulf foreign material destroy the causative agent aid in signaling processes of immunity and contribute to the initiation of the healing process Eosinophils basophils and mast cells although each cell type has their own unique characteristic all of these cells produce lipid mediators and cytokines that induce in ammation In addition they all contain cytoplasmic granules and are particularly important in in ammation associated with immediate hypersensitivity reaction and allergic disorders In ammatory Mediators Chemical mediators produce the signs and symptoms that accompany in ammation These mediators can either originate from 1 Plasma 2 Cells Plasmaderived mediators are synthesized in the liver include coagulation factors and the complement proteins They must be activated by a series of proteolytic processes to acquire their biological properties Cellderived mediators normally sequestered in intracellular granules that need to be secreted or are newly synthesized in response to a stimulus The majority of cell derived mediators include platelets neutrophils monocytesmacrophages mast cells endothelial cells broblasts and epithelial cells Histamine is among the rst mediators to be released during an acute in ammatory response There is the greatest concentration of histamine in the connective tissues adjacent to blood vessels It causes dilation of arterioles and increases the permeability of venules Arachidonic acid metabolites arachidonic acid is a 20 carbon unsaturated fatty acid that is found in the phospholipids of cell membranes This acid initiates a series of complex reactions that lead to the production of in ammatory mediators Dietary modi cation of certain acids may be effective in preventing some negative manifestations of in ammation Platelet activating factor PAF is generated from a complex lipid stored in cell membranes affects many cell types and induces platelet aggregationclotting Also it activates neutrophils and is a potent eosinophil chemoattractant Plasma proteins plasma proteins mediate the in ammatory response They belong to 3 interrelated systems 1 Clotting system 2 Complement system 3 Kinin system Cytokines and chemokines cytokines are proteins that modulate the function of cells They are well known for their role in immune responses as well as in acutechronic in ammation Tumor necrosis factor and IL1 are two of the major cytokines that mediate in ammation These cytokines are activated by macrophages These cytokines induce endothelial cells to express adhesion molecules and release other cytokines chemokines and reactive oxygen species Chemokines are a family of small proteins that act primarily as chemoattractants to recruit and direct the migration of immune and in ammatory cells They also generate a chemotactic gradient by binding to proteoglycans on the surface of endothelial cells or in the ECM There are 2 classes of chemokines 1 In ammatory chemokines 2 Homing chemokines Nitric oxide nitric oxide which is produced by a variety of cells can cause smooth muscle relaxation and antagonism of platelet adhesion aggregation and degranulation Local manifestations the severity of the reaction its speci c cause and the site of involvement introduce variations in acute in ammation These manifestations can range from simply swelling and the formation of exudates to abscess formation or ulceration Exudates vary in the terms of uid types plasma protein consent and the presence or absence of cells The different types include 1 Serous exudates watery uids 2 Hemorrhagic exudates occur when there is severe tissue injury that damages blood vessels 3 Fibrinous exudates contain large amounts of brinogen and form a thick and sticky meshwork 4 Membranous exudates are composed of necrotic cells enmeshed in a bropurulent exudate Purulent suppurative exudate contains pus composed of degraded white blood cells proteins and tissue debris An abscess is localized area of in ammation that contain a purulent exudate that may be surrounded by a neutrophil layer Ulceration an ulceration refers to a site of in ammation where an epithelial surface has become necrotic and eroded Chronic In ammation Chronic in ammation is selfperpetuating and may develop as the result of a recurrent or progressive acute in ammation Instead of neutrophils chronic in ammation involves an in ux of macrophages and lymphocytes Instead of exudates chronic in ammation involves the proliferation of broblasts Causes foreign bodies such as silica talc asbestos and surgical suture materials There are 2 types of chronic in ammation l Nonspeci c chronic in ammation 2 Granulomatous in ammation Nonspecific chronic in ammation involves a diffuse accumulation of macrophages and lymphocytes at the site of injury Granulomatous in ammation is associated with foreign bodies such as splinters sutures silica and asbestos and with microorganisms that cause tuberculosis syphilis and deep fungal infections Systemic manifestations of in ammation local injury can result in prominent systemic manifestations as in ammatory mediators are released into circulation The most prominent systemic manifestations of in ammation include 1 Acute phase response 2 Alterations in white blood cell count 3 Fever Acutephase response the acute phase response begins within hours or days of the onset of in ammationinfection Includes changes in the concentration of plasma proteins skeletal muscle catabolism negative nitrogen balance elevated erythrocyte sedimentation rate ESR and increased numbers of leukocytes Fever is the most obvious sign of the acute phase response Systemic in ammatory response syndrome caused by the release of large quantities of in ammatory cytokines IL1 and TNF Systemic in ammatory response syndrome cause 1 Generalized vasodilation 2 Increased vascular permeability 3 Intravascular uid loss 4 Myocardial depression 5 Circulatory shock Acute phase proteins during the acute phase response the liver dramatically increases the synthesis of acute phase proteins such as brinogen Creactive protein CRP and serum amyloid A protein SAA Leukocytosis can be de ned as an increase in white blood cells and is a frequent sign of an in ammatory response especially one that is caused by bacterial infection Normal white cell count 4000 but increases to 10000 cellsmicroliter Lymphadenitis the in ammatory response leads to painful palpable nodes caused in response to mediators released from the injured tissueimmune response Tissue Repair Tissue repair overlaps with the in ammatory response and regenerates injured cells This can be done with the replacement of injured cells with cells of the same types which does not leave behind a trace of injury Or the injured cells can be replaced by connective tissue which leaves a permanent scar Body organs and tissues are composed of 2 types of structures 1 Parenchymal 2 Stromal Parenchymal this type of tissue contains the functioning cells of an organ or body part Stromal stromal tissues consist of the supporting connective tissues blood vessels ECM and nerve bers Body cells are divided into 3 categories depending on their ability to undergo regeneration 1 Labile cells continue to divide and replicate throughout life replacing cells that have been destroyed ex mitotic cells 2 Stable cells cells that stop dividing when growth ceases but can are capable of undergoing regeneration when confronted with an appropriate stimulus ex bone cells 3 Permanent fixed cells these cells cannot undergo mitotic division ex neurons Healing Process Tissue healing is regulated by the actions of chemical mediators and growth factors that mediate the healing process Critical to the process of wound healing is the transition from granulation tissue to scar tissue which involves shifts in the composition of the extracellular matrix ECM Wound Healing Involves the restoration of the integrity of injured tissue by either parenchymal or connective tissue cells Depending on the extent of the tissue loss wound closure and healing occur by 1 Primary intention or 2 Secondary intention Healing by primary intention does not lead to any tissue loss Ex a sutured surgical incision Healing by secondary intention is slower than healing by primary intention and results in larger amounts of scar tissue Wound healing can be divided into 3 phases in ammatory response proliferative phase and wound contraction remodeling phase 1 In ammatory Response Is a critical period because it prepares the wound environment for healing Begins at the times of injury with the formation of a blood clot Followed by the migration of phagocytic white blood cells into the wound site The first cells to arrive are the neutrophils which ingest and remove bacteria and other cellular debris After 24 hours neutrophils are joined by macrophages which continue to ingest debris and produce growth factors that are needed for the proliferative phase 2 Proliferative Phase Usually begins within 2 to 3 days of injury This phase focuses on the building of new tissue to fill the wound space Fibroblasts are connective tissue cells that play a key role during this phase Fibroblasts synthesize and secrete growth factors collagen proteoglycans and glycoproteins needed for wound healing The final phase of the proliferative phase is epithelialization during which epithelial cells form a new surface layer that is similar to that which was destroyed by the injury 3 Wound Contraction and Remodeling Phase Begins approximately 3 weeks after injury with the development of fibrous scar and can continue for 6 months or longer There is a decrease in vascularity Continued remodeling of scar tissue by simultaneous synthesis of collagen by fibroblasts Wound contraction and remodeling lead to the development of a scar which is capable of increasing its tensile strength With time the scar shrinks so it is less visible Factors that affect wound healing l Malnutrition need adequate stores of proteins carbohydrates fats vitamins and minerals 2 Impaired blood ow and oxygen delivery require adequate blood ow to supply the necessary nutrients and to remove the resulting waste local toxins bacteria and other debris 3 Impaired in ammatory and immune responses in ammation is essential in the first stage of healing and immune responses prevent infections from occurring and causing complication to the wound healing process 4 Infection wound separation and foreign bodies all of these factors delay wound healing which may lead to further complication and worsening of wound condition 5 Bite wounds bites are troublesome in terms of infection Treatment of bite wounds involves vigorous irrigation and cleaning as well as debridement or removal of necrotic tissue The effect of age on wound healing Children have a greater capacity for repair than the adult but may lack the reserves needed to ensure proper healing Older adults are more vulnerable to chronic wounds and wound healing is impaired with aging Older adults have reduced collagen and fibroblast synthesis impaired wound contraction and slower reepithelialization of open wounds CH16 AIDS What is it Acquired immunode ciency syndrome AIDS is a disease caused by infection with the human immunode ciency virus HIV How is it transmitted When infected blood semen or vaginal secretions from one person are deposited onto a mucous membrane or bloodstream of another This is mostly done by sexual contact Other forms are blood to blood IV drug use or perinatally childbirth HIV can be transmitted from the infected woman to her baby in utero during labor and delivery or through breastfeeding However if the mother and baby are treated with l or 2 additional antiretroviral medications along with zidovudine a decrease in HIV transmission occurs It is possible that health care providers HCP be transmitted with HIV through needlestick infection Transmission is associated with the size of the needle amount of blood injected and stage of illness from the person Relevant Facts Before 1985 people were not screened for HIV so 7080 of hemophiliacs treated with factor 8 received blood transfusions from those donors and ended up with HIV Reminder Hemophilia is a blood disorder where blood doesn t clot normally There is growing evidence that people with STDs are at greater risk for acquiring AIDS Sexually Transmitted Diseases such as ulcerative syphilis herpes simplex virus infection human papilloma virus and chancroid Nonulcerative diseases include gonorrhea chlamydia and trichomoniasis FYI the ulcerative infections are transmitted by skintoskin contact and therefore cannot be fully protected with condom use This is why they are the most common STDs The HIV infected person is infectious even when no symptoms are present What are the molecular and biologic features of HIV HIV is a retrovirus so it carries its genetic information in RNA The virus capsid protein p24 is the target used antigen in screening for the HIV virus Steps of growth replication are attachment uncoating reverse transcriptase integration HIV replication kills the CD4T lymphocytes aka T helper cells macrophages and dendritic cells which are necessary for normal immune function The CD4T cells are important because they lead cell mediated immunity o Ex CD4T asking Natural Killer cells NK to destroy virus infected cells tubercle bacilli and foreign antigens Treatment of HIVAIDS relies on the use of agents that interrupt steps of the HIV replication process Phases of HIV Infection 1 PrimaryAcute Signs and Symptoms of Acute HIV Infection fever fatigue myalgia arthralgia rash headache night sweats GI problems Lymphadenopathy Aseptic meningitis Pharyngitis Oral or genital ulcers mononucleosis Opportunistic Infections E Cryptococcal meningitis in ammation of the membranes that cover brain and spinal cord Symptoms headache nausea vomiting mental changes like confusion and hallucinations lethargy light sensitivity ToXoplasmosis infection caused by a parasite found in undercooked meat and cat feces Symptoms brain in ammation seizures blurry vision mental issues Papovavirus leukoencephalopathy deterioration of the CNS white matter which contain myelinated neurons that contribute with our daily quick responses in neural activity Symptoms absent mindedness confusion ts dementia MUCOCUTANEOUS Herpes Simplex Virus skin to skin contact that can manifest itself with tingling itching buming then giving rise to oral or genital sores u like symptoms urination problems and an eye infection Candidiasis oral or genital thrush PNEUMONIA lung infection caused by bacteria or fungus Symptoms coughwith sputum fever shortness of breath pneumocystis jiroveci pneumonia PCP mycobacterium avium intracellulare cytomegalovirus SKIN Staphylococcus Scabies HPV Human Papilloma Virus Molluscum contagiosum DIARRHEA Protozoa Cryptosporidium Isospora belli Giardia lamblia Bacteria Mycobacterium avium intracellulare VIRUSES Cytomegalovirus not harmful for healthy people fatal for immunecompromised people DEMENTIA CAUSED BY AIDS LYMPHOPROLIFERATIVE DISEASE CNS lymphoma Persistent generalized lymphadenopathy B cell lymphoma AIDS nephropathy KAPOSI SARCOMA cancerous tumor of connective tissue associated with AIDS Other than the skin warts other symptoms include bloody sputum and SOB Wasting Syndrome involuntary weight loss of at least 10 diharrea more than 2 stools per day chronic weakness fever 2 Chronic AsymptomaticLatency Phase the longest phase where person usually does not display any signs 3 Overt Phase person has a CD4count of less than 200 cells meaning that without therapy the patient will die within 2 to 3 years NonHodgkin Lymphoma can spread throughout all of the nodes systemic Transformation of b antibodies amp t lymphocytes painless Hodgkin arises from a single node or chain of nodes local Presence of Reed Stemburg Clinical Features fever night sweats weight loss Clinical Presentation of HIV Infection in Children failure to thrive CNS abnormalities and developmental delays Infants bom with HIV are usually shorter Children have an early onset of PCP while in adults that develops later 2 Positive PCR tests for HIV are needed to diagnose a child with the infection because they can be HIV antibody positive for up to 18 months of age Chapter 26 Hemostasis the stoppage of blood ow Disorder categories inappropriate formation of clots within vascular systemthrombosis Two types increase platelet functioncause accelerated activity of coagulation system the failure of blood to clot in response to an appropriate stimulusbleeding Hemostasis 5 stages vessel spasm formation of platelet plug blood coagulation clot retraction clot dissolution on patho quiz Vessel spasm constricts the vesselreduces blood ow Caused by endothelial injury caused by localhumoral mechanisms Prostaglandins released from vessel endothelium produces vasodilationinhibits platelet aggregation Injury to a blood vessel causes vascular smooth muscle in the vessel wall to contract This instantaneously reduces the ow of blood from the vessel rupture Both local nervous re exes and local humoral factors such as thromboxane A2 TXA2 which is released from platelets contribute to the vasoconstriction Platelet plug initiated as platelets come in contact w vessel wall Sent from bone marrow to spleen Granules contribute to vasoconstriction Plug formation involves adhesion then aggregation Seconds after vessel injury von Willebrand factor released from the endothelium binds to platelet receptors causing adhesion of the platelets to the exposed collagen fibers inset As the platelets adhere to the collagen fibers on the damaged vessel wall they become activated and release adenosine diphosphate ADP and TXA2 The ADP and TXA2 attract additional platelets leading to platelet aggregation Blood coagulation convert fibrinogen to fibrin fibrin creates a meshwork that cements plateletsother components together to form the clot Controlled by procoagulant factors that promote factors or inhibit it with anticoagulation factors Blood coagulation is a complex process involving the sequential activation of various factors in the blood There are two coagulation pathways 1 the intrinsic pathway begins in the circulation and is initiated by activation of circulating factor XII and 2 the extrinsic pathway which is activated by a cellular lipoprotein called tissue factor that becomes exposed when tissues are injured Both pathways lead to the activation of factor X the conversion of prothrombin to thrombin and conversion of brinogen to the insoluble brin threads that hold the clot together Clot retraction Contributes to hemostasis by squeezing serum from the clot j oining the edges of the broken vessel Requires large amount of platelets Within a few minutes after a clot is formed the actin and myosin in the platelets that are trapped in and the clot begins to contract in a manner similar to that in muscles As a result the brin strands of the clot are pulled toward the platelets thereby squeezing serum plasma without brinogen from the clot and causing it to shrink Clot dissolution allows blood ow to reestablishpermanent tissue repair to take place Clot dissolution begins shortly after a clot is formed It begins with activation of plasminogen an inactive precursor of the proteolytic enzyme plasmin When a clot is formed large amounts of plasminogen are trapped in the clot The slow release of a very powerful activator called tissue plasminogen activator tPA from injured tissues and vascular endothelium converts plasminogen to plasmin which digests the brin strands causing the clot to dissolve Hypercoagulability results in platelet adhesion formation of platelet clotsdisruption of blood ow Causes increased platelet function disturbances in ow endothelial damage increased sensitivity of platelets Thrombocytosis elevation of platelets stimulation of thrombopoietin increase megakaryocyte proliferationplatelet production Caused by tissue damage due to cancer surgerybone marrow disorder Hypercoagulability w increased clotting activity antithrombin IIIprotein C are de cientunable to unclot coagulation factors Cthrombin Stasis of blood ow causes accumulation of activated clotting factorsplateletsprevents interactions w inhibitors venous thrombosisDVT Caused by cancer smoking heart failure stasis Thrombocytopenia a decrease in platelet number if greater decrease in platelet count greater risk of bleeding Results from a decrease in platelet production increased sequestration of platelets in the spleen or decreased platelet survival affecting bone marrow Associated illnesses aplastic anemia leukemia HIV cancer cytomegalovirus Druginduced thrombocytopenia drugs act as haptens to induce an antigenantibody responseformation of immune complexes that cause platelet destruction by complement mediated lysis Taking of the drug reduces platelet count when stopped taking drug platelet count increases Idiopathic ITP an autoimmune disorder that results in platelet antibody formationexcess destruction of platelets Associated w AIDS systemic lupus hepatitis C heparin leukemia Thrombotic Thrombocytopenic allowing VWF to accumulatecause platelet aggregationadhesion to endothelium Due to an enzyme de ciencyinherited or acquired of antibody directed against the enzyme Impaired platelet function acquired through drugs inherited diseases Prevents platelet aggregation leads to bleeding due to inability to clot VWf diseasehemophilia VWF factorfactor VIII are deficientmutated therefore unable to circulate and promote clotting adhesion of platelets to the vessel wall Vascular defects weak vessels Scurvy poor collagen synthesisfailure for endothelial cells to cement together properly Cushing disease protein wastingloss of vessel tissue supportimpaired collagen synthesisexcess cortisol Disseminated lntravascular Coagulation widespread coagulationbleeding in vascular compartment thrombosishemolytic anemiatissue ischemia Begins with massive activation of coagulation sequence as a result of unregulated generation of thrombin results in systemic formation of fibrin Extrinsic liberation of tissue factors associated w obstetric complications trauma bacterial sepsis cancers Intrinsic endothelial damage caused by viruses infections immune mechanisms stasis of blood temperature extremes and activation of factor XII gram negative sepsis hypoxia acidosis shock Treatment replace clotting components prevent further activation of clotting mechanisms CHAPTER 27 Disorders of the Red Blood Cells Disorders of Red Blood Cells Monday September 29 2014 1247 PM The Red Blood Cell 0 The unique shape contributes in two ways Biconcave shape provides a larger surface area for oxygen diffusion Thinness of cell membrane enables oxygen to diffuse rapidly between the exterior and innermost regions of the cell Flexibility of membrane allows RBC to squeeze through capillaries easily and therefore get to all of the most peripheral body tissue Spectrin is a fibrous protein that maintains the biconcave shape and exibility of the red cell membrane Spectrin is anchored down to a protein called ankyrin which is found on the inner surface of the membrane is anchored by an integral protein Purpose 0 To transport oxygen to the tissues with the facilitation of hemoglobin Hemoglobin o Is a protein that carries oxygen in red blood cells 0 Composed of two pairs Alpha Beta Each polypeptide consists of globin protein portion and a heme unit 0 Each molecule of hemoglobin can carry four molecules of oxygen Two Types of normal hemoglobin O 0 Adult Hemoglobin HbA Consists of a pair of alpha chains and a pair of beta chains Fetal Hemoglobin HbF Consists of a pair of gamma chains Has higher affinity for oxygen than HbA Hemoglobin Synthesis 0 OOOOO Depends on the availability of iron Lack of iron results in small amounts of hemoglobin in the red blood cells Approx 2g in females 6g in men 80 of iron is found in hemoglobin heme 20 of iron is found in bone marrow Iron is recycled when red blood cells age Iron frm meat is absorbed through the small intestine especially the duodenum When iron is low or when erythropoiesis is stimulated absorption is increased Iron Absorption Combines with Beta globulin Apotransferrin To form tranferrin Transported to plasma Red cell Production Erythropoiesis production of red blood cells Until 5 years of age bones produce red cells to meet growth needed for child After 20 years of age red cell production takes place mainly in the membranous bones of the vertebrae stemum ribs and pelvis red bone marrow is replaced with fatty yellow bone marrow Pluripotent stem cells gt Erythroblastsgt red blood cells Erythropoietin is a hormone that is produced when there is a decrease in oxygen levels Erythropoietin also regulates cell production Red Cell Destruction 0 0 Approx life span of RBC is 120 days RBC ages Metabolic activity in the cell decreases Enzyme activity declines ATP decreases Membrane lipids become reduced Cell membrane becomes fragile O Rate of RBC destruction is equivalent to RBC production of 1 per day Destruction of RBC are guided by a group of large phagocytic cells found in Spleen Liver Bone marrow Lymph nodes Phagocytic cells recognize old and defective RBC and ingest and destroy them through enzymatic reactions Steps of destruction Heme portion of hemoglobin is converted to bilirubin Bilirubin attaches to plasma proteins for transport in the blood Bilirubin is removed from the blood by the liver and conjugated w glucuronide to render it water soluble so that it can be excreted in the bile Plasma insoluble form of bilirubin unconjugated bilirubin Water soluble form of bilirubin conjugated bilirubin J aundice yellowing discoloration of the skin due to unconjugated bilirubin accumulation in the blood or RBC destruction and consequent bilirubin production are excessive Hemolytic anemia RBC destruction takes place in the circulation Red Cell Metabolism amp Hemoglobin Oxidation O O 0 RBC lack mitochondria and relies on glucose and the glycolytic pathway for its metabolic needs End product of glycolytic pathway is 23 diphosphateglycerate Which binds to the hemoglobin molecule and reduces the affinity of hemoglobin for oxygen Facilitates release of oxygen at the tissue level Also increases the release of oxygen to the tissues during conditions of hypoxia by reducing hemoglobin39s affinity for oxygen Hemolysis occurs as the result of oxidative stress generated by either an infection or exposure to certain drugs Lab Tests 0 Red blood cell count measures the total number of RBC in a micro liter of blood Percentage of Reticulocytes provides an index of the rate of RBC production Hematocrit measures the red cell mass in a l00mL plasma volume Sample of blood is placed in a glass tube which is then centrifuged to separate the cells and the plasma Red cell indices used to differentiate types of anemias by size or color of red cells Stained blood smears provide info about size color and shape of red cells and the presence of immature or abnormal cells O If results are abnormal resort to examination of bone marrow Which is aspirated with a special needle from the posterior iliac crest or the sternum Automated blood cell counters rapidly provide accurate measurements of RBC content and cell indices Anemia O Anemia is the de ciency of red cells or hemoglobin which results from excessive loss increased destruction or impaired production of RBCiron deficiency megaloblastic and aplastic anemias Blood loss anemia is characterized by loss of iron containing red blood cells from the body hemolytic anemia involves destruction of red blood cells in the body with iron being retained in the body Effects of Anemia are grouped into three categories Manifestations of impaired oxygen transport and the resulting compensatory mechanisms Reduction in red cell indices and hemoglobin levels Signs and symptoms associated with the pathologic process that is causing the anemia Manifestations of anemia are caused by the decreased presence of hemoglobin in the blood tissue hypoxia due to deficient oxygen transport and recruitment of compensatory mechanisms designed to increase oxygen delivery to the tissues Blood Loss Anemia O O O Manifestations depends on rate of hemorrhage and whether the bleeding loss is internal or external Rapid blood loss can cause circulatory shock and circulatory collapse Blood loss anemia can either be Acute Mainly due to loss of intravascular volume which can cause cardiovascular collapse and shock Mainly caused by hemodilution which is movement of uid into the vascular compartment Hypoxia stimulates proliferation of committed erythroid stem cells in the bone marrow Takes about 5 days for the progeny of stem cells to differentiate fully RBC returns to normal within 3 to 4 weeks Chronic Does not affect blood volume but instead leads to iron deficiency anemia when iron stores are depleted Commonly caused by GI bleeding and menstrual disorders Hemolytic Anemias 0 Is the caused by Premature destruction of red cells The retention in the body of iron and the other products of hemoglobin destruction O O Increase in erythropoiesis Red cell destruction breakdown can occur within or outside the vascular compartment Intravascular hemolysis Less common and occurs as a result of complement xation in transfusion reactions mechanical injury or toxic factors Characterized as hemoglobinemia hemoglobinuria jaundice and hemosiderinuria Extravascular hemolysis Occurs when red cells become less deformable making it dif cult for them to traverse the splenic sinusoids Manifestations include anemia and jaundice Intrinsic Causes include defects of the red cell membrane various hemoglobinopathies and inherited enzyme defects Extrinsic caused by agents extemal to the RBC such as drugs bacterial and other toxins Inherited disorders of the Red cell membrane Hereditary spherocytosis transmitted as autosomal dominant trait in 75 of cases which is the most common inherited disorder Caused by abnormalities of the spectrin and ankyrin membrane proteins that lead to a gradual loss of the membrane surface Loss of membrane causes the cell to become a tight sphere instead of a concave disk Clinical signs mild hemolytic anemia jaundice splenomegaly and bilirubin gallstones Sickle cell disease An inherited disorder in which an abnormal hemoglobin leads to chronic hemolytic anemia pain and organ failure Etiology and Pathogenesis Abnormal structure of HbS results from a point mutation in the beta chain of the hemoglobin molecule Deoxygenated hemoglobin aggregates and polymerizes in the cytoplasm creating a semi solid gel that changes the shape and deformability of the cell Clinical Course May experience hemolytic anemia chronic hyperbilirubinemia and vaso occlusive crises Blood vessel occlusion Most Severe complication Pain occurs through vessel occlusion and hypoxia and can occur suddenly in any part of the body O O O Usually sites obstructed by sickled cells include abdomen chest bone and joints The spleen is especially susceptible to damage by HbS due to the spleens sluggish blood ow and low oxygen tension hemoglobin in red cells traversing the spleen becomes deoxygenated causing ischemia Diagnosis and Screening Prenatal diagnosis is done by analysis of fetal DNA obtained through amniocentesis Cord blood or heel stick samples are subjected to electrophoresis to separate the HbF from the small amount of HbA and HbS Management No known cure Major focus on prevention of sickling episode Symptom management Treatment of precipitate episodes Such as Infections Cold exposure Physical exertion Acidosis Dehydration The Thalassemias Group of inherited disorders of hemoglobin synthesis leading to decreased synthesis of either the alpha or beta globin chains of HbA The Beta Thalassemias The alpha chains are denatured to form precipitatesheinz bodies in the bone marrow red cell precursors Heinz body impair DNA synthesis and cause damage to the red cell membrane The Alpha Thalassemia Caused by gene deletion that results in defective a chain synthesis Most common in Asians Inherited Enzyme defects Most common inherited enzyme defect that results in hemolytic anemia is deficiency of G6PD Only expressed in males and homozygous females Makes red cells more Vulnerable to oxidants and causes direct oxidation of hemoglobin to methemoglobin which cannot transport oxygen and denaturing of the hemoglobin molecule to form heinz bodies which are precipitated in the red blood cell Acquired Hemolytic Anemias Caused by agents extrinsic to the RBC such as drugs bacterial and other toxins antibodies and physical trauma 0 Iron Deficiency Characterized by decreased hemoglobin synthesis can result from dietary de ciency loss of iron through bleeding or increased demands for red cell production Etiology and Pathogensis Low body iron In adults the main cause is chronic blood loss In men and postmenopausal women blood loss may occur from GI bleeding because of peptic ulcer vascular lesion intestional polyps hemorrhoids or cancer Clinical Manifestations Related to impaired oxygen transport and lack of hemoglobin Fatigability Palpitations Dyspnea Angina Tachycardia Diagnosis and Treatment Prevention is a primary concern in infants and children Treatment dealing with controlling chronic blood loss Increasing dietary intake of iron Administering supplemental iron 0 Vitamin B12 Deficiency Anemia Vitamin b l2cobalamin Essential for DNA synthesis Nuclear maturation De ciency of cobalamin develops slowly Any defects in its pathway may cause a deficiency Absorption occurs in stomach Attaches to intrinsic factor Epithelial cell attaches with the IF B 12 then binds with carrier protein transcobalamin II then transports to tissue sites and storage Clinical Manifestations Severe anemia Mild jaundice Diagnosis and Treatment Schilling tests Measures 24 hour urinary excretion Treatment consists of lifelong treatment consisting of intramuscular injections or high oral doses of vitamin bl2 o Folic Acid De ciency Anemia Folic acid is required for DNA synthesis and red cell maturation De ciency produces the same type of changes that occur in Vitamin B12 deficiency Folic acid is readily absorbed from the intestine also is found in Vegetables Cereals Meats o Aplastic Anemia ls described as a disorder of pluripotent bone marrow stem cells which results in a reduction of all three hematopoietic cell lines Red blood cells White blood cells Platelets Etiology and pathogenesis Causes are exposures of high doses of radiation chemicals and toxins that suppress hematopoiesis directly or through immune mechanisms Clinical Manifestations Can occur at any age Weakness fatigability and pallor Diagnosis and Treatment Use a CBC to diagnosis to see the count of white blood cells and red blood cells and platelets Treatment therapy through replacing stem cell by bone marrow peripheral blood transplantation or immunosuppressive therapy 0 Chronic Disease Anemia Occurs as a complication of chronic infections in ammation and cancer Such as AIDS autoimmune disorders such as rheumatoid arthritis systemic lupus Through the production of in ammatory cytokines that interfere with erythropoietin production or response 0 ABO Blood Groups Essential for effective transfusion therapy and requires knowledge of ABO antigens and antibodies Persons who have neither A nor B antigens are classified as having type 0 blood Those with an A Antigen are classified as having type A blood Those with B Antigens are having type B blood Persons with type A antigens on their red blood cells develop type B antibodies Persons with Type B antigens develop type A antibodies in their serum Persons with Type 0 blood develop Type A and B antibodies Persons with Type AB blood develop no antibodies 0 Rh Types D antigen of the Rh system is important in transfusion compatibility and is routinely tested With Antigen D means Rh positive Without antigen D means Rh negative 0 Blood Transfusion Reactions sensation of heat along the vein Flushing of the face Pain in the lumbar area Urticaria hives Headache Chills Fever Constricting pain the chest Cramping pain the abdomen Nausea Vomiting Tachycardia Hypotension dyspnea o Polycythemia Is an abnormally high total red blood cell mass with a hematocrit greater than 54 in men and greater than 47 in women Categorized Relative Absolute Polycythemia primary Is a neoplastic disease of the pluripotent cells of the bone marrow characterized by an absolute increase in total red blood cell mass accompanied by elevated white cell and platelet counts Hypertension is common and there may be complaints of headache dizziness inability to concentrate and some difficulty with hearing and vision because of decreased cerebral blood ow Treatment is to reduce blood viscosity Ex withdrawing blood by periodic phlebotomy Absolute polycythemia secondary results from a physiologic increase in the level of erythropoietin commonly as a compensatory response to hypoxia Treatment focuses on relieving hypoxia 0 Red Cell Changes in the Neonate At birth changes in the RBC re ect the transition to extrauterine life and the need to transport oxygen from the lungs At birth hemoglobin concentrations are high towards the end hemoglobin concentration begins to decline Neonatal red cells also have a shorter life span of 50 to 70 days During early neonatal period there is also a switch from HbF to HbA o Hyperbilirubinemia in the Neonate Is an increased level of serum bilirubin which is a common cause of j aundice in the neonate The increase is related to the increased RBC breakdown and the inability of the immature liver to conjugate bilirubin J aundice in the neonate is caused by Elevated bilirubin levels Breast feeding Hemolytic disease of the newbom Hypoxia Infection Acidosis Places the neonate at risk for the development of a neurologic syndrome called Kemicterus Caused by the accumulation of unconjugated bilirubin in brain cells Which can cause brain damage 0 Hemolytic Disease of the Newbom Occurs in Rh positive infants of Rh negative mothers who have been sensitized After an Rh negative mother has been sensitized the antibodies from her blood are transferred to infants through the placental circulation these antibodies will react with the red cell antigens of the rh positive infant Causing Agglutination and hemolysis Leading to severe anemia with compensatory hyperplasia and enlargement of the blood forming organs 0 Red Cell Changes w Aging Anemia is an increasingly common health problem in the elderly Hemoglobin levels decline after middle age As with other body systems the capacity for red cell production also changes with aging An inability to replace red blood cells closely correlates with the increased prevalence of anemia in the elderly which is usually the result of bleeding infection malignancy or chronic disease CH 28 White blood cells o Granulocytes from myeloid stem cell in bone marrow Neutrophils Eosinophils Basophils o Monocytesmacrophages from myeloid stem cell in bone marrow o Lymphocytes T lymphocytes mature in thymus differentiate into CD4 helper T cells gt orchestrate immune response and CD8 cytotoxic T cells gtprovide for cellmediated immune responses B lymphocytes mature in bone marrow differentiate to form immunoglobulin producing plasma cells Hematopoietic growth factors 3 functional groups 1 Development of specific cell lineage 2 Those that affect early multipotential progenitor cells 3 Indirectly regulate hematopoiesis by inducing the expression of growth factor genes in other cells Lymph nodes collections of lymphoid tissue located along the lymphatic vessels Leukopenia decrease in number of leukocytes in blood mostly affects neutrophils Neutropenia decrease in number of neutrophils leaves more chance of getting infected Agranulocytosis absence of neutrophils Congenital Neutropenia o Cyclic neutropenia rare autosomal dominant disorderabnormality involving early hematopoietic precursor and is associated with the neutrophil elastase Characteristized by regular periodic oscillations of peripheral neutrophils during neutropenic valuesfever stomatitis pharyngitis o Severe congenital neutropenia Kostmann syndrome autosomal dominant or recessive characterized by an arrest in myeloid maturation at promyelocyte stage of development gt neutrophil count less than 200 cells Characterized by severe bacterial infections associated with mutations in neutrophil elastase gene o Alloimmune neonatal neutropenianeutropenia that occurs after transplacental transfer of alloantibodies to infant s neutrophils Involves phagocytic destruction of antibodycoated neutrophils by splenic macrophages Affected infants present with delayed separation of umbilical cord mild skin infections fever and pneumonia within first 2 weeks of life resolve with antimicrobial therapy Acquired Neutropenia o Autoimmune neutropeniaresults from antibodies directed against neutrophil cell membrane antigens or bone marrow progenitors Classified as Primary not associated with any other detectable pathologic process usually occurs in children and benign treatment antimicrobial agents for recurring infections Secondary associated with another detectable pathologic process mainly in rheumatoid arthritis and systemic lupus erythematosus o Infectionrelated neutropenia viral bacterial rickettsia and parasitic can cause this most common is viral Caused by production of autoantibodies that caused increased and premature destruction of neutrophils direct infiltration of developing hematopoietic cell lines elaboration of toxins that suppress bone marrow function and production of splenomegaly with increased neutrophil sequestration and destruction Common manifestation of AIDS o Drugrelated neutropenia arose from the use of chemotherapeutic drugs in treatment for cancer Factors patientrelated age nutritional comorbid conditions Diseaserelated neoplastic bone involvement type of cancer and history of anemia Treatmentrelated radiation therapy to bone marrow previous chemo treatment regimen Idiosyncratic drug reactions that are different from the effect obtained in most persons that cannot be explained in terms of allergy Drugs that affect clozapine Blactam antibiotics o Signs and symptoms If mild or moderate skin lesions stomatitis pharyngitis and diarrhea If severe malaise chills and fever weakness and fatigue Infectious Mononucleosis selflimiting lymphoproliferative disorder caused by EpsteinBarr virus o Occurs at any age occurs principally in adolescents and young adults o Spreads by droplet contact including kissing nasopharyneal oropharyngeal and salivary epithelial cells o Virus may kill infected B cell or incorporate itself into cell s genome o Lymph nodes are enlarged o Common manifestations benign hepatitis and splenomegaly o Treatment bed rest analgesics Neoplastic Disorders of Hematopoietic and Lymphoid Organs o Include lymphomas acute and chronic leukemias and plasma cell dyscrasias Lymphomasoriginate in peripheral lymphoid structures where B and T lymphocytes undergo differentiation and proliferation Leukemiasarise from hematopoietic precursors in the bone marrow can involve the T and B lymphocytes granulocytes and other blood cells Dyscraisis in lymph nodes Malignant Lymphomassolid tumors composed of neoplastic lymphoid cells proliferation of cells in origination o NonHodgkin Lymphoma Either Bcell or Tcell neoplasmas etiology unknown In any lymphoid tissues mostly in lymph nodes Manifestations Slowgrowing painless lymphadenopathy transform into aggressive forms of leukemia lymphoma Interrnediate aggressive fever drenching night sweats weight loss increased susceptibility to bacterial viral amp fungal infections Diagnosis amp Treatment Lymph node biopsy amp immunophenotyping diagnosis Treatmentdepends on histologic stage o Early stage adjuvant radiation therapy chemotherapy o Aggressivestage chemotherapy rituximab monoclonal antibodies bone marrow amp peripheral stem cell transplantation potentially o Hodgkin Lymphomalymphoma that features the presence of an abnormal cell called reedstemberg cell Occurs in two periods 1 15 to 40 yrs 2 55 Differs from NHL o Hodgkin Lymphomalymphoma that features the presence of an abnormal cell called reedstemberg cell Occurs in two periods 1 15 to 40 yrs 2 55 Differs from NHL Nodular lymphocytepredominant HL exhibits nodular growth pattem without diffuse areas amp rare reedstemberg cells called lymphohistiocytic cells localized slowly progressive Classical HL clonal proliferation of typical mononuclear Hodgkin cells and multinucleated reedstemberg cells with invariable expression of CD30 0 4 types nodular sclerosis mixed cellularity lymphocyterich lymphocyte depleted Manifestations painless enlargement of node s chest discomfort cough dyspnea fevers chills night sweats weight loss fatigue anemia Diagnosislymph node biopsy CT scan bipedal lymphangiogram PET scan if initial screening doesn t work bilateral bone marrow biopsy most common Treatment irradiation and chemotherapy Leukemias malignant neoplasms of cells originally derived from hematopoietic precursor cells Characterized by diffuse replacement of bone marrow with proliferating immature neoplastic cells o Classif1cations lymphocytic or myelocytic and acute or chronic Lymphocytic immature lymphocytes and their progenitors Myelogenous pluripotent myeloid stem cells in bone marrow interfere with all blood cell maturation o Etiology unknown exposure to benzene amp use of antitumor drugs Molecularly does damage by disrupting or dysregulation of genes that normally regulate blood cell development blood cell homeostasis o Acute Leukemia cancers of hematopoietic progenitor cells Two types ALL most common cancer precursor B or T lymphocytes have numeric and structural changes in leukemic chromosomes AML mostly in older seen in children amp young adults myeloid precursor cells in bone marrow genetically acquired alterations Symptoms fatigue from anemia lowgrade fever night sweats weight loss hypermetabolism bone pain amp tendemess Diagnosis blood and bone marrow studiesgt bone marrow biopsy cytogenic studies CT scan presence of immature wbcs in circulation and bone marrow Treatment induction therapy elicit remission intensi cation therapy reduce leukemic cells maintenance therapy maintain remission o Chronic Leukemia proliferation of fully differentiated myeloid and lymphoid cells Two types CLLelderly disorderclonal malignancy of B lymphocytes hallmark is isolated lymphocytosis o Treatment combination chemotherapy with MOA rituximab CML disorder of pluripotent hematopoietic progenitor cell Characterized by excessive proliferation of marrow granulocytes erythroid precursors and megakaryocytes hallmark is presence of BCRABL gene o Treatment allogeneic bone marrow or stem cell transplantation Plasma Cell Dyscrasias expansion of single clone of immunoglobulinproducing plasma cells and a result increase in serum level of a single monoclonal immunoglobulin o Multiple Myeloma Bcell malignancy of terminally differentiated plasma cells occurs mostly in older than 60 yrs Cause unknown but associated with chromosomal disorders risk factors chronic immune stimulation autoimmune disorders exposure to ionizing radiation and exposure to pesticides or herbicides manifestations in bone and bone marrow bone resorption amp destruction vulnerable to recurring bacterial infections soft tissue plasmacytomas diagnosis lytic bone lesions bone marrow plasmacytosis treatment melphalan and prednisone Chapter 59 Arthritis 1 Primary Affecting body systems in addition to the musculoskeletal system These conditions share in ammation of the joints as prominent or accompanying symptoms The in ammation is primary resulting from an immune response Arthritis cannot be cured 2 Secondary In rheumatic conditions limited to a single or few diarthrodial joints the in ammation is secondary Resulting from a worsening process and the resulting joint irregularities that occur as the bone attempts to remodel itself Rheumatoid Arthritis Is a systemic in ammatory disease can affect multiple parts of the body 0 Affects women 3x more then men Its prevalence increases with age 0 There are two types one that is acquired later in life that is around the age of 65 and has less of an impact compared to the one that is acquired earlier in life The disease is initiated by the activation of the Tcell mediated response to an immunologic trigger microbial agent Pathology of Rheumatoid Arthritis Autoimmune disease immune system attacks the synovium a thin membrane that lines the joints It is a chronic condition It can occur at almost any age most commonly develops in ages between 40 amp 70 No one knows the cause of the disease but some factors include genetics amp hormone imbalances Manifestation Rheumatoid Arthritis Usually has an insidious onset such as fatigue anorexia weight loss and generalized aching and stiffness It can occur severely and often with only a few joints that are either brief in duration or relentlessly progressive Joint Manifestation Person may complain of joint pain and stiffness that lasts for 30 minutes and frequently for several hours The most frequently affected joints initially are the fingers hands wrists knee and feet The distal interphalangeal joints are rarely affected is the dislocation of the joint resulting in misalignment of the bone ends Neck discomfort tis common In rare cases long standing disease can lead to neurologic complications such occipital headaches muscle weakness and numbness and tingling in the upper extremities ExtraArticular Manifestations Mild enough to cause only a few problems They erythrocyte is elevated due to in ammation Anemia is common Rheumatoid nodules are granulomatous lesions that developed around small blood vessel s 0 They are found over pressure points and remain present unless surgically removed is the in ammation of small and medium sized arteries but is it uncommon to occur 0 Ulceration may occur in the lower extremities particularly around the malleolus area the ankle 0 Heart lungs GI tract may be affected as well Diagnosis 6 out of the 10 possible points must be present to make the diagnosis 0 Four categories are present in the diagnosis I Joint involvement serology bodily uids with antibodies acute phase reactants and duration of symptoms In a physical exam the affect joints show In ammation Tenderness Warmth Reduced motion 0 Thickening spongy feeling due to the increase in synovial thickening Anticitrullinated proteinpeptide antibodies can test and have a higher speci city in the identifying RA Radiographic images do not detect RA in early stages Synovial uid analysis is a helpful method in detecting RA due to its characteristics such as cloudy appearance white blood cell count is elevated due to in ammation and the complement components are decreased due to in ammation Treatment There is no cure however there are many different types of pain medication that goals are to decrease pain decrease in ammation and restoremaintain joint function Physical rest reduces joint stress Emotional rest helps relax muscles Systemic Lupus Erythematous Chronic in ammatory disease that affect virtually any organ system including musculoskeletal More common in blacks Hispanics and Asians and least common in whites There are four types of Lupus the most common one is SLE Pathogenesis of Systemic Lupus Erythematous The cause is unknown It is characterized by the formation of autoantibodies and immune complexes SLE has autoantibodies that are polyclonal copy themselves that direct against elements of the blood and plasma proteins Androgens males appear to protect against the development of SLE whereas estrogens females seem to favor its development Possible environmental triggers include UV lights chemicals hair dyes some foods and infectious agents Manifestation The symptoms vary from person to person depending on what part of the body is affected Can be mile moderate or severe Common manifestations are 0 Acute skin lesions of the classic malar or butter y rash on the nose and cheeks 0 Hair loss is common 0 Pericarditis is the most common of the cardiac manifestations o Malar skin rashes o Hematologic cytopenias Diagnosis and Treatment 4 out of the 11 criteria to be considered in the diagnosis No single test can diagnosis SLE in all people OOOO The most common laboratory test performed is the immuno uorescence test for ANA The anti DNA antibody test is more speci c for the diagnosis of SLE The goals of treatment include preventing loss of organ function reducing severity and preventing complications from medication therapy Drugs are used to reduce in ammation and pain Systemic SclerosisScleroderma Autoimmune disease of connective tissue characterized by excessive collagen deposition in the skin and intemal organs such as lungs gastrointestinal tract heart and kidneys Involves hardening and thickening of the fascia through fibrosis Women are four times as frequently as men 0 Peak incidence in the 2550 years of age group Clinical Manifestations Has two forms either diffused or generalized or the limited or CREST variant 0 CREST syndrome is an acronym for several different symptoms I C calcinosis I RRaynaud s Phenomenon I EEsophageal dysmobility I S Sclerodactyly I T Telangiectasia s o ABCDCREST I A autoantibodies I B Bibasilar pulmonary fibrosis I Ccontractures of digital joints I D dermal thickening proximal to wrists Generally 4 of these symptoms must be present in order to be diagnosis involvement of the esophagus leads to hypomotility and difficulty swallowing malabsorption may develop if the submucosal and muscular atrophy affect the intestine pulmonary involvement leads to dyspnea and eventually respiratory failure vascular involvement of the kidneys is responsible for malignant hypertension and progressive renal insufficiency cardiac problems include pericarditis heart block and myocardial fibrosis Diagnosis and Treatment 0 If the heart lung or kidneys are severely damaged it is an indicator that the patient will not survive 0 ACE Angiotensinconverting enzyme inhibitors is a treatment that decreases the mortality resulting from hypertensive renal disease Polymyositis and Dermatomyositis Chronic in ammatory myopathies Pathogenesis Multifactorial and includes cellular and humoral immune mechanisms Systemic Manifestations Common Cardiac and pulmonary complications often adversely affect the outcome Often characterized by muscle weakness muscle tenderness and muscle pain Tr eatment Control in ammation and prevent long term damage to muscles joints and intemal organs Corticosteroids are the mainstay of treatment Seronegative Spondyloarthripathies Has an absence of RF Ankyl Group of multisystem in ammatory disorder that affects axial skeleton particularly the spin People who have semonegative spondylarthirpatheis are at high risk for thyroiditis and should have tests done regularly Pathogenesis None osing Spondylitis Chronic systemic in ammatory disease of the joints in the vertebral column and sacroiliac joints manifested by pain and progressive stiffening of the spine Found in all diseases More common in men then women Manifested in two ways 0 Younger person with AS 0 Peripheral spondyloarthropathy which involves olgoarthritis of the lower limbs with pitting edema Pathogenesis The pathogenesis is unknown however the presence of mononuclear cells in the acutely involved tissue suggests an immune response Genetic and environmental factors play a role in the pathogenesis of the disease 90 of those with the disease have the HLA27 antigen and nearly 100 who have uveitis or aortitis have the marker Theory 1 The gene that determines the HLAB27 antigen may be linked to other genes that determine the increased susceptibility to infections or environmental agents Theory 2 Molecular mimicry An autoimmune reaction to an antigenic determinant site in the host s tissues may occur as a consequence of an immunologic response to an identical antigen of a foreign agent usually an infectious agent Clinical Manifestations Persistent or intermittent low back pain Lumbosacral pain with discomfort in the buttocks and hip areas Loss of motion of the spinal cord Loss of lumbar lordosis Kyphosis of thoracic spine and extension of the neck Shown through Xray Spine fused in the exed position Acute anterior uveitis Diagnosis There are useful measurements for monitoring the disease status such as pressure on the sacroiliac joints Laboratory ndings frequently include elevated ESR XRay images however can sometimes be negative Mobility Treatment 0 Main goal is to control pain and maintain mobility by suppressing in ammation Proper posture and position Sleeping in a supline position on a rm matress and using a small pillow Therapeutic and musclestrengthening exercises Heat applications in the shower or bath Swimming Maintaining an ideal weight NSAlDs reduce in ammation relieve pain and reduce muscle spasm DMARDs are potential secondline therapies however their ef ciency in ankylosing spondylitis is unproven 0 Sulfasalazine and methotrexate have shown effectiveness for peripheral joint involvement 0 AntiTNFa therapies rapidly reduce both axial and peripheral symptoms of ankylosing spondylitis Reactive Arthropathies The infecting agents cannot be cultured and are not viable once they reach the joints Reactive arthritis also has been observed in people who have AIDS Reactive arthritis may also result from the presence of a foreign substance in the joint tissue Reactive arthritis and bacterial arthritis are similar but bacterial can be cultured NSAIDS are used in treating the arthritic symptoms Short antibiotic courses are not useful Reiter Syndrome Clinical manifestation of reactive arthritis Accompanied by extra articular symptom s such as uveitis bowel in ammation carditis Develops in generically susceptible host after bacterial infection due to chlamydia trachomatis genitourinary tract Psoriatic Arthritis Is a heterogeneous disease Occurs in people with psoriasis Pathogenesis ls unknown Genetics amp environment play an important role in the skin ManifestationTreatment There are five subgroups Oligoarticular or asymmetric Spondylarthropathy Polyarticular or symmetric Distal interphalangeal Mutilans Enteropathic Arthritis In ammatory bowel disease Osteoarthritis Syndrome Also called degenerative joint disease In ammation occurs when cartilage attempts to repair itself creating osteophytes It is a disability and pain in older adults It affects men at ages 45 and women at ages 55 Age gender and race all play an important role Obesity is a particular risk factor for OA of the knee Pathogenesis 0 Cause is unknown but biochemical forces that place stress on the joints e g bearing weight are thought to interact with biochemical and genetic factors to contribute to OA 0 Characterized by signi cant changes in both the composition and mechanical properties of cartilage Manifestation 0 Clinical manifestations arise suddenly or insidiously 0 Initially pain describes as aching and difficult to localize o Worsens with use and activity relieved by rest 0 In extreme situations night pain may be experienced during rest Diagnosis amp Treatment There is no cure 0 Treatment symptomatic and includes physical rehabilitative pharmacologic and surgical measures 0 Physical measures improving supporting structures of the joint and strengthening muscles surrounding o Balance rest exercise o Use of splints to protect and support joint o Heat and cold to relieve pain and muscle spasm o Weight reduction o Musclestrengthening exercises 0 Oral medication aim to reduce in ammation or providing analgesia o NSAIDS are popular and are OTC Surgery is considered when there is severe pain and joint function is severely reduced ex hip replacement bunion resections total knee replacement CrystalInduced Arthropathies Metabolic bone and joint disorder result form biochemical and metabolic disorder that affect the joint Crystal deposition in joints produces arthritis Gout Disorder characterized by increased serum uric acid and urate crystal deposits in kidneys and joints More common in older men however young men have it too There are two types Primary and Secondary Gout Primary cause of disorder is unknown or cause is an inborn error in metabolism and is characterized primarily by hyperuricemia and gout 90 of cases more common in men Secondary cause of the hyperuricemia is known but the gout is not the main disorder Pathogenesis Elevation of serum uric acid levels because of enzyme defects Overproduction of purines Decreased salvage of free purine bases Augmented breakdown of nucleic acids Decreased urinary excretion Monosodium urate crystals precipitate in joint initiate the in ammatory response Manifestation 0 1st phase the asymptomatic hyperuricemia not recognizable at this stage no symptoms 0 2nd phase acute gout arthritis monoarticular and usually affect the first metatarsophalangeal for example ankles heels knees wrists and ngers begins at nights onset of pain is abrupt redness and swelling is observed attack may last for days or weeks 0 3rd phase intercritical gout here symptoms go away and joint abnormalities are not evident last for months or years like this 0 4th phase chronic tophaceous gout attacks recur with increased frequency joint changes occur and become permanent 0 Gout has been linked to cardiovascular disease obesity metabolic syndrome and renal insufficiency some people with dyslipidemia also have gout Diagnosis Joint uid analysis arthrocentesis to see whether uric acid crystals are present Tests to measure levels of uric acid in bloodurine XRays may help rule out other types of arthritis Treatment Use ice to reduce swelling Rest the affected joints Take shortterm medicines as prescribed by doctor Oral corticosteroids Colchicine Nonsteroidal antiin ammatory drugs NSAIDs KIDS Juvenile Idiopathic Arthritis gt disease that causes persistent joint pain swelling and stiffness gt manifestations JIA is category of diseases with three types of onset o systemic onset disease daily intermittent high fever rash generalized lymphadenopathy hepatosplenomegaly leukocytosis leukemia o pauciarticular arthritis affects no more than 4 joints positive ANA and HLAB27 test results o polyarticular arthritis affects 5 or more joints gt treatments o rstline drugs NSAIDs O secondline agents lowdose methotrexate sulfasalazine o biologic response modi ers Systemic Lupus Erythematous autoimmune disease characterized by the production of unusual antibodies in the blood gt manifestations re ect the extent and severity of systemic involvement gt treatment NSAIDs corticosteroids antimalarial drugs immunosuppresive agents Juvenile Dermatomyositis rare in ammatory myopathy primarily involving skin and muscle and associated with a characteristic rash gt manifestations symmetric proximal muscle weakness elevated muscle enzymes evidence of vasculitis gt treatment gt corticosteroids to reduce in ammation Juvenile Spondyloarthropathies gt group of rheumatic diseases that typically cause pain and in ammation in the joints in the lower part of the body gt manifests in peripheral joints rst mimicking pauciarticular J IA gt treatment gt physical therapy education attention to school and growth and developent issues gt use of salicylates NSAIDs and biological modi ers Elderly Rheumatoid Arthritis gt chronic progressive disease that causes in ammation in the lining of the joints gt manifestations painful deformity and immobility usually in the ngers wrists feet ankles o there are subsets of RA that could have distinct manifestations courses and outcomes gt treatments o can help relieve pain with pain medications O can go to physical therapy to keep joints exible O can get surgery to x the damaged joint Systemic Lupus Erythematosus gt autoimmune disease characterized by the production of unusual antibodies in the blood 0 body s immune system attacks its own tissues and organs treatmentdepends on each person s case of lupus o common meds used corticosteroids antimalarials aspirin Osteoarthritis gt breakdown of j oint cartilage and the underlying bone o common in weightbearing joints hips knees spine gtgt manifestations pain stif iess swelling p the joints gt Treatment there is no cure but there are wisays to treat the p 0 joint replacement surgery 0 aacetamiriophen NSAlDs narcotics physical therapy mcupational therapy ChrystalInduced Arthropathies Gout Arthritis caused by buildup of uric acid crystals a joint Psesudogout Arthritis caused by sabnormael forrnation of calcium pyrophosphatie CPP crystals oint cartilae gt both are comrnon g elderly people Pcseudiogout Arthritis gt maniifestationsi similar t0 rheumatoid arthritis osteoaartlnitis gout art 0 joint pain swollen joint tendernesss laden ichmnic in amrnation gt treatmentt aims to stop joint in ammatiron O NSAIS 0 removal of the uid that has the crystals 0 cortisone injections 0 colchicine
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