Efnisyfirlit

• Front Matter
  • Dedication
  • Reviewers
  • Contributors
  • Contributors to Methods of Analysis
  • Preface
    • THE FIFTH EDITION TEXTBOOK: WRITTEN AND ELECTRONIC
    • STUDENT READERS
    • ANCILLARIES
      • For the Instructor
        • Evolve
      • For the Student
        • Evolve
  • Acknowledgments
  • Methods of Analysis Available on Evolve
  • Color Plate
    • Color Plate 1 Structure of the antibody molecule. A, In this molecular model of a typical antibody molecule, the light chains are represented by strands of red spheres (each represents an individual amino acid). Heavy chains are represented by strands of blue spheres. Notice that the heavy chains can complex with a carbohydrate chain. B, This simplified diagram shows the variable regions, highlighted by yellow bars that represent amino acid sequences unique to that molecule. Constant regions of the heavy and light chains are marked C. The inset shows that the variable regions at the end of each arm of the molecule form a cleft that serves as an antigen-binding site.
    • Color Plate 2 Binding of antigen by an antibody. This ribbon model of an antibody shows the heavy chains in red and the light chains in yellow. Note the blue antigen molecules bound to each antigen-binding site.
    • Color Plate 3 Model of enzyme action. Enzymes are functional proteins whose molecular shape allows them to catalyze chemical reactions. Substrate molecule AB is acted on by a digestive enzyme to yield simpler molecules A and B as products of the reaction. Notice how the active site of the enzyme chemically fits the substrate—the lock-and-key model of biochemical interaction. Notice also how the enzyme molecule bends its shape in performing its function.
    • Color Plate 4 Three ways to visualize the same folded protein molecule. Three common types of protein models are shown. The ribbon model shows the areas where alpha helices and folded sheets form within the molecule. The space-filling model shows each atom as a “cloud” filing up the space occupied by that atom. The surface-rendering model shows the three-dimensional boundaries of the whole protein molecule, often also color-coding for charge regions on the surface of the protein.
    • Color Plate 5 Hepatitis B virus (HBV) genome organization, map of viral transcripts, and proteins. The partially double-stranded 3.2-kb viral DNA is shown in the inner circle. The single-stranded (ss) region is indicated in yellow-orange. Viral transcripts are indicated in the outermost circles (thin lines). The three forms of HBsAg, HBcAg, and HBeAg (surface, core, and early antigen) polypeptides are also shown.
    • Color Plate 6 Organization of HCV genome and viral proteins.
    • Color Plate 7 Clinical, virological and serological events associated with hepatitis C. A, Acute HCV infection. B, Acute HCV infection with progression to chronic HCV infection.
    • Color Plate 8 Conversion of 7-dehydrocholesterol to activated vitamin D by ultraviolet (UV) light and by liver and kidney.
    • Color Plate 9 Pancreas. A, Pancreas dissected to show the main and accessory ducts. The main duct may join the common bile duct, as shown here, to enter the duodenum by a single opening at the major duodenal papilla, or the two ducts may have separate openings. The accessory pancreatic duct is usually present and has a separate opening into the duodenum. B, Exocrine glandular cells (around small pancreatic ducts) and endocrine glandular cells of the pancreatic islets (adjacent to blood capillaries). Exocrine pancreatic cells secrete pancreatic juice, alpha endocrine cells secrete glucagon, and beta cells secrete insulin.
    • Color Plate 10 Wall of the small intestine. Note folds of mucosa are covered with villi and each villus is covered with epithelium, which increases the surface area for absorption of food.
    • Color Plate 11 Structure of skeletal muscle. A, Skeletal muscle organ composed of bundles of contractile muscle fibers held together by connective tissue. B, Greater magnification of a single fiber showing smaller fibers—myofibrils—in the sarcoplasm. Note the sarcoplasmic reticulum and T tubules forming a three-part structure called a triad. C, Myofibril magnified further to show a sarcomere between successive Z lines (Z disks). Cross striae are visible. D, Molecular structure of a myofibril showing thick myofilaments and thin myofilaments.
    • Color Plate 12 Levels of control. The many complex processes of the body are coordinated at many levels: intracellular (within cells), intrinsic (within tissues/organs), and extrinsic (organ to organ).
• Part 1 Laboratory Techniques and Laboratory Management
  • Chapter 1 Basic Laboratory Principles and Techniques
    • Key Terms
    • PART 1: Basic Laboratory Principles and Techniques
      • BOX 1-1 SECTION OBJECTIVES
    • WATER AS A REAGENT
      • Reagent Grade Water
      • Purification Process
        • Distillation
        • Deionization
        • Reverse Osmosis
        • Ultrafiltration
        • Ultraviolet Oxidation and Sterilization
        • Ozone
      • Grades of Water Purity
      • Storage and Handling of Reagent Water
      • Suggested Uses
      • Quality Control and Impurity Testing
        • Microbial Monitoring
        • Resistivity
        • pH
        • Pyrogens
        • Silica
        • Organic Contaminants
      • System Documentation and Record Keeping
        • BOX 1-1 KEY CONCEPTS
        • BOX 1-2 SECTION OBJECTIVES
    • CHEMICAL LABORATORY SUPPLIES
      • Chemicals
      • Primary Standards
      • Standard Reference Materials
      • Organic Solvents
      • Gases
      • Chemical Safety
      • Desiccants
        • Table 1-1 Some Common Drying Agents (Desiccants)
        • BOX 1-2 KEY CONCEPTS
        • BOX 1-3 SECTION OBJECTIVES
    • LABORATORY PLASTIC AND GLASSWARE COMPOSITION AND CLEANING
      • Tubing
      • Types of Glass
      • Types of Plastic
        • Table 1-2 Types of Commonly Used Glass and Their Properties
      • Cleaning of Glass and Plastic Utensils
        • BOX 1-3 KEY CONCEPTS
        • BOX 1-4 SECTION OBJECTIVES
    • LABORATORY UTENSILS
      • Beakers
      • Funnels
        • Fig. 1-1 Examples of commonly used laboratory utensils. 1, Erlenmeyer flask. 2, Separatory funnel. 3, Round-bottom flask. 4, Beaker. 5, Graduated cylinder. 6, Volumetric flask. 7, Long-stem funnel (filtering). 8, Powder funnel. 9, Buret. 10, Desiccators.
      • Desiccators
      • Graduated Cylinders
        • Fig. 1-2 Example of National Institute of Standards and Technology (NIST) specifications found imprinted on Class A volumetric flasks.
      • Burets
      • Flasks
        • Volumetric Flasks
      • Syringes
        • Table 1-3 Accuracies of Volumetric Flasks
      • Pipets
        • Fig. 1-3 Examples of transfer to deliver (TD) pipets. 1, Mohr. 2, Mohr long tip. 3, Serological. 4, Serological large opening. 5, Serological long tip.
        • Table 1-4 Accuracies (in mL) of Manual Pipets
      • Micropipets
        • Fig. 1-4 Examples of to deliver (TD) pipets. 1, Ostwald-Folin. 2, Class A volumetric.
        • Fig. 1-5 Steps in using Eppendorf type of micropipet. A, Attaching proper tip size for range of pipet volume and twisting tip as it is pushed onto pipet to give an airtight, continuous seal. B, Holding pipet before use. C, Detailed instructions for filling and emptying of pipet tip. Follow manufacturer's complete instructions for care and use of micropipets.
      • Dilutors and Dispensers
    • VOLUMETRIC TECHNIQUES
      • Class A Pipets
        • Fig. 1-6 A, Proper pipetting technique as described in text. B, Example of rubber pipetting bulb used to aspirate sample into pipet.
      • Micropipets
      • General Procedures for Solution Preparation
      • Quality Control of Micropipets, Dispensers, and Dilutors
        • General
        • Quality Control Validation
          • Fig. 1-7 Spectrophotometric apparatus for pipet calibration.
          • BOX 1-4 KEY CONCEPTS
    • UNITS OF MEASUREMENT
      • SI Units
        • Table 1-5 Basic Quantities and Units of the Système International d'Unités (SI)
        • Table 1-6 SI-Derived Units Used in Medicine
        • Table 1-7 SI Prefixes
      • SI Units in the Clinical Laboratory
        • BOX 1-5 SECTION OBJECTIVES
    • MEASUREMENT OF MASS
      • Fig. 1-8 Switching principle of an electronic force compensator balance.
      • Types of Balances
      • Requirements for Operation
        • Table 1-8 Characterization of Types of Balances in Relation to Their Operation
        • Table 1-9 Individual NIST Tolerances for Class S Weights
      • Maintenance Procedures
    • THERMOMETRY
      • Types of Thermometers
      • Calibration of Liquid-in-Glass Thermometers
    • WATER BATHS, HEATING BLOCKS, AND OVENS
    • CENTRIFUGES
      • Types
      • Centrifuge Components
      • Maintenance and Quality Assurance
      • Principles of Centrifugation
        • Fig. 1-9 Examples of balanced and unbalanced loads. A, If it is assumed that all tubes have been filled with an equal amount of liquid, this rotor load is balanced. The opposing bucket sets A-C and B-D are loaded with an equal number of tubes and are balanced across the center of rotation. Each bucket also is balanced with respect to its pivotal axis. B, Even if all the tubes are filled equally, this rotor is loaded improperly. None of the bucket loads is balanced with respect to its pivotal axis. At operating speed, buckets A and C will not reach the horizontal position. Buckets B and D will pivot past the horizontal. Also note that the tube arrangement in the opposing buckets B and D is not symmetrical across the center of rotation.
        • BOX 1-5 KEY CONCEPTS
        • Fig. 1-10 Nomogram for relating relative centrifugal force (RCF) to revolutions per minute (rpm).
        • BOX 1-6 SECTION OBJECTIVES
    • LABORATORY SAFETY
      • General Safety Practices
        • Table 1-10 Classes of Types of Fires
        • Table 1-11 Comparison of Fire Extinguisher Types
      • The Chemical Hygiene Plan
      • Standard Operating Procedures
        • Box 1-1 Elements of a Chemical Hygiene Plan
      • Inventory
      • Storage of Chemicals
      • Labeling and Handling Requirements
        • Fig. 1-11 Identification system of the National Fire Protection Association.
        • Fig. 1-12 Department of Transportation (DOT) labels.
      • Waste and Chemical Control
        • Box 1-2 Compounds That Cannot Be Disposed of in a Drain
      • Protection Against Biohazards and Medical Wastes
        • Universal Precautions
          • Fig. 1-13 Safety blood collection needle and adaptor.
      • Personal Protective Equipment
      • Task Assessment
      • Housekeeping Procedures
        • Fig. 1-14 Biohazard labels.
        • Disposal
        • Vaccination
        • Training
      • Latex Allergy
        • BOX 1-6 KEY CONCEPTS
    • PART 2: Calculations in Clinical Chemistry38–40
    • DILUTION
      • Example
      • Example
      • Example
      • Another Application of Dilutions
      • Exercises
        • Serial Dilution Example
          • Exercises
    • WEIGHTS AND CONCENTRATIONS
      • Definitions and Examples
        • Percent Concentrations
        • Weight per Unit Weight (w/w)
          • Example
        • Volume per Unit Volume (v/v)
          • Example
        • Weight per Unit Volume (w/v)
          • Example
        • Molarity
          • Examples
        • Normality
          • Examples
          • Example
          • Example
        • Specific Gravity
          • Example
      • Exercise
        • Water of Hydration
          • Example
        • Mole Fraction
          • Example
          • Example
          • Example
      • Examples of Calculations
      • Exercises
    • CALCULATIONS BASED ON PHOTOMETRIC MEASUREMENTS (BEER'S LAW)
      • Colorimetry
      • Absorbance and Transmittance
        • Examples
          • Determining Concentrations Using Absorbance (A) Readings
      • Molar Extinction Coefficient
        • Example
        • Example
      • Exercises
    • BUFFERS
      • Examples
    • ENZYME CALCULATIONS
      • Example
      • Example
    • STANDARD CURVES
      • Graphs
      • Exercises
        • Fig. 1-15 Standard curve for glucose analysis: absorbance versus concentration on linear-linear graph paper.
        • Fig. 1-16 Standard curve for glucose analysis: percent transmittance (%T) versus concentration on linear-linear graph paper.
      • Exercises Using One Known Standard Value to Determine Concentrations of Unknowns
        • Fig. 1-17 Standard curve for glucose analysis: percent transmittance (%T) versus concentration on log-linear graph paper.
      • Renal Clearance Test Calculations
      • Examples
      • Timed Urine Tests
      • Examples
    • ADDITIONAL EXERCISES
    • APPENDIX: ANSWERS TO PROBLEMS
    • REFERENCES
    • INTERNET SITES
  • Chapter 2 Spectral Techniques
    • Key Terms
      • BOX 2-1 SECTION OBJECTIVES
    • LIGHT AND MATTER1,2
      • Properties of Light and Radiant Energy
        • BOX 2-1 KEY CONCEPT
        • Table 2-1 Electromagnetic Spectrum
        • Table 2-2 Colors and Complementary Colors of Visible Spectrum
      • Interactions of Light With Matter
        • Photons and Matter Interactions
        • Absorption Process
        • Emission Process
          • BOX 2-2 SECTION OBJECTIVES
    • ABSORPTION SPECTROSCOPY4–11
      • Radiant Energy Absorption
        • Fig. 2-1 Absorption spectrum of oxyhemoglobin.
        • Fig. 2-2 Transmittance of radiant energy through a cuvette. IO is the incident radiation; Is is the transmitted radiation.
        • Table 2-3 Electron Absorption Bands for Representative Chromophores
        • Fig. 2-3 Scale showing relationship between absorbance and percent transmittance.
      • Beer-Lambert Law
        • Fig. 2-4 Relationships of absorbance (A) and percent transmittance (B) to concentration.
        • Fig. 2-5 Effect of stray radiation on true absorbance.
        • BOX 2-2 KEY CONCEPT
        • BOX 2-3 SECTION OBJECTIVES
        • Fig. 2-6 Components of a spectrophotometer. 1, Source of radiant energy; 2, entrance slit; 3, wavelength selector; 4, exit slit; 5, cuvette and cuvette holder; 6, detector; 7, readout device.
      • Instrumentation
        • Single-Beam Spectrophotometer
        • Sources of Radiant Energy
          • Fig. 2-7 Intensity of radiant energy versus wavelength for a variety of light sources.
        • Wavelength Selectors
          • Fig. 2-8 Diagram of a simple light-emitting diode (LED). The electrons flow from the n to the p side and cross the junction underneath when voltage is applied. When they move, the electrons fall into “holes” in the p side. The energy of the “fall” is converted into light. The composition of the p and n semiconducting materials and the applied voltage define the wavelength of the emitted light.
        • Filters
        • Monochromators
          • Fig. 2-9 Idealized distribution of radiant energy emerging from exit slit of wavelength selector. For a filter or a monochromator with entrance and exit slits of equal width, a symmetrical distribution of transmitted energy occurs, as shown.
        • Band Pass
          • Fig. 2-10 Transmission characteristics of several types of optical materials used for cuvettes.
        • Slits
        • Cuvettes
      • Detectors
        • Photomultiplier Tubes
        • Photodiodes
          • Fig. 2-11 Response of cathodes of several photomultiplier tubes to energy of different wavelengths. Sensitivity is expressed as milliamperes of current generated per watt of incident radiation.
          • Fig. 2-12 Schema of photomultiplier tube. Each dynode (electrode used to generate secondary emissions of electrons) is represented by a crescent. Light impinges on each cathode and frees an electron. Electron is drawn toward first dynode (stage) by applied voltage. Secondary electrons are released and are passed on to successive dynodes, which are at increasingly higher voltages, as depicted by the + symbols. Increasing numbers of secondary electrons are generated at each stage. In this diagram, a tenfold amplification of the initial signal is produced at the anode. A photomultiplier tube may increase the signal several thousand–fold.
      • Charge-Coupled Devices
      • Instrument Performance
        • Table 2-4 Guidelines for Photometric Enzyme Instruments
      • Selection of Optimum Conditions and Limitations
        • Fig. 2-13 Schema of idealized absorption spectrum. λ1, λ2, and λ3 represent the absorption bands of a chromophore.
      • Quality Control Checks of Spectrophotometers17
        • Wavelength Accuracy
        • Linearity of Detector Response
        • Stray Radiation
        • Photometric Accuracy
      • Reflectance Spectrophotometry
        • Fig. 2-14 Diagram of reflectance spectrophotometer. 1, Light source; 2, slit; 3, filter or wavelength selector; 4, collimating lens or slit; 5, test surface; 6, collimating lens or slit; 7, detector; 8, readout device.
      • Recording Spectrophotometry
      • Multiwavelength Spectrophotometry22
        • BOX 2-3 KEY CONCEPT
        • BOX 2-4 SECTION OBJECTIVES
    • ATOMIC ABSORPTION23,24
      • Principle
      • Instrumentation
        • Fig. 2-15 Essential components of atomic absorption spectrophotometer. 1, Hollow-cathode lamp; 2, chopper; 3, flame and burner assembly; 4, entrance slit; 5, wavelength selector; 6, exit slit; 7, detector; 8, readout device.
        • Hollow-Cathode Lamp
        • Burner
        • Flameless AA
        • Monochromator and Detector
      • Sources of Error
    • FLAME PHOTOMETRY25
      • Principle
        • Inductively Coupled Plasma Atomic Emission Spectroscopy (ICP-AES)26
    • FLUOROMETRY27–30
      • Principle
        • Fig. 2-16 Schema showing conversion of light energy into different forms of molecular and radiant energy.
        • Fig. 2-17 Absorption (excitation) and emission (fluorescence) spectra of a fluorescent compound.
      • Instrumentation
      • Limitations
        • Fig. 2-18 Essential components of a fluorometer.
      • Time-Delayed Fluorescence30
      • Chemiluminescence31,32
        • Fig. 2-19 Schema showing difference between short- and long-lived fluorescence.
      • Electrochemiluminescence33
      • Fluorescence Polarization28,34,35
        • BOX 2-4 KEY CONCEPT
    • NEPHELOMETRY AND TURBIDIMETRY36–38
      • Principle
        • Interaction of Light With Particles
          • Fig. 2-20 Effect of particle size on scattering of incident light in a homogeneous solution. d, Particle diameter; λ, wavelength of incident light.
      • Detection of Scattered Light
        • Turbidimetry
        • Nephelometry
          • Fig. 2-21 Schema of turbidity measurement. ϑ, Angle of detection.
          • Fig. 2-22 Schema of nephelometric measurements. ϑ, Angle of detection.
          • Fig. 2-23 Schema of basic components of a nephelometer.
          • Instrumentation
            • Schematic Layout of Instruments.
            • Light Source.
        • Angle of Detection39
      • Limitations: Turbidimetry versus Nephelometry
        • Endogenous Color and Choice of Wavelength
        • Comparison of Sensitivity
        • End Point versus Kinetic Analysis
          • Fig. 2-24 Kinetic analysis of light scattering. A, Intensity of scattered light signal versus time. B, Rate of change of scattered light signal versus time.
    • REFRACTIVITY
      • Principle
      • Applications
        • Fig. 2-25 Schema illustrating bending of light when it passes from a medium of one density into a medium of a different density, with an angle of deflection, ϑ1.
      • Interference
        • Fig. 2-26 Schema of an Abbé refractometer.
      • Instrumentation
        • BOX 2-5 KEY CONCEPT
    • REFERENCES
    • BIBLIOGRAPHY
  • Chapter 3 Chromatography: Theory, Practice, and Instrumentation
    • Key Terms
      • BOX 3-1 SECTION OBJECTIVES
    • OVERVIEW OF CHROMATOGRAPHY
      • Branches of Chromatography
      • General Principles
        • Fig. 3-1 Branches of chromatography according to mobile phase and physical apparatus.
        • Fig. 3-2 Branches of chromatography according to mechanism of separation on stationary phase.
      • Resolution, Efficiency, and Speed of Analysis
        • Resolution
          • Fig. 3-3 Separation of a solute, S, by partition into two different solvent systems. In the first system, A, solute has a distribution coefficient, KD, of 1.0, indicating an equal partitioning between upper and lower phases after mixing. In the second system, B, solute has a KD of 9.0, indicating a partitioning of nine parts of the solute in the upper phase and one part of the solute in the lower phase after mixing. Cu, Upper-phase concentration; Cl, lower-phase concentration.
          • Fig. 3-4 Calculation of resolution of sample components actually separated by HPLC. The distances d1 to d3 are the actual amounts of time from injection (↓) to apex of eluting peak for each component, 1 to 3, respectively. Peak widths w1 to w3 are measured by triangulation at the base of each peak for components 1 to 3, respectively. Both d and w must be measured the same way from the time of injection, that is, in units of time (minutes or seconds), length (inches or centimeters), or elution volume (milliliters). Resolution, R, is unitless.
        • Chromatographic Efficiency
          • Fig. 3-5 Model chromatograms exemplifying high-efficiency separations and low-efficiency separations.
        • Retention
        • Selectivity
          • Fig. 3-6 A, Calculation of capacity factor, k, from a highperformance liquid chromatogram (HPLC). Sample was retained by stationary phase and underwent chromatography. B, Calculation of selectivity factor, α, from HPLC chromatogram. Solutes A and B were retained by stationary phase and underwent a chromatographic separation as indicated.
        • Polarity
          • Fig. 3-7 Physicochemical interactions between molecules that constitute concept of polarity. A, Dispersive or van der Waals interactions. B, Dipole interactions. C, Hydrogen bonding. D, Electrostatic interactions.
        • Stationary-Phase Polarity
          • BOX 3-1 KEY CONCEPT
          • Fig. 3-8 Mechanism of separation of a metabolite of methylanisole by silica gel chromatography. Hydrogen bonds, … …; covalent bonds, –.
          • BOX 3-2 SECTION OBJECTIVES
    • MECHANISMS OF CHROMATOGRAPHY
      • Adsorption
        • Fig. 3-9 Mechanism of adsorption chromatography by separation of 3-methylanisole and two of its biochemical metabolites. The most polar sample components, such as 3-methyl-4-hydroxyanisole, are retained the most by polar silica gel stationary phase (heavy arrow). Sample components of intermediate polarity, such as 2,5-dimethoxytoluene, are retained to a much lesser degree (light arrow), whereas relatively nonpolar components, such as 3-methylanisole, are not retained and prefer the nonpolar mobile phase, hexane.
      • Partition
        • Fig. 3-10 Mechanism of liquid-liquid chromatography as exemplified by separation of the monoglycerides, diglycerides, and triglycerides of lauric acid. Silica gel stationary phase has a monolayer of water strongly held by hydrogen bonding. Solute molecules are partitioned between the liquid mobile phase (chloroform : methanol) and the liquid stationary phase, or water monolayer. The most polar sample components, the monoglycerides, are retained most by the polar stationary phase (heavy arrow). Sample components of intermediate polarity, such as the diglycerides, are retained to a much lesser degree (light arrow), whereas relatively nonpolar components, such as the triglycerides, are not retained and prefer the relatively nonpolar stationary phase.
        • Fig. 3-11 Chemical preparation of bonded, stationary phase (reversed phase). Organochlorosilane reacts with nucleophilic hydroxyl (OH) groups of silica gel, forming siloxane covalent bond (Si—O—Si).
        • Table 3-1 Selected Groups of Solutes in Order of Increased Retention in Normal-Phase and Reversed-Phase Chromatography
      • Ion Exchange
      • Gel-Permeation (Molecular or Size Exclusion) Chromatography15
        • Fig. 3-12 Mechanism of size-exclusion chromatography. Stationary phase, in form of porous beads, contains pores of varying diameter. Mobile phase outside and inside pores is the same, except the liquid inside is immobilized. When a sample containing solutes varying from small to large molecules elutes through the column, small molecules penetrate all pores and are retained, thus being eluted later than large molecules, which move only in mobile phase. Molecules of intermediate size penetrate only some pores, thereby being retained to a lesser degree than small molecules.
        • BOX 3-2 KEY CONCEPT
        • BOX 3-3 SECTION OBJECTIVES
    • SAMPLE PREPARATION FOR CHROMATOGRAPHY
      • Nature of Problem
      • Mechanical Methods for Initial Isolation of Analyte
      • Chromatographic Methods for Initial Isolation of Analyte
      • Extraction Methods for Analyte Isolation
      • Processing of Sample Extracts
        • BOX 3-3 KEY CONCEPTS
    • REFERENCES
    • BIBLIOGRAPHY
      • Books
      • Comprehensive Abstracts, Journals, and Series in Chromatography
      • INTERNET SITES
  • Chapter 4 Chromatographic Techniques
    • Key Terms
      • BOX 4-1 SECTION OBJECTIVES
      • Fig. 4-1 Schematic diagram of a column liquid chromatographic system.
    • LIQUID CHROMATOGRAPHY
      • Quantitation
        • Approaches
        • Standardization
          • Fig. 4-2 Calibration curve for theophylline using internal standard technique.
      • Selection of a Chromatographic Mode
        • Size-Exclusion Chromatography
          • Box 4-1 Requirements for Internal Standard (IS) Selection and Use
        • Ion-Exchange Chromatography
        • Adsorption Chromatography
        • Partition and Bonded-Phase Chromatography
        • Reversed-Phase Chromatography9
          • Stationary-Phase Considerations
            • Fig. 4-3 Retention in reversed-phase chromatography is the result of the interaction of the nonpolar portion of the compound such as tyrosine (enclosed in box) with the nonpolar stationary phase. Hydrophilic groups (circled) tend to decrease retention.
            • Fig. 4-4 Schematic diagram of a silica-based octadecyl reversed-phase support that has been end capped. Notice presence of residual silanol groups on surface.
          • Mobile-Phase Considerations
            • Solvent Strength.
            • Ion Suppression.
          • Chromatography of Basic Compounds on Conventional Reversed-Phase Packing Material
            • Fig. 4-5 Change in k as a function of pH for estriol-16αglucuronide and phenol. Decrease in k at pH 2 is attributable to ionization of glucuronic acid; decrease at pH 10 is attributable to ionization of phenolic group.
            • Table 4-1 Useful Buffers for Reversed-Phase HPLC
        • Ion-Pair Chromatography
        • Affinity Chromatography12–14
          • Table 4-2 Biochemical Pairs Used in Affinity Chromatography
        • Chromatography of Enantiomers15
      • Different Types of HPLC Packing Materials
        • Different Supports Addressing Problems of Silica Supports
          • Table 4-3 Reversed-Phase HPLC: General Information and Packing Materials
          • High-Performance Polymeric Supports19
            • Table 4-4 Ion-Exchange HPLC: General Information and Packing Materials
            • Table 4-5 Normal-Phase and Size-Exclusion HPLC: General Information and Packing Materials
          • Other High-Performance Packing Materials
        • High-Speed Analysis
      • Instrumentation
        • Solvent Delivery Systems
        • Sample Introduction Systems
        • Columns and Connectors
        • Detection Systems
          • Absorbance Detection (See Chapter 2.)
          • Electrochemical Detection28
            • Amperometric and Coulometric Detection.
            • Conductivity Detection.
          • Mass Spectrometric Detection
      • Applications
        • BOX 4-1 KEY CONCEPTS
        • Table 4-6 Clinically Relevant Compounds Determined by HPLC
        • BOX 4-2 SECTION OBJECTIVES
    • GAS CHROMATOGRAPHY
      • Fig. 4-6 Basic components of a gas chromatographic system.
      • Molecules That Can Be Separated by Gas Chromatography
        • Temperature Dependence
          • Table 4-7 Differences Between Packed and Capillary Columns
        • Column Performance
      • Mobile-Phase Considerations
        • Table 4-8 Common Carrier Gases
      • Stationary-Phase Considerations
        • Gas-Solid Stationary Phases
        • Gas-Liquid-Solid Supports for GLC
        • Liquid Phases
          • Fig. 4-7 Schema of solid support particle for gas chromatography with liquid stationary-phase coating.
          • Table 4-9 Examples of Commonly Used Stationary Phases and Their Applications
      • Derivatization
        • Fig. 4-8 Tetramethyl derivatization of barbiturate drugs.
      • Selection of a Mobile Phase
      • Components of a Gas Chromatograph
        • Carrier Gas
        • Sample Injection Port
        • Column Tubing
        • Thermal Compartment (Oven)
          • Fig. 4-9 Schema of theoretical separation of four compounds showing varying elution patterns with different temperature programming.
        • Detectors
          • Thermal-Conductivity Detector
            • Fig. 4-10 Schema of thermal-conductivity detector.
            • Table 4-10 Detectors and Appropriate Gases
          • Flame Ionization Detector
            • Fig. 4-11 Schema of flame ionization detector.
          • Nitrogen-Phosphorus Detector
          • Electron-Capture Detector
            • Fig. 4-12 Schema of alkali metal flame detector.
          • Mass Spectrometer as a Detector
          • Fourier-Transform Infrared Spectrometer
          • Chromatogram Readout
      • GC Applications
        • BOX 4-2 KEY CONCEPTS
        • BOX 4-3 SECTION OBJECTIVES
    • MASS SPECTROMETRY33,38,39
      • General Principles
      • Mass Spectrometer
        • Ion Source
          • Fig. 4-13 Electron-impact mass spectrum of cocaine.
          • Fig. 4-14 A quadrupole mass spectrometer.
          • Fig. 4-15 Schema of an ion source.
          • Fig. 4-16 Schema of quadrupole mass filter. A, Ion injection. B, Quadrupole rods. C, Oscillating ion beams. D, Collector.
        • Mass Filter
          • Electronic Separation
            • Fig. 4-17 Schema of 90-degree magnetic sector showing direction focusing of divergent ion beam.
          • Magnetic Separation
          • Magnetic Sector Mass Spectrometry
        • Detectors
      • Creation of Ion Fragments
        • Electron Ionization (EI)
        • Chemical Ionization
      • Mass Fragmentation
        • Fig. 4-18 Electron ionization. F, Fragment; M, molecule; M+, molecular ion.
        • Fig. 4-19 Fragmentation pattern of cocaine.
        • Fig. 4-20 A, Isobutane chemical ionization spectrum of cocaine. B, Methane chemical ionization spectrum of cocaine.
      • Comparison of Electron Ionization and Chemical Ionization
      • Analysis by Mass Spectrometry
        • Full-Scan Analysis
        • Selected Ion Monitoring
        • Quantitation
      • Separation Techniques
        • Gas Chromatography/Mass Spectrometry (GC/MS)
          • Fig. 4-21 Selected ion monitoring plot for quantitation of Δ9-tetrahydrocannabinol in plasma. Undeuterated (d0) and deuterated (d3) drugs were monitored.
          • Fig. 4-22 Diagram of ion-evaporation process.
        • Two-Dimensional GC/MS (2-D GC/MS)
        • Liquid Chromatography/Mass Spectrometry (LC/MS)
          • Atmospheric Pressure Ionization
            • Fig. 4-23 The ion trap mass spectrometer.
        • Solids Probe
      • Other Mass Spectrometers
        • Ion Trap Detector
        • Time-of-Flight MS
        • Tandem Mass Spectrometry
          • Fig. 4-24 Schema of a tandem mass spectrometer (MS/MS). CI, Chemical ionization.
      • Forensic Drug Testing
      • Misconceptions
    • REFERENCES
    • BIBLIOGRAPHY
      • Books
      • Comprehensive Abstracts, Journals, and Series in Chromatography
      • INTERNET SITES
  • Chapter 5 Laboratory Analysis of Hemoglobin Variants
    • Key Terms
      • Methods on Evolve
      • Box 5-1 Clinical Indications for Testing for Hemoglobin Variants and Thalassemias
      • BOX 5-1 SECTION OBJECTIVES
    • DETECTION, IDENTIFICATION, AND QUANTIFICATION OF HEMOGLOBIN FRACTIONS
    • DEVELOPMENT OF HPLC ANALYSIS OF HEMOGLOBIN FRACTIONS
      • Overview of Technology for Detection of Hemoglobin Fractions by HPLC (see Chapter 4)
    • COMPARISON OF DIFFERENT HPLC SYSTEMS FOR HEMOGLOBINOPATHY ANALYSIS
      • General Instrumentation (see Chapter 4)
        • Table 5-1 Comparison of HPLC Systems for Analysis of Hemoglobin Variants
        • BioRad
          • Fig. 5-1 Schematic representation of the performance of automated high-performance liquid chromatography (HPLC) analysis of hemoglobin fractions. Vertical lines on either side of the peaks indicate the manufacturer's assigned “windows” for Hb F, Hb Ao, and Hb A2, respectively.
          • Fig. 5-2 Examples of chromatograms from (A) BioRad on the Variant II, (B) Primus on the Ultra2, and (C) Tosoh on the G7.
        • Primus
        • Tosoh
          • BOX 5-1 KEY CONCEPTS
    • QUANTIFICATION AND IDENTIFICATION OF HEMOGLOBIN FRACTIONS
      • Quantification of Hb A2
        • Box 5-2 Causes for Alterations in Quantity of Hb A2
          • Congenital
          • Acquired
        • BOX 5-2 SECTION OBJECTIVES
      • Quantification of Hb F
        • Box 5-3 Conditions Associated With Elevated Quantity of Hb F
          • Congenital
          • Acquired
        • Table 5-2 Examples of Retention Times for Common Variants
      • Identification and Quantification of Other Hemoglobin Fractions
      • Imprecision and Linearity Studies
      • Advantages and Cautions for the Use of HPLC
      • Use of Retention Times and Peak Quantity and Characteristics for Hb Identification
        • BOX 5-2 KEY CONCEPTS
        • BOX 5-3 SECTION OBJECTIVES
    • ABNORMAL VARIANT FRACTIONS
      • β-Variants
        • Fig. 5-3 Sample chromatograms for (A) a normal adult and (B) a normal neonate on the BioRad Variant II. Time (minutes) represents the retention time (RT) for each fraction to elute. The RT for each fraction is shown at the peak. For the normal adult, the RT for Hb F is 1.12, for Hb A is 2.48, and for Hb A2 is 3.64. For the normal neonate, the RT for Hb F is 1.20 and for Hb A is 2.52. The peak preceding Hb F is the acetylated Hb F (RT ≈0.4). In the absence of Hb A2 the variant system labels the vertical axis as Volts.
        • Fig. 5-4 A, Effect of charge on the proportion of abnormal hemoglobin in individuals heterozygous for 72 stable β-variants. Each data point represents a mean value for a given variant. The solid points (•) denote measurements of Huisman (Am J Hematol 14:393, 1983) with the use of high-resolution chromatography. Substitutions involving a histidine residue were scored as a change of ½ charge. The “−1” group differs significantly from the “+1” group (p < 0.001) and from the “0” group (p ≤ 0.05). B, Effect of α-thalassemia on a proportion of six positively charged β-variants (•) and of two negatively charged variants (o).
      • α-Variants
        • Fig. 5-5 Sample chromatograms on the BioRad Variant II of patients for (A) Hb S trait (αAγA = 0.2%, αAβA = 61.9%, αAδA = 3.8%, αAβS = 34.1%), (B) β-thalassemia trait (αAδA = 5.2%), (C) Hb S/β-thalassemia (αAγA = 7.0%, αAβA = 18.1%, αAδA = 6.4%, αAβS = 68.5%), and (D) homozygous Hb S (αAγA = 6.4%, αAδA = 4.1%, αAβS = 89.5%). Note the sharp peak at the beginning of the chromatograph in 6C. This peak represents contaminating bilirubin. Time (minutes) represents the retention time (RT) for each fraction to elute. The RT for each fraction is shown at the peak.
        • Fig. 5-6 Sample chromatograms on the BioRad Variant II of patients for (A) Hb G-Philadelphia trait (αAγA = 0.2%, αAβA = 79.3%, αAδA = 1.2%, αGβA = 18.8%, αGδA = 0.5%) and (B) heterozygous for Hb G-Philadelphia and α-thalassemia (αAγA = 0.3%, αAβA = 67.9%, αAδA = 0.8%, αGβA = 29.2%, αGδA = 1.1%). Time (minutes) represents the retention time (RT) for each fraction to elute. The RT for each fraction is shown at the peak.
        • Fig. 5-7 Sample chromatograms on the BioRad Variant II of patients for (A) Hb D-Punjab trait (αAγA = 1.1%, αAβA = 56.3%, αAβD = 42.6%), (B) α-thalassemia trait (αAγA = 0.1%, αAβA = 98.0%, αAδA = 1.9%), and (C) heterozygous for Hb D-Punjab trait and α-thalassemia (αAγA = 1.2%, αAβA = 55.4%, αAδA = 0.9%, αAβD = 25.1%). Note the absence of Hb A2 in 7A caused by co-elution of the variant hemoglobin fraction. In the absence of Hb A2 the variant system labels the vertical axis as Volts. Time (minutes) represents the retention time (RT) for each fraction to elute. The RT for each fraction is shown at the peak. The peak seen at RT = 1.30 represents Hb A1c.
    • ABNORMAL QUANTITIES OF HEMOGLOBIN FRACTIONS: THE THALASSEMIAS
      • β-Thalassemia
      • α-Thalassemia
    • INTERACTION OF VARIANTS AND THALASSEMIAS: INTERPRETATION OF CHROMATOGRAMS
      • Fig. 5-8 Sample chromatograms on the BioRad Variant II of (A) an adult with Hb Hasharon trait (αAγA = 0.7%, αAβA = 63.6%, αAδA = 1.8%, αHβA = 21.9%) and (B) a newborn with Hb Hasharon trait (αAγA = 44.3%, αAβA = 34.9%, αHγA = 10.1%, αHβA = 10.7%). Time (minutes) represents the retention time (RT) for each fraction to elute. The RT for each fraction is shown at the peak. The two small, characteristic peaks preceding the Hb Hasharon peak are unknown but may represent the glycated Hb Hasharon. The small, unintegraged peak following Hb Hasharon is presumably the variant Hb A2 fraction, αHδA.
      • Fig. 5-9 Sample chromatogram on the BioRad Variant II of a patient double heterozygous for the α-variant Hb G-Philadelphia and the β-variant Hb S (αAγA = 0.9%, αAβA = 51.6%, αAδA = 2.4%, αGβA = 14.5%, αAβS = 17.6%, αGβS = 14.0%). Time (minutes) represents the retention time (RT) for each fraction to elute. The RT for each fraction is shown at the peak. Note the small, unintegrated peak following Hb GPhiladelphia, which is the variant A2 fraction, αGδA.
      • Fig. 5-10 Sample chromatograms on the BioRad Variant II of patients for (A) Hb E trait (αAγA = 0.7%, αAβA = 66.8%, αAβE = 32.5%) and (B) Hb Lepore trait (αAγA = 1.4%, αAβA = 85.5%, Lepore = 13.1%). Time (minutes) represents the retention time (RT) for each fraction to elute. The RT for each fraction is shown at the peak. Hb Lepore is a δβ-globin chain. Both Hb E and Hb Lepore co-elute with Hb A2.
    • HPLC VS ELECTROPHORESIS METHODS FOR VARIANT DETECTION
      • Box 5-4 Factors* to Be Considered in Hemoglobin Variant Identification
    • QUANTIFICATION OF HB F AND HB A2
    • HEMOGLOBINOPATHY DETECTION PROTOCOL STRATEGIES
      • BOX 5-3 KEY CONCEPTS
    • REFERENCES
    • INTERNET SITES
  • Chapter 6 Electrophoresis
    • Key Terms
      • BOX 6-1 SECTION OBJECTIVES
    • APPLICATION OF ELECTRICAL FIELD TO A SOLUTION CONTAINING A CHARGED PARTICLE
      • Forces on a Particle
        • Fig. 6-1 Application of an electrical field to a solution of ions makes ions move.
      • Mobility of a Particle
      • Effect of pH on Mobility
      • Electrolytes
      • Ion Movement and Conductivity
    • FACTORS AFFECTING MOBILITIES OF MACROMOLECULES
      • Charge and Conformation
      • Ionic Atmosphere and Zeta Potential
      • Relaxation Effect
        • Fig. 6-2 State of charged substances in water solution. A, Small ions (Na+ and Cl−) with associated water molecules (“hydration”). B, Macromolecules in water move with water molecules associated with charged and polar groups on the surface of the macromolecule. Smaller ions of opposite charge also are associated with the charged groups, and these alter the effective charge of the macromolecule to an extent given by the “zeta potential.” This is the effective electrical field strength (potential) of the macromolecule and of any smaller ions embedded in solvent carried along with the macromolecule (“water of hydration”). The zeta potential is measured at the “surface of shear”: the boundary between what moves with the macromolecule and the rest of the solvent. Hydration of the small ions (Fig. 6-2, B) is not shown. Gray area, Water of hydration.
      • Electrophoretic Effect
    • SUPPORT MEDIA
      • Functional Basis
      • Electro-Osmosis
      • Types of Supporting Media
      • Molecular Sieving
        • Fig. 6-3 Polyacrylamide gels are produced by polymerizing a mixture of acrylamide and a bifunctional (cross-linking) acrylamide derivative. The derivative shown is that in common use.
        • BOX 6-1 KEY CONCEPTS
        • BOX 6-2 SECTION OBJECTIVES
        • Fig. 6-4 Part of the data printout from a deoxyribonucleic acid (DNA) sequencing experiment. Each peak is from the fluorescence of a polynucleotide that is one residue (nucleotide) longer than the one that produced the peak to its left and one residue shorter than the polynucleotide that produced the signal to its right. The separation occurs by capillary electrophoresis (Applied Biosystems Prism apparatus) through linear (un–cross-linked) polyacrylamide. Each polynucleotide is terminated by an analog of adenine (A), cytosine (C), guanine (G), or thymine (T) that has a different fluorescence spectrum; these are recorded and identified as they migrate past the detector. The peaks get broader because of diffusion as polynucleotide length (numbers between the DNA sequence at the top and the profiles at the bottom) and electrophoresis time increase.
    • ENHANCED-RESOLUTION TECHNIQUES
      • Discontinuous Buffers
        • Fig. 6-5 “Stacking” of an analyte with a low charge-to-mass ratio, such as a protein in a discontinuous solvent system. The analyte is shown mixed in a solvent with a low(er) conductivity (lower concentration or effective mobility of ions or both) (top). With an electrical field applied, the current must be the same along the path, so the voltage is greater in the low-conductivity region (middle). The analyte has a greater effective mobility than the coion so moves to the boundary between the solutions and concentrates there, until its movement carries the same current as the low- and high-conductivity solutions (bottom).
      • Separations Based on Molecular Size
    • SELECTION OF METHODS AND CONDITIONS
      • Support Media
        • Paper and Cellulose Acetate
        • Gels
        • Starch and Agar
          • Table 6-1 Enhanced-Resolution Techniques
        • Polyacrylamide
          • Table 6-2 Use of Supporting Media in Separation Based on Molecule Size
          • Table 6-3 Common Effects of Electrophoretic Variables on Separation
        • Capillary Electrophoresis
        • Electroblotting
        • Electrochromatography
      • Conditions
        • Horizontal versus Vertical Position
        • Sample Application
        • Current and Voltage Considerations
        • Separation Time
          • BOX 6-2 KEY CONCEPTS
          • BOX 6-3 SECTION OBJECTIVES
    • LOCATING THE ANALYTE
      • Direct Observation
      • Staining
      • Proteins
      • Choice of Stain
        • Table 6-4 Commonly Used Stains and Support Media for Various Substances
      • Other Localization Techniques
    • CLINICAL APPLICATIONS
      • Table 6-5 Common Problems of Electrophoretic Separations
      • Fig. 6-6 Separations of serum proteins with the Beckman-Coulter Paragon CZE 2000. Separation times are 5 to 10 minutes; detection occurs by absorbance at 214 nm. Upper trace, Normal serum protein pattern, with categories of separated proteins identified. Lower two traces, Patterns produced with the use of serum from individuals with acute or chronic inflammatory conditions.
      • BOX 6-3 KEY CONCEPT
    • BIBLIOGRAPHY
    • INTERNET SITES
  • Chapter 7 Immunological Reactions
    • Key Terms
    • BOX 7-1 SECTION OBJECTIVES
    • ANTIGENS
      • Factors Affecting Antigenicity
        • Chemical Nature
        • Size
        • Haptens
        • Complexity
        • Antigenic Determinants
          • Fig. 7-1 Antigen X contains many different antigenic determinants, designated A to Q in this schematic representation. Antibody molecules when combined with antigen X bind to different sites. The maximum number of molecules of antibodies bound in this figure is 3; therefore, the valence is 3.
        • Conformation and Accessibility
        • Foreignness
      • Genetics
        • BOX 7-1 KEY CONCEPTS
        • BOX 7-2 SECTION OBJECTIVES
    • ANTIBODIES
      • Structure
        • H and L Chains
      • Fab and Fc Fragments
        • Fig. 7-2 Diagram of immunoglobulin G (IgG) molecule (immunoglobulin monomer). C, Constant region; COO−, C-terminus of immunoglobulin; H, heavy; L, light; NH3+, N-terminus; S–S, disulfide bonds; V, variable region. Arrows indicate papain and pepsin cleavage sites.
        • Table 7-1 Properties of Human Immunoglobulin Classes
      • V and C Regions
      • Light-Chain Types
      • Heavy-Chain Types
      • Immunoglobulin G
      • Immunoglobulin M
      • Immunoglobulin A
      • Immunoglobulin D
      • Immunoglobulin E
        • Engineered Antibodies
          • BOX 7-2 KEY CONCEPTS
          • BOX 7-3 SECTION OBJECTIVES
    • ANTIGEN-ANTIBODY REACTIONS (see Color Plate 2)
      • Binding Forces
      • Antibody Affinity
      • Heterogeneity of Immune Response
      • Antibody Avidity
        • Fig. 7-3 Binding of antibodies (Ab) present in the same antiserum with different affinities to the same hapten (dinitrobenzene linked to amino group of lysine). A, Ab1 fits with nearly whole hapten and is thus of high affinity. B, Ab2 fits with less of molecule and not so closely and has a moderate binding affinity, whereas (C) the low-affinity Ab3 is complementary in shape to such a small portion of hapten surface that its binding energy is very little above that occurring between completely unrelated proteins. Only a portion of the antibody-combining site is shown.
        • Fig. 7-4 Multivalent bonding of antigen-antibody increases bonding strength. A single bond created by divalent antibody molecules between a single antigenic determinant on two adjacent antigens is much weaker than a binding created by two divalent antibodies bound simultaneously to two unique antigenic determinants on two adjacent antigens. The strength and complexity of this multivalent bonding are described by the term avidity.
      • Cross-Reactivity
      • Genetic Basis of Antibody Diversity
        • BOX 7-3 KEY CONCEPTS
        • BOX 7-4 KEY CONCEPTS
    • ANTIGEN-ANTIBODY PRECIPITATION REACTIONS
      • Precipitation Curve
        • Fig. 7-5 The quantitative precipitin curve in which the amount of antibody-antigen complex that precipitates is plotted as a function of antigen concentration.
        • Fig. 7-6 Representation of sizes of molecular complexes formed at varying ratios of antigen and antibody.
      • Lattice Theory
      • Other Factors Affecting Precipitation
      • Precipitation Reactions in Gel
      • Double Immunodiffusion
        • Fig. 7-7 Depiction of radial protein gradients in Ouchterlony immunodiffusion. Concentric circles represent decreasing protein concentrations. Both antigen (AG) and antibody (AB) diffuse radially from application wells. Precipitation (heavy black arc) occurs at the point of antigen-antibody equivalence. The precipitin line is closer to the well of lower concentration and is concave toward the reagent of higher molecular weight.
      • Radial Immunodiffusion
        • Fig. 7-8 Radial immunodiffusion patterns. The band of precipitation (gray area) extends as a disk from the center of each circular well. The area of precipitation is proportional to the concentration.
        • Fig. 7-9 Graph of the concentration of antigen expressed as milligrams per liter versus the square of the diameter of the precipitin ring. Std, Standard.
      • Other Quantitative Methods
        • BOX 7-4 SECTION OBJECTIVES
    • BIBLIOGRAPHY
    • INTERNET SITES
  • Chapter 8 Immunochemical Techniques
    • Key Terms
    • BOX 8-1 SECTION OBJECTIVES
    • REAGENTS
      • Antibody as Reagent
        • Monoclonal Antibodies
        • Selection
        • Affinity
          • Fig. 8-1 Monoclonal antibody production. Antibody production is initiated by immunization of an animal with antigen. After the immune response, spleen cells are isolated, each of which produces a single, unique antibody. These cells are fused with an immortal myeloma cell line by exposure to polyethylene glycol (PEG). In the culture medium that contains HAT (a mixture of hypoxanthine, aminopterin, and thymidine), unfused myeloma cells, which cannot bypass the metabolic block caused by aminopterin, die. Unfused spleen cells also die naturally after 1 to 2 weeks. Fused cells survive, having the immortality of the myeloma cells and the HAT resistance of the spleen cells. Fused cells then are cultured at high dilution and are selected by screening for secretion of antibodies with the desired characteristics. Eventually, a culture of antibody-secreting cells derived from a single spleen cell produces reagent amounts of monoclonal antibody.
        • Specificity
          • Box 8-1 Examples of Molecules in Biological Fluids Frequently Measured by Immunological Techniques
            • Large Molecules
            • Small Molecules
      • Antigen as Analyte
        • Range of Analytes
        • Sample Types and Stability
        • Immunological versus Biological Quantitation
        • Reference Materials
          • BOX 8-1 KEY CONCEPTS
          • BOX 8-2 SECTION OBJECTIVES
    • QUANTITATION OF ANTIGENS AND ANTIBODIES BY IMMUNOLOGICAL REACTIONS IN GELS
    • IMMUNOFIXATION (WESTERN BLOT)
      • Principles
      • Reagents
        • Fig. 8-2 Diagram of enzyme-linked immunoelectrotransfer blot technique (Western blot). A, Human immunodeficiency virus (HIV)-1 proteins are layered onto a sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE), subjected to electrophoresis, and separated according to their molecular weight. B, The discrete proteins then are electrophoresed (blotted) to a nitrocellulose matrix and are incubated, first with a specimen containing HIV-1 antibody (Ab), which binds to the discrete HIV-1 antigen (Ag) bands. C, Enzyme-labeled antihuman Ab then is added. The excess is washed away, and enzyme substrate is added. D, HIV-1 Ab directed toward discrete HIV-1 antigen bands is present; the discrete bands can be visualized as pigmented bands.
      • Common Pitfalls
      • Test Sensitivity and Interpretation of Results
    • IMMUNONEPHELOMETRY
      • Nephelometry
        • Principles
      • Common Pitfalls
        • Limitations
        • Monoclonal Antibody Reagents
      • Nephelometric Inhibition Immunoassay (NINIA)
        • Principles
          • Fig. 8-3 Digoxin standard curve using nephelometric inhibition immunoassay.
          • BOX 8-2 KEY CONCEPTS
          • BOX 8-3 SECTION OBJECTIVES
    • AGGLUTINATION ASSAYS
      • Principles
      • Factors Influencing Agglutination Reaction
        • Particle Charge
        • Antibody Type
        • Electrolyte Concentration and Viscosity
        • Antigenic Determinants
        • Concentration, Temperature, and Time of Incubation
      • Direct Agglutination
        • Fig. 8-4 Passive (indirect) agglutination reaction. Antigen is adsorbed onto the surface of the carrier particle, which then is agglutinated by antigenspecific antibody.
        • Fig. 8-5 Agglutination-inhibition reaction. Same reaction as that shown in Fig. 8-4, but inhibited by soluble antigen.
      • Indirect Agglutination
      • Agglutination Inhibition
    • ANTIGLOBULIN TESTING
      • Sample Requirements
      • Reagents
        • Fig. 8-6 Direct Coombs' test for antibody to red blood cells.
        • Fig. 8-7 Indirect Coombs' test for antibody.
      • Instrumentation
      • Common Pitfalls
      • Limitations
    • COMPLEMENT-FIXATION ASSAYS
      • Complement Proteins
        • Fig. 8-8 Complement fixation one-stage testing. For measurement of total hemolytic complement, test serum is added as source of complement. For measurement of complement components as complement source, test sera to which purified complement components are added are used; for example, to measure complement component 3, all components except C3 are added in excess to the test serum. Therefore, the reaction is limited only by the concentration of C3 in the test serum.
        • Fig. 8-9 Complement-fixation two-stage testing. Antigen or antibody can be measured by holding constant all but the variable to be tested, in this case, unknown antibody.
      • One-Stage Testing
      • Two-Stage Testing
      • Sample Requirements and Preparation
      • Reagents
      • Limitations
        • BOX 8-3 KEY CONCEPTS
        • BOX 8-4 SECTION OBJECTIVES
    • INDICATOR-LABELED IMMUNOASSAYS
      • Labels
        • Fig. 8-10 Enzyme immunoassay. Sandwich technique with antibody label.
    • IMMUNOMETRIC ASSAYS
      • Principles
        • Heterogeneous, Noncompetitive, Labeled Antibody (Immunometric Technique)
          • Fig. 8-11 Enzyme immunoassay. Detection of immunoglobulin (Ig)E specific for an allergen.
        • Heterogeneous, Competitive-Binding Assays
      • Sample Requirements and Preparation
      • Reagents
        • Solid Phase
        • Substrate
      • Instrumentation
        • Fig. 8-12 Enzyme immunoassay. Competitive binding.
      • Interfering Substances
        • Heterophilic Antibodies (HAMA)
        • Nonspecific Binding
        • Sample Interferences
        • Interferences Affecting the Detection Reaction
      • Common Pitfalls
      • Test Sensitivity and Precision
        • BOX 8-4 KEY CONCEPTS
    • SUMMARY
      • Table 8-1 Summary of Immunological Techniques
    • BIBLIOGRAPHY
      • General
      • Electrophoresis and Immunofixation
      • Nephelometry
      • Fluoroimmunoassays
      • Enzyme Immunoassays
      • Chemiluminescent Immunoassays
      • Precision Profile and Functional Sensitivity
      • Interferences
    • INTERNET SITES
      • General
      • Agglutination and Complement Fixation
      • Precision Profile and Functional Sensitivity
  • Chapter 9 Principles for Competitive-Binding Assays
    • Key Terms
      • BOX 9-1 SECTION OBJECTIVES
    • PROTEIN BINDING AND THE LAW OF MASS ACTION
      • Table 9-1 Specific Binding Proteins Present in Blood or Other Tissues
    • ENDOGENOUS BINDING PROTEINS
      • BOX 9-1 KEY CONCEPTS
      • BOX 9-2 SECTION OBJECTIVES
    • BEHAVIOR OF COMPETITIVE-BINDING ASSAYS
      • Fig. 9-1 Linear dose-response curve for a competitive protein-binding assay. Concentration (M) has been multiplied by 108.
    • COMPETITIVE-BINDING ASSAY FORMATS
      • Heterogeneous Assays
        • Table 9-2 Techniques to Separate Protein-Bound from Free Labeled Ligand
      • Homogeneous Immunoassays
        • BOX 9-2 KEY CONCEPTS
        • BOX 9-3 SECTION OBJECTIVES
    • LABELED LIGANDS
      • Types of Labels
      • Factors Determining Choice of Label
        • Radioisotopes
          • Table 9-3 Some Labels for Competitive-Binding Assays
          • Table 9-4 Fluorophores Used as Labels in Competitive-Binding Assays
        • Enzymes
        • Substrates
        • Fluorophores
        • Luminogens
        • Electrochemiluminescence (ECL)
        • Microparticles
          • BOX 9-3 KEY CONCEPTS
          • BOX 9-4 SECTION OBJECTIVES
    • DETECTION LIMITS (SENSITIVITY)
    • CROSS-REACTIVITY (SPECIFICITY)
      • Table 9-5 Cross-Reactant Binding as a Function of Antibody Affinity
      • Fig. 9-2 Cross-reactivity of caffeine with a polyclonal antibody to theophylline in a homogeneous fluorescent immunoassay. Cross-reactivity is determined at concentrations of theophylline and caffeine required for 50% of the dose response. This is equivalent to 46.5% of the bound label. Refer to Table 9-6 for cross-reactivity data.
      • Fig. 9-3 Cross-reactivity of caffeine with a monoclonal antibody to theophylline in the same immunoassay indicated in Fig. 9-2. Cross-reactivity is determined at 43.2% of bound label, equivalent to 50% B/B0. The figure insert shows dose-response curves after results are reduced and replotted, as described in the Data Reduction section (below).
      • Table 9-6 Caffeine Cross-Reactivity With Polyclonal or Monoclonal Antibodies to Theophylline
    • DATA REDUCTION
      • Fig. 9-4 Functional determination of cross-reactivity in a homogeneous turbidimetric inhibition assay. The observed increase in apparent concentration to a midrange control is measured in the presence of increasing concentrations of 1,3-dimethyluric acid, •; 1-methylxanthine, ▴; 3-methylxanthine, •; and caffeine, □.
      • Table 9-7 Functional and Classical Cross-Reactivity Determinations for an Antitheophylline Monoclonal Antibody
      • BOX 9-4 KEY CONCEPTS
      • BOX 9-5 SECTION OBJECTIVES
    • EXAMPLES OF NON-ISOTOPIC COMPETITIVE-BINDING ASSAYS
      • Heterogeneous Assay Techniques
        • Enzyme-Linked Immunosorbent Assay
          • Table 9-8 Enzyme Labels for Immunoassays
          • Fig. 9-5 Principle of the competitive enzyme-linked immunosorbent assay (ELISA) with the ligand labeled with an enzyme and a typical dose-response curve.
          • Fig. 9-6 Principle of the competitive enzyme-linked immunosorbent assay (ELISA) where the antibody is labeled with an enzyme. This is an immunometric assay.
          • Fig. 9-7 Dose response for an automated chemiluminescent enzyme-linked immunosorbent assay (ELISA) for estradiol. The antiestradiol antibody is coupled to a plastic solid phase while the estradiol derivative is coupled to the alkaline phophatase label.
      • Time-Resolved Fluorescence (see also Chapter 2, p. 60)
        • Fig. 9-8 Capture of biotinylated antipeptide antibody as a function of biotin density in an indirect capture assay, where dK/S is a measurement of reflected light. Streptavidin immobilized to biotinylated latex microparticles is incubated simultaneously with an increasing amount of biotinylated antibody containing 1.2, ▾; 4.3, ▴; 6.0, □; or 10.7, • biotins per molecule of antibody, respectively, and a constant concentration of peptide–alkaline phosphatase conjugate. The complex was retained on a glass-fiber filter and was washed before the addition of substrate.
      • Rapid Assays
    • HOMOGENEOUS ASSAY TECHNIQUES
      • Homogeneous Enzyme Immunoassay
        • Fig. 9-9 Principle of the homogeneous enzyme immunoassay (enzyme-multiplied immunoassay technique, EMIT) and a typical dose-response curve.
        • Fig. 9-10 Inhibition of activity of gentamicin–glucose-6phosphate dehydrogenase conjugate by monoclonal antibody to gentamicin.
        • Fig. 9-11 Dose-response curve for the homogeneous gentamicin enzyme immunoassay.
      • Fluorescence Polarization Immunoassay (see Chapter 2, pp. 61-62)
        • Fig. 9-12 Reaction time course for the cloned-enzyme donor immunoassay digoxin assay method. Response is in the absence, □, and the presence of 1.0, ♦; 2.0, ▴; 3.0, ○; and 4.0 ng, • of digoxin per milliliter of sample.
      • Electrochemiluminescence (see p. 61)
        • Fig. 9-13 Principle of the fluorescence polarization immunoassay (FPIA) and a typical dose-response curve.
        • Fig. 9-14 Simultaneous electrochemiluminescence competitive binding reaction between estradiol and estradiol-labeled Ru(bpy)32+ for antiestradiol binding sites (Step 1) followed by binding of labeled immune complexes to streptavidin-coated paramagnetic particles (Step 2), which then are bound and brought to the elctrode by the magnet (Step 3), where the label is oxidized, thus beginning the cascade of reactions that lead to light emission.
        • Fig. 9-15 Principle of the electrochemiluminescent reaction that follows the competitive binding reaction in Fig. 9-14. Both the label and tripropylamine (TPA) are oxidized simultaneously by the electrode, as shown in Steps 4a and 4b. Both oxidized species react, generating the excited unstable label (Step 5) that emits light when it returns to the ground state (Step 6).
      • Luminescent Oxygen Channeling Immunoassay
        • Fig. 9-16 Principle of the homogeneous luminescent oxygen channeling immunoassay (LOCI) method. Photosensitive dye in the sensitizer (S) particles generates singlet oxygen that reacts with dyes in the chemiluminescer (C) particles paired by antibody-ligand binding. The luminescent light energy produced upon reaction is transferred to a fluorescent dye, which then emits a fluorescent signal (Steps a and d). Steps b and c illustrate the competitive binding reactions and the indirect capture of the antibody-bound biotinylated ligand, thus creating complex aggregates of sensitizer-chemiluminescer particles. The dose reponse is indirectly proportional to the concentration of ligand in the sample. SA, Streptavidin.
      • Microparticle-Based Light-Scattering Inhibition Immunoassays
        • Fig. 9-17 Reaction time courses for a theophylline turbidimetric inhibition immunoassay in the absence, •, and the presence of 2.5, ○; 5.0, □; 10.0, □; 20.0, ▴; and 40.0, ▵ μg of theophylline per milliliter of sample.
    • ATTRIBUTES AND LIMITATIONS OF DIFFERENT APPROACHES TO COMPETITIVE-BINDING ASSAYS
      • Table 9-9 Characteristics of Some Competitive-Binding Assays
      • Table 9-10 Some Potential Immunoassay Limitations and Interferences
      • BOX 9-4 KEY CONCEPTS
    • BIBLIOGRAPHY
      • Immunoassays
      • Enzyme Immunoassay
      • Enzyme-Linked Immunosorbent Assay (ELISA)
      • Homogeneous Enzyme Immunoassay
      • Immunoassay Interference
      • Time-Resolved Fluorescence Immunoassay
      • Light-Scattering Assays
      • Luminescence Immunoassay
      • INTERNET SITES
  • Chapter 10 Laboratory Approaches to Serology Testing
    • Key Terms
    • BOX 10-1 SECTION OBJECTIVES
    • HUMORAL IMMUNE RESPONSE
      • Fig. 10-1 Primary and secondary humoral immune responses. This figure illustrates the typical antibody response to exposure to antigen. Primary humoral immune responses are typified by the appearance of immunoglobulin (Ig)M within the first 3 to 5 days following exposure, followed by IgG production within the first week. Amnestic responses typically are mediated by IgG, which appears earlier (typically within 3 days) and in greater abundance than in a primary response.
      • BOX 10-1 KEY CONCEPTS
      • BOX 10-2 SECTION OBJECTIVES
    • APPLICATION OF SEROLOGY TO CLINICAL MEDICINE
      • Detection of Antibody
      • Agglutination Reactions
      • Immunofluorescence
      • Functional Assays
      • Direct Immunoassays
      • Multiplex and Array Assays
      • Special Considerations
        • Fig. 10-2 Multiplexed serological testing. Multiplexed serological assays can be categorized into two broad categories. A, Microspotted arrays are sandwich immunoassays with individual antigens bound to small areas (<80 μm in diameter) on a polystyrene microchip. A single serum sample then is tested against the entire repertoire of antigens on the chip; antibodies that recognize antigens bind to specific areas of the chip and are labeled with a secondary fluorophore-labeled antibody. The pattern of fluorophore labeling on the chip is read by a laser scanner and is decoded to reveal the antibodies present in the serum sample. B, Bead-based arrays utilize multiple individual antigens bound to microspheres that can be differentiated on the basis of size or fluorophore labeling. Patient antibodies are labeled with a secondary fluorophore-labeled antibody, and the pattern of fluorophore labeling is analyzed by flow cytometry.
        • BOX 10-2 KEY CONCEPTS
        • BOX 10-3 SECTION OBJECTIVES
    • CURRENT CLINICAL APPLICATIONS
      • Syphilis
        • Fig. 10-3 Serological diagnosis of syphilis and neurosyphilis. A, Diagnosis of syphilis in the absence of a detectable organism in a primary lesion depends on serological diagnosis; serodiagnosis begins with a screening test, typically a nontreponemal antibody to demonstrate recent or active infection, and is followed by a treponemal test for specificity. B, Diagnosis of neurosyphilis should begin with a serum rapid nontreponemal test (such as plasma reagin [RPR] or a treponemal test to demonstrate prior exposure to Treponema pallidum. Evaluation of the cerebrospinal fluid (CSF) should begin with a count of nucleated cells in the white blood cells (WBCs) and should be followed by a fluorescent treponemal antibody test (FTA) for maximal specificity. Limited sensitivity of the FTA on CSF (30%) indicates that negative results should be followed by a Venereal Disease Research Laboratory test (VDRL) on CSF. DFA, Direct fluorescent antibody.
      • Lyme Disease
        • Fig. 10-4 Two-tiered serodiagnosis of Lyme disease. Serodiagnosis of Lyme disease is performed in a two-tiered manner to maximize sensitivity and specificity. Screening can be done by indirect fluorescent antibody (IFA) or enzyme-linked immunosorbent assay (ELISA), and negative results are considered to exclude a diagnosis of Lyme disease. Positive results should be followed by Western blot for specificity. Negative serodiagnosis in the setting of high clinical suspicion warrants repeat testing on a new serum sample.
      • Peptic Ulcer Disease
      • HIV
        • Fig. 10-5 Serological diagnosis of human immunodeficiency virus (HIV). Serodiagnosis of HIV begins with a screening assay of either an enzyme-linked immunosorbent assay (ELISA) or a rapid point-of-care device. A positive finding on either of these should be followed by confirmation by Western blot to HIV-1. Negative or indeterminate results should be tested by Western blot against HIV-2 and HIV-1 serotype O, and follow-up testing should be considered in 4 to 6 weeks.
      • Epstein-Barr Virus
        • Table 10-1 Antibody Reactivity to EBV Antigens
      • Congenital (TORCH) Infections
    • CAPSULAR POLYSACCHARIDE ANTIGEN VACCINATION
      • BOX 10-3 KEY CONCEPTS
    • REFERENCES
  • Chapter 11 Measurement of Colligative Properties
    • Key Terms
    • BOX 11-1 SECTION OBJECTIVES
    • COLLIGATIVE PROPERTIES
      • Osmosis
      • Osmolality
      • Osmometry
      • Osmolal Gap
      • Colloid Osmotic Pressure
        • BOX 11-1 KEY CONCEPTS
        • BOX 11-2 SECTION OBJECTIVES
    • PRINCIPLES OF MEASUREMENT
      • Freezing-Point Depression
        • Fig. 11-1 Effect of solute on ice structure. A, Crystal structure of pure water. B, Crystal structure of water with added solute. ○, oxygen atom; ○, hydrogen atom; ○, solute.
      • Vapor-Pressure Depression
        • Fig. 11-2 Effect of solute on vapor pressure. A, Pure solvent. B, Solvent with added nonvolatile solute. •, solute molecule; ○ solute molecule.
        • Table 11-1 Characteristics of Clinical Osmometers
      • Colloid Osmotic Pressure
        • BOX 11-2 KEY CONCEPTS
        • BOX 11-3 SECTION OBJECTIVES
    • CLINICAL USE OF OSMOMETRY AND COLLOID OSMOTIC PRESSURE
      • Plasma Osmolality
        • Osmolar Imbalance
        • Screening for Toxin Ingestion
          • Table 11-2 Toxic Substances Affecting Plasma Osmolality
        • Screening for Mannitol Toxicity
      • Urine Osmolality (see Chapter 30)
      • Stool Osmolality
      • Serum or Plasma Osmolality
        • Table 11-3 Estimated Effect of Anticoagulants on Osmolality (Compared with Serum)
    • COLLOID OSMOTIC PRESSURE
      • BOX 11-3 KEY CONCEPTS
    • REFERENCES
    • INTERNET SITES
  • Chapter 12 Electrochemistry: Principles and Measurements
    • Key Terms
    • Table 12-1 Electrochemical Terms, Units, Constants, Symbols, and Conversions
    • BOX 12-1 SECTION OBJECTIVES
    • POTENTIOMETRIC METHODS
      • Fig. 12-1 Schema of apparatus for potentiometry.
      • Reference Electrodes
        • Fig. 12-2 Reference electrodes. A, Saturated calomel electrode (SCE) with asbestos wick for salt bridge function. B, Silver/silver chloride electrode (Ag/AgCl) with porous Vycor for salt bridge function.
      • Indicator Electrodes
        • Ion-Selective Electrodes
          • Fig. 12-3 Schema of an ion-selective electrode (ISE), external reference electrode, and pH/mV meter.
        • Liquid and Polymer Membrane Electrodes
          • Fig. 12-4 Schema of liquid membrane ion-selective electrode (ISE), where M+ represents analyte cation, and R represents neutral carrier ionophore.
          • Fig. 12-5 Model of K+ complex of valinomycin. Gray region represents K+ ion. Bold oxygens are binding atoms.
        • Solid-State Membrane Electrodes
          • Fig. 12-6 Representative pH electrode.
          • Table 12-2 Ion-Selective Electrodes (ISEs) Used in Clinical Chemistry
        • Glass Membrane Electrodes
          • Fig. 12-7 Schema of gas-sensing electrode for carbon dioxide (CO2).
        • Gas-Sensing Electrodes
      • Care and Methodology
      • Experimental Considerations and Interferences
        • BOX 12-1 KEY CONCEPTS
        • BOX 12-2 SECTION OBJECTIVES
    • VOLTAMMETRIC METHODS
      • Fig. 12-8 Generalized hydrodynamic voltammogram for reduction of Ox to Red. Potential scanned negatively left to right. E1/2 is half-wave potential; il, limiting current.
      • Voltammetry Electrodes
        • Working Electrodes
          • Fig. 12-9 Schema of oxygen electrode. A, Cross-sectional view showing diffusion of oxygen (O2) sample through the membrane. B, View of electrode assembly from bottom.
        • Auxiliary Electrodes
        • Reference Electrodes
      • Oxygen Electrode
        • Fig. 12-10 Schema of glucose electrode.
      • Glucose Electrode
      • Anodic Stripping Voltammetry
        • BOX 12-2 KEY CONCEPTS
        • BOX 12-3 SECTION OBJECTIVES
    • COULOMETRIC METHODS
      • Titration of Chloride
        • BOX 12-3 KEY CONCEPTS
    • MULTIANALYTE ELECTROCHEMICAL CLINICAL ANALYZERS
      • Benchtop Clinical Analyzers
      • Point-of-Care Clinical Analyzers
    • BIBLIOGRAPHY
      • General
      • Potentiometric Methods
      • Voltammetric Methods
      • Coulometric Methods
      • i-STAT
      • Biosensors
      • INTERNET SITES
  • Chapter 13 Molecular Diagnostics
    • Key Terms
    • BOX 13-1 SECTION OBJECTIVES
    • DNA STRUCTURE
      • Mutations and Gene Expression
        • Fig. 13-1 Structure of DNA. DNA molecule is double helix that consists of two sugar-phosphate backbones with four bases—cytosine (C), guanine (G), adenine (A), and thymine (T)—attached. C and G residues and A and T residues on opposite strands pair through hydrogen bonding.
        • BOX 13-1 KEY CONCEPTS
        • BOX 13-2 SECTION OBJECTIVES
    • TECHNIQUES OF DNA ANALYSIS
      • Restriction Digestion and Gel Electrophoresis
      • Southern Transfer
        • Fig. 13-2 Identification by Southern blot hybridization of DNA fragment containing gene X. DNA was digested with restriction endonuclease, and resulting fragments were fractionated according to size by electrophoresis in agarose gel. DNA fragments in gel were denatured and blotted to nitrocellulose filter as a result of flow of buffer through gel and nitrocellulose filter to dry paper towels. Subsequent hybridization of DNA on filter to 32P-labeled gene X probe and autoradiography revealed single DNA fragment containing gene X.
      • Polymerase Chain Reaction (PCR)
        • Fig. 13-3 Schematic representation of the first cycle of a PCR reaction.
      • PCR-Based Techniques and Applications
        • Specific Mutation Detection Techniques
          • Restriction Endonuclease Digestion
            • Fig. 13-4 Restriction endonuclease–mediated detection of the cystic fibrosis (CF) mutation, W1282X. The Mnl1 site is present in the wild-type allele and not in the mutant. −, normal; +/−, heterozygote (carrier); +/+, homozygous (affected).
          • PCR-Mediated, Site-Directed Mutagenesis (PSM)
          • Amplification Refractory Mutation System (ARMS)
          • Allele-Specific Oligonucleotide Hybridization (ASO, or Dot-Blot)
            • Fig. 13-5 PCR-mediated site-directed mutagenesis (PSM)-based detection of the α1-antitrypsin Z mutation. After amplification containing a mismatched base, the Taq1 site is present in the wild-type allele and not in the mutant. −, normal; +/−, heterozygote (carrier); +/+, homozygous (affected).
            • Fig. 13-6 Amplification refractory mutation system (ARMS)-based assay for the connexin26 hereditary deafness allele, 35delG. The primer complementary to the wild-type allele amplifies the wild type, but not the mutant. This result is shown in the top panel of the gel. A second polymerase chain reaction (PCR) is done with a primer complementary to the mutant allele, which amplifies the mutant but not the wild type. The result is shown in the bottom panel of the gel. −, normal; +/−, heterozygote (carrier); +/+, homozygous (affected).
            • Fig. 13-7 Luminex-100 flow cytometry platform. Patient DNA is amplified with a sequence-tagged primer. The denatured polymerase chain reaction (PCR) product is hybridized to dye-labeled microspheres to which allele-specific oligonucleotide probes have been affixed. Fluorescent dye–labeled probes complementary to the sequence tags then are added. The presence of the fluorescent probes is detected by flow cytometry using a red (A) and a green (B) laser.
          • Reverse Dot-Blot
          • Flow Cytometry
            • Fig. 13-8 TaqMan mutation detection. The TaqMan probe hybridizes to the wild-type allele and is degraded by the 5′ to 3′ exonuclease activity of Taq polymerase. The starburst figure depicts fluorescence of the fluorophore (F) after release from the effect of the Quencher (Q). The probe does not bind to the mutant allele, the probe is not degraded, and fluorescence is not observed.
          • Real-Time PCR
          • The 5′ Exonuclease Assay (TaqMan)
          • FRET Probe Analysis
            • Fig. 13-9 Fluorescence resonance energy transfer (FRET) probe-specific mutation detection. Left panel, Both probes form perfectly base-paired double-stranded DNA. Right panel, One probe has a mismatch and melts earlier when the temperature is increased. The starburst figure depicts fluorescence of the second fluorophore (F2) when it is in close physical proximity to the first fluorophore (F1) and can be excited by FRET.
          • MLPA (Multiplex Ligation Probe Amplification)
      • Mutation Scanning Techniques
        • Single-Stranded Conformational Polymorphism (SSCP) Analysis
        • Heteroduplex Analysis
          • Fig. 13-10 Single-stranded conformational polymorphism analysis. Lane 1 depicts a size marker, Lane 2 shows a polymerase chain reaction (PCR) product from a normal control, Lanes 5 and 8 depict PCR products that have identical sequences. Lanes 3, 4, and 6 depict PCR products that have one allele with sequence identical to the control and another allele with a sequence variant, Lane 7 depicts a PCR product from an individual homozygous for a sequence variation.
        • Denaturing Gradient Gel Electrophoresis (DGGE) and Temperature Gradient Gel Electrophoresis (TGGE)
          • Fig. 13-11 Detection of mutations through heteroduplex analysis on MDE gels. Lanes 2, 6, and 7 depict polymerase chain reaction (PCR) products from individuals heterozygous for different sequence variants.
        • Denaturing High-Performance Liquid Chromatography (DHPLC)
        • Protein Truncation Test
          • Fig. 13-12 Denaturing high-performance liquid chromatography (DHPLC). The homoduplex peak elutes at approximately 3.7 minutes. Heteroduplexes elute earlier.
        • DNA Sequencing
          • Fig. 13-13 Protein truncation test. After amplification with a primer containing T7 RNA polymerase promoter and transcription initiation sequences, the polymerase chain reaction (PCR) product is transcribed into RNA, and the RNA is translated into protein in vitro. The protein products are resolved by sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE). Lane 2 depicts a truncated protein caused by a mutation that results in an in-frame stop codon. The asterisk (*) identifies the full-length non-truncated protein.
          • Fig. 13-14 A schematic of fluorescent Sanger sequencing using dye-terminator chemistry. A sequencing primer (5′—) is annealed to the single-stranded template, or the DNA to be sequenced. DNA polymerase extends the primer in the 5′ to 3′ direction. The reaction is carried out in the presence of all four deoxynucleotide triphosphates and all four dideoxynucleotide triphosphates (ddNTPs). The ddATP is labeled (L) with dye 1, ddTTP is labeled with dye 2, etc. After the extension reaction is complete, a collection of fragments is obtained, each ending in a labeled dideoxynucleotide. These products are separated by electrophoresis in a single capillary and are detected with a multiwavelength fluorescence detector. The sequence of the original template is read from the resulting electropherogram.
          • BOX 13-2 KEY CONCEPTS
          • BOX 13-3 SECTION OBJECTIVES
    • CANCER (see also Chapter 53)
      • Oncogenes
      • Tumor Suppressor Genes
      • Familial Cancer Syndromes
      • Sporadic Cancers
        • Table 13-1 Genetic Alterations in Selected Cancers
      • Translocations in Leukemia and Lymphoma
      • Detection of Minimal Disease
        • BOX 13-3 KEY CONCEPTS
        • BOX 13-4 SECTION OBJECTIVES
    • INFECTIOUS DISEASE
      • Table 13-2 Applications of Molecular Diagnosis for Management of Infectious Diseases
      • Table 13-3 Molecular Assays for HIV Detection and Quantification
      • Human Immunodeficiency Virus (HIV) Viral Load and Drug Resistance Testing
        • HIV Viral Load
      • Viral Resistance
      • Viral Phenotyping
        • Table 13-4 Commercially Available Phenotypical Assays for HIV
      • Viral Genotyping
        • BOX 13-4 KEY CONCEPTS
        • BOX 13-5 SECTION OBJECTIVES
    • GENETIC DISORDERS
      • Table 13-5 Molecular Diagnosis of Selected Inherited Diseases
      • BOX 13-5 KEY CONCEPTS
    • FUTURE APPLICATIONS
    • BIBLIOGRAPHY
      • General
      • Cancer Genetics
      • Infectious Disease and HIV
      • Genetics
  • Chapter 14 Therapeutic Drug Monitoring
    • Key Terms
    • FATE OF DRUG AND NEED FOR THERAPEUTIC DRUG MONITORING (TDM)
      • BOX 14-1 SECTION OBJECTIVES
      • Table 14-1 Commonly Monitored Drugs, Recommended Sampling Times, Half-Lives, Therapeutic Ranges, and Critical Values
      • Concept of Therapeutic Range
        • Fig. 14-1 Graph of blood-drug concentrations as function of dose and time. DM, Dose; τ, interval between doses; Cssmax, concentration maximum at steady state; Cssmin, concentration minimum at steady state. In this sample, τ is chosen to be equivalent to the half-life of elimination.
        • Box 14-1 Major Causes of Unexpected Serum Drug Concentrations Outside of the Therapeutic Range
      • LADME System to Describe Drug Disposition
        • Liberation, or Drug Release, from a Dosage Form
        • Absorption
        • Distribution
        • Metabolism
        • Elimination
        • Effects of Biological Variation on LADME
        • Physiological and Pathological Factors Influencing Drug Disposition
      • Blood Levels as Indicators of Clinical Response
      • Blood Levels After Single Dose of Drug
        • Fig. 14-2 Blood level–time curves of a hypothetical drug upon different routes of administration.
        • Fig. 14-3 Influence of liberation process on course of blood level–time curves. I, Fast-dissolving tablet; II, tablet with slower dissolution rate; III, sustained-release tablet; IV, tablet with poor bioavailability.
        • Fig. 14-4 Influence of distribution process on course of blood level–time curves of digoxin. In acute congestive heart failure, a higher blood level is observed because of decreased volume of distribution.
        • Fig. 14-5 Influence of metabolism processes on course of blood level–time curves. Enzyme inhibition and liver damage may greatly increase blood level, whereas enzyme induction may decrease it.
        • BOX 14-1 KEY CONCEPTS
        • BOX 14-2 SECTION OBJECTIVES
        • Fig. 14-6 Influence of elimination processes on course of blood level–time curve of gentamicin. In the presence of renal failure, peak concentration after short-term infusion is higher, and blood level remains elevated with a longer elimination half-life.
    • DOSAGE REGIMENS USED IN ACHIEVING THERAPEUTIC TARGET CONCENTRATION
      • Steady-State Therapeutic Drug Concentrations
        • Box 14-2 Factors Determining an Individualized Dose Size*
      • Dosing Regimens
        • MEC or MIC Method
        • Cssmax, or Peak, Method
        • Cssmax-Cssmin, or Limited Fluctuation, Method
        • Cssav, or Log Dose-Response, Method
        • TW, or Therapeutic Window, Method
          • BOX 14-2 KEY CONCEPTS
          • BOX 14-3 SECTION OBJECTIVES
    • PHARMACOKINETICS
      • First-Order Kinetics
      • Zero-Order Kinetics
        • Michaelis-Menten Kinetics
      • Compartment Models
        • Fig. 14-7 One-compartment model blood level–time curve after extravascular administration, with monoexponential slopes for elimination, ke, and absorption, ka.
      • Terminal Disposition Rate Constant
      • Zero-Time Blood Level
      • Absorption Rate Constant
        • Fig. 14-8 Two-compartment model blood level–time curve after extravascular administration, with monoexponential slopes for slow disposition, β; fast disposition, α; and absorption, ka.
      • Elimination Half-Life
      • Volume of Distribution
        • Fig. 14-9 Scheme of total area under the blood level–time curve. AUC0→∞, Area under curve from time = 0 to time = ∞.
      • Area Under Blood Level–Time Curve
      • Total Clearance
      • Steady State
    • PHARMACOGENOMICS
      • Table 14-2 Valid Pharmacogenomic Biomarkers
      • BOX 14-3 KEY CONCEPTS
      • BOX 14-4 SECTION OBJECTIVES
    • APPLICATION OF PHARMACOKINETICS TO TDM
      • Clinical Assessment
        • Box 14-3 Clinical Settings Requiring Therapeutic Drug Monitoring
        • Application
        • Limitations
      • Assessment by Drug Analysis
        • Fig. 14-10 Scheme to identify cases and situations for which drug monitoring is indicated.
        • Basis for Monitoring
          • Fig. 14-11 Scheme showing optimal sampling times for monitoring for different methods used for dosage regimens.
        • Limitations
        • Sampling
          • Fig. 14-12 Relationship between serum theophylline concentration and effectiveness and toxicity.
        • Frequency of Drug Monitoring
        • Turnaround Times
        • Stat Analyses
          • Box 14-4 Drugs for Which Analyses Should Be Available in the Stat Laboratory
            • Stat Analyses in Suspected Drug Overdose
            • Other Analyses
        • Critical Value Callback
      • Assessment by Pharmacokinetic Calculations
        • Adjustment of Dosage at Steady State
        • Three-Point Method of Sawchuk
        • Bayesian Forecasting
    • QUALITY ASSURANCE
    • FUTURE PROSPECTS
      • BOX 14-4 KEY CONCEPT
    • REFERENCES
    • INTERNET SITES
  • Chapter 15 Clinical Enzymology
    • Key Terms
      • Methods on Evolve Website
      • BOX 15-1 SECTION OBJECTIVES
    • THE NATURE OF ENZYMES
      • Composition and Structure
      • Apoenzymes and Cofactors
      • Catalysts
        • Fig. 15-1 Energy diagram showing reduction in activation energy ΔGEA << ΔGA that occurs for same reaction with and without enzyme catalyst. A, Activated state (also *); EA, enzyme activation; ES, enzyme-substrate complex; G, Gibbs free energy; P, product; S, substrate.
        • Box 15-1 Properties of Enzymes as Catalysts
      • Reactive Sites
      • Specificity of Reaction
      • Subunit Structure
      • Anabolism and Catabolism
        • Table 15-1 Plasma Half-Lives for Clinically Important Enzymes
        • BOX 15-1 KEY CONCEPTS
        • BOX 15-2 SECTION OBJECTIVES
    • ENZYME CLASSIFICATION
      • International Union of Biochemistry (IUB) Names and Codes
        • Table 15-2 Examples of Enzyme Nomenclature
      • Enzyme Commission (EC) Classification
      • Nonstandard Abbreviations
        • BOX 15-2 KEY CONCEPTS
        • BOX 15-3 SECTION OBJECTIVES
    • MEASUREMENT OF ENZYMES
      • Fig. 15-2 A, Typical enzyme reaction with initial lag phase, linear change of absorbance, and final phase of substrate depletion. Enzyme activity is the slope of the linear phase. B, Time course of an enzyme reaction with three different amounts of enzyme present. Curve A has a high activity, B has a medium activity, and C has a low activity. As enzyme activity is increased in an assay system, lag phase decreases, linear phase decreases, and substrate depletion occurs sooner. ΔA, Change of absorbance; ΔT, change of time.
      • Fig. 15-3 Absorption spectrum of 5 × 10−5 M NAD+ in 0.1 M Tris buffer, pH 7.5 (dotted line), and absorption spectrum of 4 × 10−5 M NADH in 0.1 M Tris buffer, pH 9.5 (solid line).
      • Enzyme Assays
      • Principles of Kinetic Analysis
        • Fig. 15-4 A, Relationship of substrate, S, to velocity of reaction. At low substrate concentrations, the rate is first order (linearly dependent) with respect to substrate concentration. At high substrate concentrations, the rate becomes zero order (independent) with respect to substrate concentration. Km, Michaelis-Menten constant; Vmax, maximal rate of reaction. B, Relationship between velocity and substrate concentration for an allosteric enzyme. Presence of positive or negative effectors shifts curve toward the + or − side, respectively.
        • Fig. 15-5 Schematic depiction of first- and zero-order kinetics.
      • Km and Vmax
        • Box 15-2 Derivation of the Michaelis-Menten Equation
      • Determination of Enzyme Activity
        • Units of Activity
          • Fig. 15-6 Graphic representation of linear forms of the Michaelis-Menten equation.
        • Standardization by Extinction Coefficient (see Chapter 1, part B, p. 38)
        • Standardization by a Serum Calibrator
        • Other Units of Concentration
          • BOX 15-3 KEY CONCEPTS
          • BOX 15-4 SECTION OBJECTIVES
    • ANALYTICAL FACTORS AFFECTING ENZYME MEASUREMENTS
      • Fig. 15-7 Enzyme activity as a function of pH. Optimal pH range is 7.8 to 8.2; lower activities are observed at pH < 7.8 and pH > 8.2.
      • pH
      • Buffer
      • Cofactors
      • Activators and Inhibitors
        • Fig. 15-8 The three types of inhibition are shown with use of the Lineweaver-Burk graphic method to demonstrate the effects of types of inhibition of Km and Vmax.
      • Coupling Enzymes
        • Table 15-3 Kinetic Effects of Inhibition
      • Temperature
        • Fig. 15-9 Enzyme activity as a function of temperature of assay. Activity decreases at low temperatures. As temperature is raised, activity increases until rate of denaturation is greater than the increase in activity.
        • Table 15-4 Enzyme Stability under Various Storage Conditions (Less Than 10% Change in Activity)
      • Defining Assay Conditions
      • Enzymes as Reagents
      • Storage of Enzymes
        • BOX 15-4 KEY CONCEPTS
        • BOX 15-5 SECTION OBJECTIVES
    • CLINICAL ENZYME MEASUREMENTS
      • Extracellular versus Cellular Enzymes
    • FACTORS AFFECTING REFERENCE VALUES (see Chapters 18 and 24)
      • Sampling Time
      • Age
      • Sex
      • Race
      • Exercise
        • BOX 15-5 KEY CONCEPTS
        • BOX 15-6 SECTION OBJECTIVES
    • ISOENZYMES (see Chapter 16)
      • Nomenclature
      • Isoforms
        • Table 15-5 CK Isoforms
        • BOX 15-6 KEY CONCEPTS
    • BIBLIOGRAPHY
    • INTERNET SITES
  • Chapter 16 Protein Isoforms: Isoenzymes and Isoforms
    • Key Terms
      • Methods in Evolve
      • BOX 16-1 SECTION OBJECTIVES
    • FUNCTION AND CHARACTERISTICS
      • Protein Isoforms
        • Box 16-1 Examples of Protein Isoforms
      • Properties of Isoenzymes and Isoforms
      • Structural Basis
      • Genetic Basis
      • Post-Translational Modifications
      • Microenvironmental Distribution
      • Macroenvironmental Distribution
        • Table 16-1 Creatine Kinase Activity in Various Human Tissues
      • Lactate Dehydrogenase
      • Creatine Kinase(see Chapter 36 for additional details)
      • Alkaline Phosphatase (ALP)5
      • Developmental Distribution
        • BOX 16-1 KEY CONCEPTS
        • BOX 16-2 SECTION OBJECTIVES
    • CLINICAL SIGNIFICANCE OF ISOENZYMES
      • Change in Isoenzyme Patterns in Pathological Processes
        • Specific Isoenzymes
        • Creatine Kinase (CK)
          • Box 16-2 Skeletal Muscle Conditions Causing Elevations of Serum CK-MB
        • Alkaline Phosphatase (ALP)
        • Lactate Dehydrogenase (LD)
        • Other Isoenzymes
        • Future of Protein Isoform and Isoenzyme Analysis
          • BOX 16-2 KEY CONCEPTS
          • BOX 16-3 SECTION OBJECTIVE
    • MODES OF PROTEIN ISOFORM AND ISOENZYME ANALYSIS (Table 16-2)
      • BOX 16-3 KEY CONCEPT
      • Table 16-2 Modes of Isoenzyme (Isoform) Analysis
    • REFERENCES
    • INTERNET SITES
  • Chapter 17 Interferences in Chemical Analysis
    • Key Terms
    • Fig. 17-1 Absorbance and percentage of transmittance scales juxtaposed.
    • BOX 17-1 SECTION OBJECTIVES
    • LIMITATIONS OF DETECTORS
      • Absorption Spectrophotometer
        • Absorbance Variance
          • Fig. 17-2 Relative absorbance error versus absorbance (A) and percentage transmittance (%T) for a ±1% error in measurement of transmitted light. Relative error is minimum at 36.8% T, and A is 0.434.
          • Table 17-1 Absorbance Error as a Function of Percentage of Transmittance
        • Instrument Limitations
      • Fluorescence Spectrophotometer
        • BOX 17-1 KEY CONCEPTS
        • BOX 17-2 SECTION OBJECTIVES
    • IN VITRO INTERFERENCES
      • Spectral Interferences
        • Absorbance
          • Fig. 17-3 Partial spectrum of oxyhemoglobin (HbO2).
          • Fig. 17-4 Standard curve for measurement of total protein by the biuret reaction: A540 versus concentrations. Solid arrow, A540 for 50 g/L standard; dotted arrow, A540 for same standard containing hemoglobin.
          • Table 17-2 Effect of Turbidity on Measurement of LD Activity, U/L
        • Turbidity
        • Fluorescence
      • Correction of Spectral Interferences
        • Sample Blank
        • Kinetic Measurements
          • Fig. 17-5 Absorbance changes versus time for colorimetric reaction, with and without interferent present. Arrows 1 and 2, Time frame for kinetic analysis; arrow 3, end-point reading.
          • Fig. 17-6 Kinetic analysis of both reactions shown in Fig. 17-5. Change in absorbance (ΔA) per minute versus concentration during linear portion of curve of absorbance versus time between arrows 1 and 2 in Fig. 17-5.
        • Biochromatic Analysis3
          • Fig. 17-7 Spectral curves for chromophore and nonreactive blank, where blank absorbance is equal at λ1 and λ2.
          • Fig. 17-8 Spectral curves of chromophore and interferent, solid line, and background interferents, dotted line. Average of A280 and A320 represents background absorbance at Amax for chromophore (300 nm).
          • Table 17-3 Examples of Chemically Interfering Biochemicals
        • Dilution
      • Chemical Interferences
      • Correction of Chemical Interferences
        • Fig. 17-9 Relative absorbance versus time curves for alkaline picrate reaction, for creatinine (TC), slow-reacting interferents (SR), and fast-reacting interferents (FR). Arrows, Time during which absorbance, over time, primarily reflects change attributable to the TC reaction.
        • Fig. 17-10 Complex reaction of mixture containing fastreacting (FR) and slow-reacting (SR) interferents plus creatinine (TC). Only by measurement of the change in absorbance over time can TC reaction be isolated and SR and FR interferences minimized.
      • Chromatographic Interferences
        • Box 17-1 Interferences Common to Immunoassays
          • Exogenous Interference
          • Endogenous Interference
      • Immunochemical Interferences
        • Box 17-2 Interferences for Enzyme Immunoassays
          • Exogenous Interference
          • Measurement of Enzyme Activity
        • BOX 17-2 KEY CONCEPTS
        • BOX 17-3 SECTION OBJECTIVE
    • IN VIVO INTERFERENCES
      • Drugs
    • SOURCE-REFERENCE MATERIAL
      • Evaluation of Analytical Interference
      • Allowable Interference
        • BOX 17-3 KEY CONCEPTS
    • REFERENCES
    • INTERNET SITES
  • Chapter 18 Sources and Control of Preanalytical Variation
    • Key Terms
      • BOX 18-1 SECTION OBJECTIVES
    • PRECOLLECTION CAUSES OF VARIATION
      • Procedural Errors in Test Order Processing
        • Box 18-1 Standards From the Clinical and Laboratory Standards Institute*
      • Cyclical Biological Variables
        • Fig. 18-1 Diurnal and ultradian pattern of hormone release. Most pituitary hormones show pronounced diurnal variation, with levels generally higher during sleep than during the day. Some, such as growth hormone (illustrated here), are released in episodic bursts during the day. A randomly obtained result is difficult to interpret because it may represent a peak, a trough, or some point between.
        • Table 18-1 Intraindividual Variation for Common Laboratory Tests
      • Patient-Related Physical Variables
        • Fig. 18-2 Effect of exercise on laboratory test results. Data from 750 medical students show that exercise is associated with shifting of the distribution of results to higher values (displayed on x-axis; y-axis represents number of students).
        • Box 18-2 Tests Subject to Diurnal Variation
      • Procedures to Minimize Precollection Errors
        • Improving Order Processing Accuracy
        • Minimizing Patient Preparation Errors
        • Biological Cyclical Variables
          • Box 18-3 Tests Affected by Meals
        • Physical Variables
          • BOX 18-1 KEY CONCEPTS
          • BOX 18-2 SECTION OBJECTIVES
    • BLOOD COLLECTION CAUSES OF VARIATION
      • Blood Collection Technique
        • Fig. 18-3 Schematic of heparinized capillary tubes. Magnet is used to move metal filing back and forth through the sealed tube to mix the blood sample with heparin and, later, to remix the sample before analysis.
      • Sources of Blood Samples
      • Errors Related to Preservatives and Anticoagulants
        • Table 18-2 Commonly Used Anticoagulants and Preservatives and Indications for Their Use
        • Box 18-4 Effects of EDTA Contamination
      • Errors Related to Serum Separator Tubes
        • Fig. 18-4 Vacutainer phlebotomy tubes containing barrier gel (red/gray tops). 1, Tube filled with blood and centrifuged; 2, unfilled tube; and 3, tube filled with blood and not centrifuged. Note the positions of gel before (3) and after centrifugation (1). B, Clotted blood; St, red/gray stoppers; G, barrier gel; S, serum.
      • Errors Related to Faulty Collection Techniques
        • Tourniquets
          • Fig. 18-5 Effects of the application of a tourniquet plus fist clenching (upper panel) and of a tourniquet alone (lower panel) on plasma potassium concentrations. Solid circles represent the patient, and open circles the control subjects. The application of a tourniquet alone had no effect on plasma potassium levels, whereas clenching of the fist as well resulted in a strong increase in these levels in both the patient and control subjects.
        • Hemolysis
          • Box 18-5 Effects of Hemolysis on Chemistry Tests
        • Intravenous Fluid Contamination
      • Errors Related to Patient and Sample Identification
        • Fig. 18-6 Example of a chain-of-custody form.
      • Chain of Custody
      • Procedures to Minimize Phlebotomy-Related Variation
        • Patient Identification
        • Preservatives and Anticoagulants
          • Box 18-6 Tests for Which Separator Gels Are Inappropriate
        • Sample Collection
          • BOX 18-2 KEY CONCEPTS
          • BOX 18-3 SECTION OBJECTIVES
    • POSTCOLLECTION CAUSES OF VARIATION
      • Table 18-3 Effects of Specimen Handling Variables on Blood-Gas Measurements
      • Sample Transportation
        • Errors Related to Sample Transportation
      • Procedures to Minimize Sample-Transportation Errors
        • Sample Preservation During Transportation
        • Use of Mechanical Transporters
        • Transportation to Remote Sites
      • Sample Processing
        • Errors Arising from Incorrect Sample Processing
          • Fig. 18-7 Effect of heparin on potassium in lymphocytic leukemia. The graph represents “serum” potassium concentration obtained during surgery to remove the spleen in a patient with chronic lymphocytic leukemia and white blood count of about 350,000/mm3. Point A represents preoperative serum potassium. The next three points represent specimens obtained through an arterial catheter containing heparin at 1, 2, and 3.25 hours into the surgery. Point B represents serum potassium obtained from the arm opposite the arterial catheter 15 minutes after the previous specimen with “serum” potassium of 11.2 mmol/L.
        • Procedure to Minimize Sample-Processing Errors
      • Sample Storage
        • Errors Arising from Improper Sample Storage
        • Procedures to Minimize Storage Errors
          • BOX 18-3 KEY CONCEPT
          • BOX 18-4 SECTION OBJECTIVES
    • OTHER PREANALYTICAL COLLECTION CONCERNS
      • Urine Collection: Sources of Variation
        • Biological Variables
        • Time of Collection
        • Sample Stability
        • Preanalytical Variation in Other Body Fluids
      • Specimen Collection From Infants
        • Capillary Sampling
        • Blood Collection for Metabolic Diseases
          • Table 18-4 Delta Checks for Analysis
    • COMPUTER-BASED AIDS FOR ERROR DETECTION
      • Table 18-5 Delta Check Values
      • Criteria for Rejection of Specimens
        • Fig. 18-8 Flow chart for delta alerts.
        • BOX 18-4 KEY CONCEPTS
    • REFERENCES
    • INTERNET SITES
  • Chapter 19 Laboratory Management
    • Key Terms
      • BOX 19-1 SECTION OBJECTIVES
    • REGULATIONS
    • CLIA '88
      • Box 19-1 What Every Procedure Manual Must Include
      • OSHA (see pp. 23-31, Chapter 1)
      • Security
      • National Patient Safety Goals
      • Laboratory Emergency Preparedness
        • Table 19-1 The Joint Commission National Patient Safety Goals (NPSG)
      • Laboratory Compliance
        • Table 19-2 Suggested Laboratory Records Retention Schedule
    • HOSPITAL MANAGEMENT STRUCTURE
      • Organization of a Hospital
        • Fig. 19-1 Chart of a hospital organizational structure.
      • Organization of a Clinical Chemistry Laboratory
        • BOX 19-1 KEY CONCEPTS
        • BOX 19-2 SECTION OBJECTIVES
    • GOOD MANAGEMENT SKILLS AND PERSONAL CHARACTERISTICS
      • Fig. 19-2 Organizational chart for a department of pathology.
      • Fig. 19-3 Organizational chart for a chemistry laboratory.
      • Fig. 19-4 Summary chart of Clinical Laboratory Improvement Amendments (CLIA) '88 personnel qualifications for a laboratory director for moderate-complexity testing.
    • COMMUNICATION MANAGEMENT
      • Communication within the Total Organization
        • Fig. 19-5 Summary chart of Clinical Laboratory Improvement Amendments (CLIA) '88 personnel qualifications for a laboratory director for high-complexity testing.
      • Communication within the Laboratory
        • Box 19-2 Desirable Management Skills and Personal Characteristics for Laboratory Managers
    • PERSONNEL MANAGEMENT
      • Staff
        • Box 19-3 Useful Information to Keep in Each Employee's Personnel File
      • Job or Position Description
      • Work Scheduling
      • Continuing Education and Employee Competency
        • Continuing Education
        • Employee Competency
      • Alternative Positions
    • RESOURCE MANAGEMENT
    • FINANCIAL MANAGEMENT
      • Budgeting
        • Table 19-3 Static versus Flexible Budget Analysis
      • Capital Justification
        • Box 19-4 Elements of a Proforma
        • Table 19-4 Example of a Financial Proforma Calculation
        • Table 19-5 Comparison of Outright Purchase* versus Reagent Rental
      • Purchasing
      • Cost Accounting
        • Box 19-5 Direct versus Indirect Costs
          • Direct Costs
          • Indirect Costs
      • Overview of Reimbursement Issues
    • INFORMATION MANAGEMENT
      • Table 19-6 Examples of Laboratory Management Reports Provided by an LIS
      • Financial Performance
      • Productivity
        • Box 19-6 Financial Performance Monitors
      • Test Utilization
      • Turnaround Time
        • BOX 19-2 KEY CONCEPTS
        • BOX 19-3 SECTION OBJECTIVES
    • PERFORMANCE IMPROVEMENT
      • Fig. 19-6 Forms for quality assurance monitoring.
      • Quality Assurance Monitors
        • Patient Test Management
        • Quality Control Assessment
        • Proficiency Testing Assessment
        • Comparison of Test Results
        • Relationship of Patient Information to Patient Test Results
        • Personnel Assessment
        • Communications
        • Complaint Investigation
        • QA Review with Staff
        • QA Records
          • BOX 19-3 KEY CONCEPTS
    • BIBLIOGRAPHY
      • General
      • Regulations
      • Security
      • Hospital Management Structure: Communication management
      • Personnel management
      • Resource management
      • Financial management
      • Continuous quality improvement
      • General Resources
      • INTERNET SITES
  • Chapter 20 Laboratory Automation
    • Key Terms
      • BOX 20-1 SECTION OBJECTIVES
    • LABORATORY PROCESSES
      • Fig. 20-1 Diagram illustrating specimen and information flow between physician and laboratory. The shaded area is that portion of the system that usually is considered part of the laboratory. The lower portion amplifies steps involved in sample processing and analysis.
      • Laboratory Error
      • Goals of Laboratory Automation
        • BOX 20-1 KEY CONCEPTS
        • Box 20-1 General Considerations for Laboratory Automation
        • BOX 20-2 SECTION OBJECTIVES
    • AUTOMATED LABORATORY SYSTEMS
      • General Considerations
      • Laboratory Automation
        • Total Laboratory Automation
      • Modular Integrated Systems (MIS)
      • Stand-Alone Systems: Sample Processing and Archiving
        • Sample Processing
          • Table 20-1 Automated Features of Some Specimen Processing and Archiving Systems
        • Archiving
          • BOX 20-2 KEY CONCEPTS
          • BOX 20-3 SECTION OBJECTIVES
    • AUTOMATION OF CHEMICAL ANALYSIS
      • Reagent Preparation
      • Proportioning of Samples and Reagents
      • Mixing
      • Incubation
      • Sensing
      • Computation
      • Readouts and Result Reporting
        • Readouts
        • Autoverification
        • Results Reporting
      • Troubleshooting and Training
        • BOX 20-3 KEY CONCEPTS
        • BOX 20-4 SECTION OBJECTIVE
    • CONCEPTS OF AUTOMATION: DEFINITIONS
      • Test Repertoire
      • Random Access
      • Discrete
      • Batch Analyzer
      • Dwell Time
      • Throughput
      • Stat. Testing
        • BOX 20-4 KEY CONCEPTS
        • BOX 20-5 SECTION OBJECTIVES
    • AUTOMATED CLINICAL CHEMISTRY INSTRUMENTS
    • AUTOMATED IMMUNOCHEMISTRY INSTRUMENTS
      • Multiplex Testing
    • TRENDS IN AUTOMATION
      • Table 20-2 Comparison of Operational Features for Some Chemistry Analyzers
      • Table 20-3 Comparison of Operational Features for Some Immunochemical Analyzers
      • BOX 20-5 KEY CONCEPTS
    • REFERENCES
    • BIBLIOGRAPHY
  • Chapter 21 Point-of-Care (Near-Patient) Testing
    • Key Terms
      • BOX 21-1 SECTION OBJECTIVES
      • Box 21-1 Names for Point-of-Care Testing
      • BOX 21-1 KEY CONCEPTS
      • BOX 21-2 SECTION OBJECTIVES
    • USE OF POINT-OF-CARE TESTING
      • Driving Forces and Potential Benefits
        • Table 21-1 Potential Benefits of Point-of-Care Testing
      • Perception versus Reality
      • Immediate Medical Management Benefits
        • Table 21-2 Critical Care Profiles
      • POCT Limitations
        • BOX 21-2 KEY CONCEPTS
        • BOX 21-3 SECTION OBJECTIVES
    • IMPLEMENTATION AND MONITORING OF POCT
      • Regulations (see also Chapter 19)
      • Training
        • Box 21-3 CLIA '88 Provider-Performed Microscopy
        • Box 21-4 Policies and Procedures Needed for POCT
        • Box 21-5 Record Keeping of POCT Information
        • Box 21-6 POCT Training Form Agenda
        • Box 21-2 CLIA '88 Waived Tests*
          • General Chemistry
          • Cardiac Marker, Tumor Marker, and Other
          • Endocrinology
          • Toxicology and Therapeutic Drug Monitoring
          • Urinalysis
          • Hematology
          • Infectious Disease
        • Box 21-7 Total Quality Management for POCT
      • Coordination of Central Laboratory Testing and POCT
        • Table 21-3 Point-of-Care Testing Committee Responsibilities
        • Box 21-8 Questions to Be Asked Before Implementation of New POCT
        • BOX 21-3 KEY CONCEPTS
        • BOX 21-4 SECTION OBJECTIVES
    • COMPLIANCE MONITORING
      • Table 21-4 Compliance Monitoring of Point-of-Care Testing
      • Box 21-9 Compliance Reports Indicators
      • Box 21-10 Quality System Essentials
    • QUALITY CONTROL OF UNIT-USE DEVICES
    • DATA MANAGEMENT AND CONNECTIVITY
    • TECHNOLOGY USED IN POCT
      • Box 21-11 “Ideal” Point-of-Care System Testing Characteristics
      • Non–Instrument-Based Systems
        • Table 21-5 Noninstrumental Technology Employed in POCT
      • Instrument-Based Systems
        • Box 21-12 Ideal POCT Analyzer QA/QA Software
        • Table 21-6 Current Technology Employed in Instrument-Based POCT
      • Noninvasive/Minimally Invasive Technology
        • BOX 21-4 KEY CONCEPTS
    • REFERENCES
    • INTERNET SITES
  • Chapter 22 Laboratory Information Systems
    • Key Terms
    • BOX 22-1 SECTION OBJECTIVES
    • LIS CHARACTERISTICS
      • Overall Functions
        • Box 22-1 Laboratory Information System (LIS) Functions
          • Preanalytical
          • Analytical
          • Postanalytical
    • LIS ROLE IN PREANALYTICAL ACTIVITIES
      • Patient Demographics
      • Order Entry
        • Box 22-2 Data Acquired During Order Entry Process
      • Phlebotomy
        • Fig. 22-1 An example of a bar-coded specimen label. The specimen number (M48484) is bar-coded. The patient number, patient demographics, time/date, and test are written in human readable form. The label is perforated, so it can be applied to both the primary specimen tube and its aliquoted (ALIQ) samples.
      • Bar Codes
        • Fig. 22-2 A draw list using bar-coded specimen labels. The labels bar-code the specimen number—one for each collection tube type. Aliquot labels are available on the left of the bar-coded specimen label.
        • BOX 22-1 KEY CONCEPTS
        • BOX 22-2 SECTION OBJECTIVES
    • LIS ROLE IN TESTING AND ANALYSIS
      • Instruments and Interfaces
      • Total Laboratory Automation (See also Chapter 20.)
      • Integrating Off-Site Testing (See Chapter 21.)
      • Results Entry
        • Automated
        • Manual
        • Data Verification
          • Box 22-3 Some Rules Used in Autoverification
        • Autoverification
          • BOX 22-2 KEY CONCEPTS
          • BOX 22-3 SECTION OBJECTIVES
    • LIS ROLE IN POSTANALYTICAL ACTIVITIES
      • Results Reporting
        • Box 22-4 Required Patient Report Information
      • Quality Control (See also Chapter 25.)
        • Fig. 22-3 A tabular patient report, printed by the Sunquest LIS.
        • Fig. 22-4 A tabular laboratory results screen on the Cerner EMR.
        • Fig. 22-5 A nontabular patient report, printed by the Sunquest LIS.
        • Fig. 22-6 A nontabular laboratory results screen on the EpicCare EMR.
      • Quality Assurance and Management Reporting (See also Chapters 18, 19, and 25.)
        • BOX 22-3 KEY CONCEPTS
        • BOX 22-4 SECTION OBJECTIVES
    • LIS TECHNOLOGY AND ITS MANAGEMENT
      • Computer Networks, the Internet, and Intranets
        • The Internet Browser14
          • Table 22-1 Popular Internet URLs
      • Maintenance
      • Privacy and Data Security
      • Regulatory Requirements, Software Validation, and Disaster Recovery
        • Box 22-5 Areas of Testing for Software Validation
    • MISCELLANEOUS
      • Role of the LIS With Other Hospital Computers
        • Fig. 22-7 The interchange of information between computer systems in a hospital environment. Most laboratory computer systems today are expected to interact with hospital administrative, financial, nursing, and other departmental systems. In an integrated system environment, blocked functions are modules. In an interfaced environment, blocks represent individual systems.
      • Future Directions
        • BOX 22-4 KEY CONCEPTS
    • REFERENCES
  • Chapter 23 Laboratory Statistics
    • Key Terms
    • BOX 23-1 SECTION OBJECTIVES
    • POPULATION DISTRIBUTIONS
      • Populations and Samples
      • Frequency Distributions
        • Fig. 23-1 A, Histogram (frequency distribution) of glucose results obtained from 20 repetitive measurements of the same specimen using bin width 40 mg/L. B, With N = 100 and bin width = 20 mg/L. C, With infinite N and bin width = 10 mg/L. D, Normal probability plot of glucose results obtained as described in C.
        • Fig. 23-2 Normal (gaussian) distribution, symmetrical about the mean.
        • Fig. 23-3 Non-normal distribution.
        • BOX 23-1 KEY CONCEPTS
        • BOX 23-2 SECTION OBJECTIVES
    • BASIC DISTRIBUTION STATISTICS
      • Measures of Central Tendencies
        • Fig. 23-4 Bimodal distribution.
      • Measures of Variation
        • Mean
        • Median*
        • Mode
        • Measures of Variance
      • Confidence Intervals
        • Fig. 23-5 Perfect normal distribution, with a mean = 0, indicating the percentage of results that are in each standard deviation interval between −4 and +4 standard deviations.
        • Table 23-1 Critical Values of t for Selected Probabilities, p, and Degrees of Freedom, df
        • Fig. 23-6 One-sided versus two-sided t-values. t-values used to calculate 90% interval and 95% one-sided limits are the same.
      • Measures of Accuracy and Precision
        • Fig. 23-7 Frequency distributions for three methods using the same means, but different distributions. 1 has the narrowest distribution, whereas the distribution of 3 is wider than that of 2.
        • Fig. 23-8 Frequency distribution for replicate analysis by two different methods, 1 and 2. These two methods are equally precise (σ1 = σ2) but are biased in relationship to each other (1 does not equal 2).
        • Fig. 23-9 Xs on these targets each denote the true value for a sample. The dots shown on each of the circles A to C denote the results of three replicate analyses by three different methods: A, imprecise but accurate; B, precise but inaccurate; C, accurate and precise.
        • BOX 23-2 KEY CONCEPTS
        • BOX 23-3 SECTION OBJECTIVES
    • PARAMETRIC COMPARISONS OF POPULATIONS
      • The Null Hypothesis and Statistical Significance
      • Two Hypotheses
        • Degrees of Freedom
          • Table 23-2 Critical Values of F for p = 0.05 and Selected Degrees of Freedom, df
      • Comparison of Random Variation (Precision)—The F-Test
      • Comparison of Means (Accuracy or Bias)— The t-Test
        • Hypothesis Testing
        • Unpaired t-Test
        • Paired t-Test
      • One-Way Analysis of Variance (ANOVA)
      • Testing a Sample for Outliers Using the Gap Test (see also p. 426)
        • BOX 23-3 KEY CONCEPTS
        • BOX 23-4 SECTION OBJECTIVES
    • NONPARAMETRIC COMPARISONS OF POPULATIONS
      • Nonparametric Distribution Statistics
      • Sign Test
        • Table 23-3 Exact Confidence Limits for Np (Binomial Distribution), p = 0.05; N = 0 to 99
        • Table 23-4 Acceptance Region for the Rank Sum T (Mann-Whitney-Wilcoxon 2-Sample Test), p = 0.05
      • Mann-Whitney Rank Sum Test (See Example 8.)
      • X2 (Chi-Square) Analysis
        • Table 23-5 Critical Values for Chi-Square
        • BOX 23-4 KEY CONCEPTS
        • BOX 23-5 SECTION OBJECTIVES
    • LINEAR-REGRESSION AND CORRELATION
      • Fig. 23-10 A, Gaussian distributions of y values around simple linear-regression line. B, Gaussian distribution around Deming regression.
      • Basic Statistics of Simple Linear Regression and Correlation
      • Testing for Outliers Using Residual Analysis
      • Limitations of Simple Linear Regression Analysis
        • BOX 23-5 KEY CONCEPTS
    • REFERENCES
    • BIBLIOGRAPHY
    • INTERNET SITES
  • Chapter 24 Reference Intervals and Clinical Decision Limits
    • Key Terms
      • BOX 24-1 SECTION OBJECTIVES
    • DEFINITION OF REFERENCE INTERVAL
    • TERMINOLOGY
      • Fig. 24-1 Perfectly separated test result distributions of healthy and diseased populations. This clear separation rarely occurs in reality.
      • Fig. 24-2 Usual test result distributions of healthy and diseased populations in which an overlap between the two occurs.
      • Fig. 24-3 Degree of test result overlap does not permit differentiation between healthy and diseased populations.
    • PROTOCOL OUTLINE FOR OBTAINING REFERENCE VALUES AND ESTABLISHING HEALTH-ASSOCIATED REFERENCE INTERVALS1
      • Box 24-1 Protocol Outline for Obtaining Reference Values and Reference Intervals
    • SELECTION OF REFERENCE INDIVIDUALS
      • Box 24-2 Examples of Possible Exclusion Criteria
      • Box 24-3 Examples of Possible Partitioning Factors
      • BOX 24-1 KEY CONCEPTS
      • BOX 24-2 SECTION OBJECTIVES
      • Box 24-4 Examples of Preanalytical Variables
        • Subject Preparation
        • Specimen Collection
        • Specimen Handling
    • PREANALYTICAL AND ANALYTICAL VARIABLES
    • ANALYTICAL METHOD CHARACTERISTICS
    • ANALYSIS OF REFERENCE VALUES
      • Statistical Methods
        • Table 24-1 Frequency Distributions of Calcium Levels in 240 Medical Students, by Sex
      • Confidence Intervals (see p. 421, Chapter 23)
        • Table 24-2 90% Confidence Intervals for Lower and Upper 95% Reference Limits
      • Treatment of Outlying Observations (see also p. 429, Chapter 23)
    • PARTITIONING OF REFERENCE VALUES
      • Box 24-5 Calculation of a z Statistic to Test for Subclass Difference
    • TRANSFERENCE
      • BOX 24-2 KEY CONCEPTS
      • Box 24-6 Factors to Consider for Transference of Reference Intervals
      • BOX 24-3 SECTION OBJECTIVES
    • PRESENTATION OF REFERENCE INTERVALS
    • INTRAINDIVIDUAL REFERENCE INTERVALS
    • CLINICAL DECISION LIMITS
      • Predictive Value Theory
        • Table 24-3 Purposes for Which Laboratory Tests Are Ordered and the Importance of Reference Intervals in Interpretation of their Results
        • Fig. 24-4 Percent diagnostic efficiency versus combined cutoff levels of creatine kinase (CK)-MB in ng/mL (lower set of values on x-axis) and percent relative index (upperset of values on x-axis), expressed as (CK-MB/total CK) × 100. Combining these two tests at different respective cutoff levels produced the highest diagnostic efficiency, 90%, at a cutoff of 5 ng/mL for CK-MB and 3% for the relative index.
        • Table 24-4 Sensitivity, Specificity, Predictive Value
      • Medical Decision Limits
      • Receiver-Operating Characteristic Curve
        • Fig. 24-5 Receiver-operating characteristic (ROC) curves showing discrimination between subjects with and without any coronary artery disease as measured by cardiac catheterization for two different biochemical indicators.
        • Fig. 24-6 Modified Gerhardt plots for serum amylase, lipase, and in the diagnosis of acute pancreatitis. See text for details.
        • Fig. 24-7 Percent diagnostic efficiency plotted versus different diagnostic cutoff levels in nanograms per milliliter for a hypothetical immunochemical serum creatine kinase (CK)-MB assay. The highest diagnostic efficiency, 90%, at the lowest cutoff, 5 ng/mL, for CK-MB is the optimal decision level.
        • BOX 24-3 KEY CONCEPTS
    • REFERENCES
    • INTERNET SITES
  • Chapter 25 Quality Control for the Clinical Chemistry Laboratory
    • Key Terms
      • BOX 25-1 SECTION OBJECTIVES
    • GOALS FOR A QUALITY CONTROL PROGRAM
      • Setting Goals
      • Total Allowable Error
        • Example
          • Table 25-1 Performance Specifications for Total Error (%)*
      • Performance Required for Proficiency Testing
        • Table 25-2 CLIA Required Performance on Proficiency Testing (Federal Register, February 28, 1992)
      • Medical Decision Limits
      • Meeting Medical Usefulness Criteria by Calculating the Significant Change Limit
        • BOX 25-1 KEY CONCEPTS
        • BOX 25-2 SECTION OBJECTIVES
    • CONTROL OF QUALITY (PROCESS CONTROL) AND ERROR DETECTION
      • Levels of Activity in the Control Process
        • Table 25-3 Calculation of Quality Control Parameters
      • Testing Quality Control Specimens—Daily Decision Making
      • Quality Control Mechanics
        • How to Choose a Quality Control Pool
          • Table 25-4 Comparison of Quality Control Materials
      • Preliminary Considerations for Estimating Limits for Quality Control Pools
      • A Simple Method for Establishing Average Temporary Target Values for Quality Control Pools
      • Calculation of the Usual Standard Deviation
      • Setting the Action Control Limits for Each Level of the Control Pool
      • Setting Quality Control Limits by Power Curves
        • Fig. 25-1 Levey-Jennings plot of quality control values. Quality control (QC) actions (testing personnel documentation of how all out-of-control values were resolved): Days 5 through 7 represent a shift from the target value (monitor carefully). Days 6 through 10 demonstrate a gradual trend toward higher values. Day 10 patient results were not reported—an unresolved problem (one control >3 standard deviations [SD]), probably need a new bottle of calibrator. On day 11, recalibrated using new bottle of calibrator. Control values are now in control range; patient specimens from day 9 were retested. Day 13 begins a shift to lower values. This shift was investigated on day 20 when one control was low by more than 3 SD. Recalibration on day 21 resolved the problem because values were nearer to the target value. Days 23 through 26 showed increased imprecision. On day 27, cleaning the flow cell resolved the problem; however, the low bias was still present. General note: When this method shows acceptable imprecision, the values are below the target. It was subsequently determined that the manufacturer's target value for this QC pool was inaccurate. Proficiency results from testing performed on March 16 were within 0.01 mg/dL from all participants' target values. After this documentation, the laboratory director approved a new target value for this QC pool.
        • BOX 25-2 KEY CONCEPTS
        • BOX 25-3 SECTION OBJECTIVES
    • DETECTION AND RESOLUTION OF QUALITY PROBLEMS
      • The Out-of-Control Decision
      • Detection of Quality Problems
        • Computer Assistance
        • Levey-Jennings Plots41,42
      • Using Patients' Data in Decision Making
        • Pattern of Patients' Results
          • Table 25-5 Use of Patient Data in Daily Quality Control
        • The Delta Check
        • Specimen Indices and Instrument Flags
      • Actions to Bring a Testing System Back Into Control
        • Example
      • Actions to Be Taken When a Method Is Out of Control
        • Fig. 25-2 Multiple analyte daily quality control check-off record. As each control is reported, it is quickly logged on a data sheet. Notes on out-of-control values and actions taken are included. A daily value for quality control calculation is selected through the use of a random number table basis.
      • Procedures to Follow During a Testing System Failure
        • BOX 25-3 KEY CONCEPTS
        • BOX 25-4 SECTION OBJECTIVES
    • CALIBRATION AND QUALITY CONTROL
      • Use of Calibrators
      • A Practical System for New Calibrator Verification
      • Quality Control of Reagent Changes and Instrument Maintenance
    • EXTERNAL QUALITY CONTROL PROGRAMS AND OTHER TOOLS FOR ACCURACY CONTROL
      • Accuracy Control Is Required by CLIA '88
        • Table 25-6 Partial List of CMS (HCFA)-Approved Providers of Proficiency Testing Programs for CLIA '88
      • Definitive and Reference Methods
        • Table 25-7 NRSCL Definitive and Reference Methods
      • Reference Materials
      • Selection of a Reference Laboratory for Assistance in Accuracy Control
      • Manufacturer's Responsibility in the Control of Testing Systems
      • Automated Quality Control Initiatives
      • Frequency of Calibration, Reagent Systems, and QC
        • Table 25-8 Theoretical Test to Reportable Ratios on an Automated Chemistry/Immunochemistry Analyzer Based on 31-Day Onboard Reagent and Calibration Stability*
      • Electronic Quality Control (see also p. 388, Chapter 21)
        • BOX 25-4 KEY CONCEPTS
    • REFERENCES
    • Bibliography
    • INTERNET SITES
  • Chapter 26 Evaluation of Methods
    • Key Terms
    • BOX 26-1 SECTION OBJECTIVES
    • PURPOSE OF METHOD EVALUATION
      • Laboratory Requirements
      • Manufacturer Requirements
        • Box 26-1 Scope of Method-Evaluation Studies
      • Medical Requirements
        • Table 26-1 Three-Tiered Analytical Performance Specifications
      • Performance Standards Based on Proficiency Testing
        • BOX 26-1 KEY CONCEPTS
        • BOX 26-2 SECTION OBJECTIVES
    • SELECTION OF METHODS
      • Evaluation of Need
        • Table 26-2 Comparison of Allowable Error as Speci. ed by CLIA '88 vs That Recommended by Fraser et al Based on Biological Variability
        • Box 26-2 Steps in the Selection Process
      • Application Characteristics
        • Box 26-3 Application Characteristics
      • Method Characteristics
      • Analytical Performance Characteristics
        • BOX 26-2 KEY CONCEPT
        • BOX 26-3 SECTION OBJECTIVES
    • LABORATORY EVALUATION OF A METHOD
      • Familiarization
      • Stability
      • Analytical Measurement Range (Linearity)
      • Random and Systematic Error
        • Fig. 26-1 Constant and proportional errors.
        • BOX 26-3 KEY CONCEPTS
        • BOX 26-4 SECTION OBJECTIVES
    • EXPERIMENTS TO ESTIMATE MAGNITUDE OF SPECIFIC ERRORS
      • Fig. 26-2 Specific evaluation experiments for estimating specific types of analytical error.
      • Random Error Estimated from Replication Studies
      • Constant Error Estimated from Interference Studies
      • Proportional Error Estimated from a Recovery Experiment
      • Error Caused by Nonlinearity
        • Fig. 26-3 Illustration of different aspects of analytical sensitivity or detection limits.
      • Sensitivity (Limit of Detection)
        • BOX 26-4 KEY CONCEPTS
        • BOX 26-5 SECTION OBJECTIVES
    • FINAL-EVALUATION EXPERIMENTS
      • Between-Day Replication Experiment
      • Comparison-of-Methods Experiment
      • Quality of the Comparative Method
        • Fig. 26-4 Traceability of creatinine methods proposed by the National Kidney Foundation.
        • t-Test Statistics: Bias, Sd
          • Fig. 26-5 Effect of range of data on correlation coefficient, r.
        • Correlation Coefficient
        • Linear-Regression Statistics
          • Fig. 26-6 Effect of range of data on linear-regression statistics.
          • BOX 26-5 KEY CONCEPTS
          • Fig. 26-7 Total analytical error.
          • BOX 26-6 SECTION OBJECTIVES
    • ESTIMATION OF TOTAL ERROR
      • Table 26-3 Point Estimate Criteria for Acceptable Performance
      • Medical Decision Charts
        • Fig. 26-8 Medical decision chart. In the unacceptable performance region, the standard deviation (SD) exceeds 50% of allowable error (EA), and precision errors alone will exceed EA more than 5% of the time, regardless of bias and quality control (QC) procedure. In the marginal performance region, the SD is so large (between 33% and 50% of EA) that the method's total error is very close to EA. Only QC procedures with unacceptably high rates of false rejection could maintain errors below EA. This means many rejected runs. In the fair performance region, QC procedures must be developed carefully to maintain errors below EA. This can be done with four to six QC measurements per run. In the Good performance region, ordinary multirule QC procedures will detect unacceptable method performance. This will involve two to three QC measurements per run. In the Six Sigma region, relatively weak QC procedures will be sufficient to detect errors that might exceed the EA. Only one or two QC measurements per run are required. See Chapter 25 for a discussion of QC procedures.
    • CONFIDENCE INTERVAL CRITERIA FOR JUDGING ANALYTICAL PERFORMANCE
      • Table 26-4 Factors for Computing One-Sided Confidence Limits for Standard Deviation
      • Confidence Interval Criterion for Random Error
        • Fig. 26-9 A, One-sided 95% upper limit of constant error, CEu. B, One-sided 95% lower limit of constant error, CEl.
      • Confidence Interval Criteria for Constant Error and for Proportional Error
      • Confidence Interval Criterion for Systematic Error
        • Fig. 26-10 Confidence interval around regression line.
        • Table 26-5 Confidence Interval Criteria for Unacceptable Performance and Acceptable Performance
      • Confidence Interval Criterion for Total Error
    • OTHER EVALUATION PROTOCOLS
      • BOX 26-6 KEY CONCEPTS
    • DISCUSSION
    • AN EXAMPLE PERFORMANCE EVALUATION FOR GLUCOSE
      • Example
      • Example
      • Example
      • Example
    • REFERENCES
    • INTERNET SITES
• Part 2 Physiology and Pathophysiology
  • Chapter 27 Classifications and Descriptions of Proteins, Lipids, and Carbohydrates
    • Key Terms
    • BOX 27-1 SECTION OBJECTIVES
    • PART 1: Proteins
    • DEFINITION AND CLASSIFICATION
      • Fig. 27-1 General structure of amino acid of L-stereoisomeric form. Heavy lines, bonds coming out of plane of page; dotted lines, bonds extending behind plane of paper.
      • Fig. 27-2 Various ionized and nonionized forms of amino acids present at various pH levels. When two opposite charges are present on the same molecule, the molecule is called a zwitterion.
      • Table 27-1 Classification and Properties of Side Chains (R Groups) for Naturally Occurring Amino Acids
      • Fig. 27-3 Scheme of synthesis of proteins. AA, amino acid; DNA, deoxyribonucleic acid; mRNA, messenger ribonucleic acid; rRNA, ribosomal ribonucleic acid (18S and 28S forms); tRNA, transfer ribonucleic acid; tRNA-AA, activated amino acid covalently bound to amino acid–specific tRNA.
      • Fig. 27-4 Spatial relationships of a polypeptide bond. C, carbon atom; H, hydrogen atom; N, nitrogen atom; O, oxygen atom.
      • Table 27-2 Types of Intramolecular Side-Chain Interactions of Protein R-Groups
    • CHEMICAL PROPERTIES
    • PHYSICAL PROPERTIES
    • BIOLOGICAL PROPERTIES
      • Table 27-3 Biological Functions of Proteins
      • BOX 27-1 KEY CONCEPTS
      • BOX 27-2 SECTION OBJECTIVES
    • PART 2: Lipids
    • DEFINITION AND CLASSIFICATION
      • Simple Lipids
        • Neutral Fats
        • Waxes
      • Conjugated Lipids
        • Phospholipids
        • Phosphatidic Acid
          • Table 27-4 Common Unsaturated Fatty Acids, Number of Double Bonds, and Length of Carbon Chain
          • Table 27-5 Classification of Phosphatides and Glycolipids
        • Lecithins
        • Cephalins
        • Phosphatidyl Ethanolamine
        • Phosphatidyl Serine
        • Phosphatidyl Inositol
        • Plasmalogens
        • Sphingolipids
        • Sphingomyelins
        • Cerebrosides
        • Sulfatides
        • Gangliosides
      • Derived Lipids
        • Fatty Acids
        • Alcohols
        • Steroids
          • Fig. 27-5 Structure of cholesterol molecule, a C27 hydrocarbon sterol.
        • Bile Acids
        • Hydrocarbons
        • Vitamins
        • Other Compound Lipids
    • CHEMICAL AND PHYSICAL PROPERTIES
      • Melting Point
      • Solubility
      • Specific Gravity
      • Alcohol Groups of Steroids
      • Triglyceride Composition
    • BIOLOGICAL PROPERTIES
      • BOX 27-2 KEY CONCEPTS
      • BOX 27-3 SECTION OBJECTIVES
    • PART 3: Carbohydrates
    • DEFINITION AND CLASSIFICATION
      • Fig. 27-6 Structural differences between aldoses and ketoses, which are aldehydes and ketones, respectively.
      • Simple Monomeric Carbohydrates (Saccharides)
        • Fig. 27-7 Interrelationships between straight-chain and ring forms of D-glucose and D-fructose, which form pyranose and furanose rings.
      • Derived Monosaccharides
      • Complex Carbohydrates
        • Fig. 27-8 Structure of N-acetylneuraminic acid (“sialic acid”).
        • Fig. 27-9 Common disaccharides linked by α-glycosidic bonds.
    • CHEMICAL PROPERTIES
    • PHYSICAL PROPERTIES
    • BIOLOGICAL PROPERTIES
      • KEY CONCEPTS BOX 27-3
      • BOX 27-4 SECTION OBJECTIVES
    • PART 4: Nucleic Acids
    • DEFINITION AND CLASSIFICATION
      • Purine and Pyrimidine Bases
        • Fig. 27-10 General structures of pyrimidine and purine bases and the International Union of Pure and Applied Chemistry (IUPAC) numbering of the ring positions.
        • Fig. 27-11 Structures of the most common pyrimidine and purine bases.
        • Fig. 27-12 General structures of the ribonucleosides and deoxyribonucleosides and the International Union of Pure and Applied Chemistry (IUPAC) numbering of the sugar positions.
        • Fig. 27-13 General structures of the 3′ and 5′ nucleotides.
        • Fig. 27-14 5′ nucleotide diphosphate and triphosphate structures.
    • DNA AND RNA
      • Fig. 27-15 5′,3′ cyclic nucleotide structure.
      • Fig. 27-16 Covalent structure of a single DNA (deoxyribonucleic acid) strand. The polarity of the molecule is shown in the 5′ to 3′ direction by the arrow.
      • Fig. 27-17 Illustration of complementary base pairing.
      • Fig. 27-18 Packaging of human DNA. A, Structural organization of the nucleosome. Nucleosomes consist of two turns of a DNA duplex coiled around a histone octamer. The histone octamer of the nucleosome consists of two molecules of each histone H2A, H2B, H3, and H4.
      • DNA and RNA Binding Affinity
        • BOX 27-4 KEY CONCEPTS
    • BIBLIOGRAPHY
      • General
      • Proteins and Amino Acids
      • Lipids
      • Carbohydrates
      • Nucleic Acids
    • INTERNET SITES
      • Proteins
      • Lipids
      • Carbohydrates
      • Nucleotides
  • Chapter 28 Physiology and Pathophysiology of Body Water and Electrolytes
    • Key Terms
      • Methods on Evolve
      • BOX 28-1 SECTION OBJECTIVES
    • BODY WATER COMPARTMENTS
      • Fig. 28-1 Body water compartments. Note that anatomical extracellular water (ECW) includes physiological extracellular water and transcellular water. ISF, Interstitial fluid.
      • Volume of Body Water Compartments
        • Fig. 28-2 Diagram of plasma, interstitial fluid (ISF), and intracellular water (ICW) in tissue at the microscopic level.
        • Table 28-1 Compartment Volumes
      • Maturational Changes in Body Water Compartment Volumes
      • Composition of Body Water Compartments
        • Plasma Compartment
          • Fig. 28-3 Changes in body water and distribution with age, expressed as a percentage of body weight.
          • Table 28-2 Composition of Body Water Compartments
        • Interstitial Fluid Compartment
        • Intracellular Water Compartment
      • Osmotic Pressure and Osmolarity of Body Fluids
        • Fig. 28-4 Increased anion gap caused by an increase in unmeasured anions. Numbers in parentheses, concentration of ions in units of mEq/L plasma. Note that the sum of cations (left-hand side of each bar graph) is always equal to the sum of anions (right-hand side of each bar graph), both under normal conditions and in the presence of lactic acidosis. The sum of concentrations of unmeasured anions (organic acids, HPO42−, SO42−, and proteins) is larger than the sum of concentrations of unmeasured cations (Ca2+ and Mg2+). During lactic acidosis, the difference between unmeasured anions and cations becomes greater because production of lactic acid increases the concentration of organic acids.
        • BOX 28-1 KEY CONCEPTS
        • BOX 28-2 SECTION OBJECTIVES
    • REGULATION OF BODY FLUID COMPARTMENT OSMOLARITY AND VOLUME
      • Extracellular Compartment
        • Water Metabolism and Hypothalamus
          • Fig. 28-5 Hypothalamic regulation of water balance.
          • Fig. 28-6 Renin-angiotensin-aldosterone system.
        • Water and Sodium Metabolism and Renin-Angiotensin-Aldosterone System
        • Water and Sodium Metabolism and the Natriuretic Peptides
        • Control of Extracellular Water Osmolarity
        • Control of Extracellular Water Volume
      • Plasma and Interstitial Fluid Compartments
        • Water Distribution
        • Solute Distribution
      • Intracellular Compartment
        • Fig. 28-7 Starling's hypothesis of water distribution between plasma and interstitial fluid compartments. Thickness of arrows representing plasma hydrostatic pressure, Pp1, and plasma oncotic pressure, πp1, indicate their relative magnitudes. Dashed arrows, Direction of net filtration pressure.
        • Fig. 28-8 Gibbs-Donnan equilibrium. Distribution of diffusible and nondiffusible ions and development of an electrical potential gradient across a membrane when a nondiffusible, polyvalent anion with a diffusible cation (C+) is added to one side of a membrane in solution of diffusible cation (C+) and anion (A−). Initially, a diffusible cation moves down its concentration gradient from side 2 to side 1. This movement generates an electrical potential gradient across the membrane (side 2 negative with respect to side 1). The diffusible anion moves down this electrical potential gradient from side 2 to side 1. At equilibrium, the concentration of diffusible cation will be greater on side 2 than side 1 (as indicated by size of symbols), whereas the concentration of diffusible anion will be greater on side 1 than on side 2. No net movement of diffusible ions occurs across the membrane because no net electrochemical gradients exist. The concentration gradient for each ion is balanced by an equal but oppositely directed electrical gradient.
        • Table 28-3 Water Balance in Average Adult Under Various Conditions
        • Cell Volume
        • Cell Solute Content
          • BOX 28-2 KEY CONCEPTS
          • BOX 28-3 SECTION OBJECTIVES
    • WATER METABOLISM
      • Water Balance
      • Disorders of Water Imbalance
        • Table 28-4 Changes in Total Body Water Volume and Distribution, Total Body Sodium Content, and Plasma Sodium Concentration With Dehydration and Overhydration
      • Dehydration
        • Deficit of Water
        • Deficit of Water and Sodium
          • Box 28-1 Causes of Dehydration (Water and Sodium Deficits)
            • Hypernatremic Dehydration
            • Normonatremic Dehydration
            • Hyponatremic Dehydration
        • Symptoms of Dehydration
      • Overhydration
        • Excessive Water
          • Box 28-2 Causes of Water Intoxication
            • Polydipsia
            • SIADH
            • Ectopic, Autonomous Secretion of ADH
        • Excessive Water and Sodium
          • BOX 28-3 KEY CONCEPTS
          • BOX 28-4 SECTION OBJECTIVES
    • SODIUM METABOLISM
      • Sodium Balance
        • Fig. 28-9 Distribution of sodium among body compartments. Bold numbers, percentages of total body sodium in various compartments; numbers in parentheses, percentages of exchangeable sodium in various compartments; ICW, Intracellular water; ISF, interstitial fluid; and TCW, transcellular water.
        • Table 28-5 Electrolyte Composition and Volume of Various Gastrointestinal Secretions in a Normal Adult
      • Disorders of Sodium Balance
        • Sodium Excess
          • Box 28-3 Clinical Conditions Resulting in Excess Body Sodium
        • Congestive Heart Failure
        • Liver Disease
        • Renal Disease
          • Box 28-4 Clinical Conditions Resulting in Deficits of Body Sodium
        • Pregnancy
        • Sodium Depletion
      • Abnormalities of Plasma Sodium Concentration
        • Box 28-5 Clinical Conditions Associated With Hyponatremia
        • Table 28-6 Urine Sodium Concentration and Osmolarity in the Differential Diagnosis of Hyponatremia
        • Table 28-7 Urine Sodium Concentration and Osmolarity in the Differential Diagnosis of Hypernatremia
        • Box 28-6 Clinical Conditions Associated With Hypernatremia
        • BOX 28-4 KEY CONCEPTS
        • BOX 28-5 SECTION OBJECTIVES
    • POTASSIUM METABOLISM
      • Potassium Balance
      • Internal Potassium Balance
      • External Potassium Balance
      • Disorders of External Potassium Balance
        • Potassium Excess
          • Box 28-7 Causes of Potassium Retention
        • Potassium Depletion
      • Abnormalities of Plasma Potassium Concentration
        • Box 28-9 Causes of Hypokalemia (see Box 25-8)
        • Box 28-10 Causes of Hyperkalemia
        • Box 28-8 Causes of Potassium Depletion
        • Hypokalemia
        • Hyperkalemia
        • Urine Potassium
          • BOX 28-5 KEY CONCEPTS
          • BOX 28-6 SECTION OBJECTIVES
    • CHLORIDE METABOLISM
      • Chloride Balance
      • Disorders of Chloride Balance
        • Chloride Excess
        • Chloride Depletion
      • Abnormalities of Plasma Chloride Concentration
      • Urine Chloride Concentration
        • BOX 28-6 KEY CONCEPTS
        • Fig. 28-10 Concentrations of electrolytes in plasma (mEq/L) with metabolic acidosis and metabolic alkalosis compared with normal. In the example of metabolic acidosis shown, there is no increase in organic acids—only loss of bicarbonate. Metabolic acidosis may be attributable to an increase in organic acids (see Fig. 28-4). In these cases, chloride may not be increased. Note that the extracellular potassium concentration is elevated in metabolic acidosis and lowered in metabolic alkalosis. Under all conditions, the concentration of anions equals the concentration of cations.
    • BIBLIOGRAPHY
    • INTERNET SITES
  • Chapter 29 Acid-Base Control and Acid-Base Disorders
    • Key Terms
      • Methods on Evolve
      • BOX 29-1 SECTION OBJECTIVES
    • ACID-BASE CONTROL
      • Acids and Bases
        • Definitions
        • Dietary and Metabolic Sources of Acids and Bases
          • Table 29-1 Physiologically Important Buffers and their Concentration, pKa, and Buffering Capacity
        • pH, Hydrogen Ion, and Buffers
        • Physiological Buffers
          • Bicarbonate buffer system
        • Hemoglobin
          • Fig. 29-1 Effects of hemoglobin oxygenation on buffering action of imidazole group of histidine. Oxygen binding affects the pKa of the imidazole ring, making the ring more acidic with release of an H+.
        • Phosphate and Proteins
      • Oxygen and Carbon Dioxide Homeostasis
        • Partial Pressure
        • Ventilation
          • Fig. 29-2 Hemoglobin buffering action in peripheral tissues. HbK, Potassium salt of hemoglobin; HbH, protonated form of hemoglobin.
          • Table 29-2 Composition of Air (Partial Pressure Expressed in mm Hg)
          • Table 29-3 Reference Values for Adult Blood-Gas Parameters in Arterial and Venous Blood
        • Gas Exchange
        • Control of Ventilation
      • Acid-Base Balance
        • Fig. 29-3 Transfer of CO2 in lungs from erythrocytes to air sacs. HbK, Potassium salt of hemoglobin; HbH, protonated form of hemoglobin.
        • Fig. 29-4 Hemoglobin-oxygen dissociation curves and factors that shift the curve right and left. A shift of curve right or left changes the level of PO2 at which hemoglobin is 50% saturated (P50).
        • BOX 29-1 KEY CONCEPTS
        • Fig. 29-5 Kidney reabsorption of bicarbonate with excretion of H+.
        • BOX 29-2 SECTION OBJECTIVES
    • ACID-BASE DISORDERS
      • Definitions
        • Base Excess
        • Oxygen Saturation
        • Anion Gap
      • Base-Deficient Disorders
        • Metabolic Acidosis
          • Fig. 29-6 Nomogram of relationship among pH, PO2, and O2 saturation. A straight line through a value of pH and of PO2 will connect with a calculated value of O2 saturation at 37°C.
      • Respiratory Acidosis
      • Base-Excess Disorders
        • Metabolic Alkalosis
        • Respiratory Alkalosis
      • Instrumentation
        • Calculated Parameters
          • BOX 29-2 KEY CONCEPTS
          • BOX 29-3 SECTION OBJECTIVES
    • ACIDOSIS
      • Metabolic Acidosis
        • Etiology
          • Fig. 29-7 Nomogram of relationship among PCO2, pH, base excess, hemoglobin, bicarbonate, and total CO2. A straight line through a value of pH and of PCO2 will connect with a calculated value of HCO3− and total CO2. Base excess or deficit can be derived from that straight line if the hemoglobin level is known.
          • Box 29-1 Origin of Acidoses
            • Respiratory Causes
            • Metabolic Disorders
              • Increased Fixed Acids
              • Bicarbonate Loss
        • Physiological Response
          • Table 29-4 Comparison of Acid-Base Disorders With Corresponding Effects On Selected Blood-Gas Parameters
        • Laboratory Findings
        • Treatment
      • Respiratory Acidosis
        • Etiology
          • Box 29-2 Symptoms Associated With Allergy
            • Respiratory
            • Gastrointestinal
            • Dermatological
          • Box 29-3 Common Allergens
        • Physiological Response
        • Laboratory Findings
        • Medical Treatment
          • BOX 29-3 KEY CONCEPTS
          • BOX 29-4 SECTION OBJECTIVES
    • ALKALOSIS
      • Metabolic Alkalosis
        • Etiology (see Box 29-4)
        • Physiological Response
        • Laboratory Findings
        • Treatment
      • Respiratory Alkalosis
        • Etiology
        • Physiological Response
        • Laboratory Findings
          • Box 29-4 Origin of Alkaloses
            • Respiratory Causes
            • Metabolic Causes
        • Treatment
          • BOX 29-4 KEY CONCEPTS
          • BOX 29-5 SECTION OBJECTIVE
    • CHANGE OF ANALYTE IN DISEASE
      • Table 29-5 Common Disorders of Acid-Base Balance and Effects on Selected Blood-Gas Parameters
      • Table 29-6 Examples of Lung Disease With a Known Genetic Basis
    • BIBLIOGRAPHY
    • INTERNET SITES
      • Asthma
      • Respiratory Diseases (Chronic Obstructive Respiratory Disease, COPD, CO Poisoning)
      • Acidoses
      • General
  • Chapter 30 Renal Function
    • Key Terms
      • Methods on Evolve
    • ANATOMY OF KIDNEY
      • Gross Anatomy
      • Microscopic Anatomy
        • Fig. 30-1 Gross anatomy of kidney and urinary system.
        • Fig. 30-2 Components of the nephron.
        • BOX 30-1 SECTION OBJECTIVES
    • RENAL PHYSIOLOGY
      • Urine Formation
        • Glomerular Filtration
          • Fig. 30-3 Portion of a glomerulus showing a peripheral region of a capillary loop cut into a healthy section. The filtration surface consists of the endothelium (En) with its open fenestrae (f) lacking diaphragms, the glomerular basement membrane (B), and the epithelial foot processes (fp), between which are the filtration slits, bridged at their base by slit membranes (short arrow). Notice that the glomerular basement membrane (GBM) consists of 3 layers—a central dense layer, the lamina densa (LD), and 2 adjoining layers of lower density—the lamina rara interna (LRI) and externa (LRE). A thick cell coat (C) is visible on the membrane of the foot processes. The lamina densa is composed of a fine (≈ 3 nm) filamentous meshwork, and wispy filaments are seen extending from the lamina densa to the endothelial and epithelial (long arrow) membranes on either side. Cap, Capillary lumen; j, junction between 2 endothelial cells; US, urinary spaces; 80,000×.
        • Proximal Tubule
          • Table 30-1 Filtration, Reabsorption, and Excretion by Kidney
        • Loop of Henle
        • Distal Convoluted Tubule
        • Collecting Duct
      • Regulation of Fluid and Electrolyte Balance (see also Chapter 28)
        • Water
        • Sodium
        • Chloride
        • Potassium
        • Calcium
        • Phosphorus
        • Magnesium
      • Acid-Base Balance
        • Excretion of Hydrogen Ions
        • Reaction With Filtered Bicarbonate Ions
        • Reaction With Filtered Buffers to Form Titratable Acids
        • Reaction With Secreted Ammonia to Form Ammonium Ion
        • Excretion as Free Hydrogen Ions
      • Nitrogenous Waste Excretion
        • Urea
        • Creatinine
        • Uric Acid
      • Hormonal Function
        • Vitamin D Metabolism
        • Renin
        • Erythropoietin
      • Protein Conservation
        • BOX 30-1 KEY CONCEPTS
        • BOX 30-2 SECTION OBJECTIVES
    • PATHOLOGIC CONDITIONS OF KIDNEY
      • Acute Glomerulonephritis
      • Nephrotic Syndrome
        • Box 30-1 Causes of Nephrotic Syndrome
      • Tubular Disease
      • Interstitial Nephritis
      • Urinary Tract Infection
      • Vascular Diseases
        • Hypertension
        • Arteriolar Disease
        • Renal Vein Thrombosis
      • Diabetes Mellitus (see Chapter 38)
      • Urinary Tract Obstruction
      • Renal Calculi
      • Acute Renal Failure
        • Fig. 30-4 RIFLE criteria for acute kidney injury. ARF, Acute renal failure; dec, decrease; ESKD, end-stage renal disease; GFR, glomerular filtration rate; UO, urine output.
        • Box 30-2 Causes of Acute Renal Failure
      • Chronic Kidney Disease
        • Box 30-3 Classification of Causes of Chronic Renal Failure
        • BOX 30-2 KEY CONCEPTS
        • BOX 30-3 SECTION OBJECTIVES
    • RENAL FUNCTION TESTS
      • Tests of Glomerular Function
        • Inulin Clearance
        • Cystatin C Clearance
        • Creatinine Clearance
        • Estimated Creatinine Clearance (e-Ccr)
        • Estimated Glomerular Filtration Rate (e-GFR)
      • Tests of Tubular Function
        • Concentration-Dilution Studies
      • Urinalysis
        • Table 30-2 Association of Pathologic Conditions Affecting the Kidney and Clinical and Biochemical Abnormalities
        • Table 30-3 Characteristic Urine Microscope Findings in Renal Disease
        • BOX 30-3 KEY CONCEPTS
        • BOX 30-4 SECTION OBJECTIVES
    • CHANGE OF ANALYTE IN DISEASE
      • Serum Electrolytes
        • Sodium
        • Hyponatremia
        • Hypernatremia
        • Chloride
        • Potassium
        • Hypokalemia
        • Hyperkalemia
      • Creatinine, Urea, and Uric Acid
      • Calcium and Phosphorus
      • Urinary Electrolytes
        • Sodium
        • Chloride
        • Potassium
      • Anion Gap (Serum)
      • Proteinuria
      • Hemoglobin and Hematocrit
      • Laboratory Screening and Evaluation of Chronic Kidney Disease
        • BOX 30-4 KEY CONCEPTS
    • REFERENCES
    • INTERNET SITES
  • Chapter 31 The Liver: Function and Chemical Pathology
    • Key Terms
      • Methods on Evolve
      • BOX 31-1 SECTION OBJECTIVES
    • ANATOMY AND NORMAL FUNCTION OF LIVER
      • Fig. 31-1 A, Anatomy of the liver. The hepatic artery, portal vein, and common hepatic duct lie close to each other in a region known as the porta hepatis. The gallbladder is close to the bottom surface of the liver and stores bile within it. Its small duct (termed the cystic duct) joins with the common hepatic duct to form the common bile duct, which (as illustrated in Fig. 34-1) passes through the head of the pancreas before draining into the duodenum at the ampulla of Vater. B, Schema of structures with lobules. BC, Bile canaliculis; D, space of Disse; E, erythrocyte; EC, endothelial cell; F, reticulum fibers; FS, fat-storing (stellate) cell; H, hepatocyte; K, Kupffer cell; N, nerve fiber; S, sinusoid; SP, fenestrae of endothelial cell forming a sieve plate; X, intercellular gap.
      • Bilirubin
        • Fig. 31-2 Formation of bilirubin from heme. M, Methyl; P, propionyl; V, vinyl.
        • Fig. 31-3 Hepatic metabolism of bilirubin. The indicated steps are (1) uptake, (2) conjugation, and (3) excretion. A small amount of bilirubin is produced by breakdown of hemecontaining proteins within hepatocytes. B, Bilirubin; G, glucuronic acid.
      • Protein Metabolism
        • Table 31-1 Major Liver-Produced Plasma Proteins
      • Carbohydrate Metabolism
      • Lipid Biosynthesis and Transport
      • Metabolic End-Product Excretion and Detoxification
        • BOX 31-1 KEY CONCEPTS
        • BOX 31-2 SECTION OBJECTIVES
    • CLINICAL PATTERNS OF LIVER DISEASE
      • Jaundice
        • Fig. 31-4 Mechanisms of hyperbilirubinemia. A, Normal bilirubin metabolism with hepatocyte uptake of unconjugated bilirubin (dark arrow) and microsomal conjugation and excretion of conjugated bilirubin (striped arrow). B, Hemolytic jaundice, in which increased bilirubin production results in increased excretion of conjugated bilirubin and a rise in excess (exceeding liver capacity) unconjugated bilirubin in blood. C, Gilbert's disease, in which decreased hepatic uptake results in a large increase in blood levels of unconjugated bilirubin. D, Physiological jaundice, in which microsomal conjugating system is not functional, resulting in a large increase in unconjugated bilirubin. Congenital deficiency is called Crigler-Najjar syndrome. E, Dubin-Johnson syndrome, in which there is a biochemical defect preventing secretion of conjugated bilirubin, resulting in a backflow into blood. F, Intrahepatic or extrahepatic obstruction in which a physical block prevents secretion of conjugated bilirubin. Hepatocellular disease results in a pattern similar to a combination of C and D.
      • Acute Hepatitis
        • Table 31-2 Genetic Diseases of the Liver
        • Table 31-3 Typical Laboratory Findings in Acute Hepatitis of Various Causes
        • Fig. 31-5 Course of serum enzyme activities in acute viral hepatitis.
        • Fig. 31-6 Course of serum enzyme activities in acute alcoholic hepatitis.
      • Chronic Hepatitis
        • Table 31-4 Laboratory Tests to Establish Cause of Chronic Hepatitis
      • Cholestatic Disorders
        • Fig. 31-7 Course of serum enzyme activities in obstructive jaundice.
      • Cirrhosis
        • Table 31-5 Laboratory Findings in Progression of Chronic Hepatitis to Cirrhosis
      • Liver Tumors
      • Liver Transplantation
    • CHANGE OF ANALYTE IN DISEASE
      • Bilirubin
      • Enzymes
      • Autoantibodies
        • Table 31-6 Factors Affecting Interpretation of Plasma Levels of “Liver” Enzymes
      • Other Analytes
        • BOX 31-2 KEY CONCEPTS
    • REFERENCES
    • INTERNET SITES
  • Chapter 32 Viral Hepatitis: Diagnosis and Monitoring
    • Key Terms
      • Abbreviations
      • Methods on CD-ROM
      • Table 32-1 Composition of Hepatitis Viruses
      • BOX 32-1 SECTION OBJECTIVES
    • INTRODUCTION TO VIRAL HEPATITIS
      • Symptoms of Acute Viral Hepatitis
      • Symptoms of Chronic Viral Hepatitis
      • General Laboratory Changes in Viral Hepatitis
        • Table 32-2 Prevalence of Hepatitis Viruses
      • Prevalence of Viral Hepatitis (Table 32-2)
      • Common Genetic Variants
        • Table 32-3 Common Genetic Variants of Hepatitis Virus Genotypes
        • BOX 32-1 KEY CONCEPTS
        • BOX 32-2 SECTION OBJECTIVES
    • HEPATITIS A
      • Clinical Background
        • Fig. 32-1 Clinical, virological, and serological events associated with hepatitis A virus (HAV) infection. ALT, Alanine aminotransferase.
      • Laboratory Changes Associated With HAV Infection
      • Diagnosis of HAV Infection
      • Monitoring HAV Infection
        • HAV Assays
    • HEPATITIS B
      • Clinical Background
        • Acute HBV Infection
        • Chronic HBV Infection
      • Hepatitis Genotypes
        • HBeAg-Negative Mutations
        • Hepatitis B Surface Antigen (HBsAg) Escape Mutants
      • Laboratory Changes Associated With HBV Infection
        • Serological Markers
      • Diagnosis of HBV Infection
        • Fig. 32-2 Serological events associated with hepatitis B virus (HBV) infection. A, Serological profile of acute hepatitis B infection with complete recovery; time in weeks. B, Serological profile of chronic hepatitis B infection; time in weeks, up to 52.
        • Box 32-1 Serological Markers of HBV Infection
        • Table 32-4 Interpretation of Hepatitis B Serology Profiles
      • Monitoring the Development of HBV Infection and the Treatment
      • Frequently Encountered Issues in the Interpretation of HBV Serology Tests
        • Molecular Tests of HBV (see Chapter 13)
          • HBV Viral Load
          • HBV Genotyping
    • HEPATITIS D
      • Clinical Background
      • Laboratory Changes Associated With HDV Infection
      • Diagnosis of HDV Infection
      • Monitoring HDV Infection
      • HDV Assays
        • Fig. 32-3 Clinical and serological events associated with hepatitis D virus (HDV). Diagrammatic illustration of clinical and serological events in typical cases of type D hepatitis resulting from acute hepatitis B virus (HBV) and HDV co-infection (top), acute HDV superinfection of a hepatitis B surface antigen (HBsAg) carrier (middle), and HDV superinfection progressing to chronic type D hepatitis in an HBsAg carrier (bottom).
    • HEPATITIS C
      • Clinical Background
      • Laboratory Changes Associated With HCV Infection
      • Diagnosis of HCV Infection
        • Fig. 32-4 Laboratory algorithm for antibody to hepatitis C virus (HCV) testing and result reporting.
        • HCV Diagnosis Test Algorithms
      • Monitoring HCV Infection
        • HCV RNA Viral Load
        • HCV Assays
          • aHCV
          • Hepatitis C RIBA
          • Qualitative HCV RNA Assay
          • Genotyping Assays (see Chapter 13)
          • Quantitative HCV RNA Test
    • HEPATITIS E
      • Clinical Background
        • Fig. 32-5 Clinical, virological, and serological events associated with hepatitis E.
      • Laboratory Changes Associated With HEV Infection
      • Diagnosis of HEV Infection
      • Monitoring HEV Infection
        • HEV Assays
          • BOX 32-2 KEY CONCEPTS
    • REFERENCES
    • BIBLIOGRAPHY
    • INTERNET SITES
  • Chapter 33 Bone Disease
    • Key Terms
      • Methods on Evolve
      • BOX 33-1 SECTION OBJECTIVES
    • BONE STRUCTURE AND FUNCTION
      • Bone Structure
        • Fig. 33-1 A, Parts of a long bone. B, Long bone in cross section: note the predominance of trabecular, cancellous bone in the diaphysis.
        • Box 33-1 Endocrine and Autocrine Factors Affecting Osteoblasts and Osteoclasts
        • Skeletal Development16
      • Bone Mass
      • Bone Function
        • BOX 33-1 KEY CONCEPTS
        • BOX 33-2 SECTION OBJECTIVES
    • BONE CHANGES16
      • Bone Modeling
      • Bone Remodeling
      • Resorption
      • Reversal
      • Formation
      • Normal and Abnormal Coupling of Modeling and Remodeling
      • Hormonal Regulation of Bone Remodeling18,32
        • Sex Hormones
        • Effects of Estrogen on Growth, Modeling, and Remodeling36–38
          • Interaction of Estrogen with GH and IGF-I
      • Biochemical Markers of Bone Turnover48–50
        • Box 33-2 Biochemical Markers of Bone Turnover
          • Bone Formation
          • Bone Resorption Markers
        • BOX 33-2 KEY CONCEPTS
        • BOX 33-3 SECTION OBJECTIVES
    • BIOCHEMISTRY AND PHYSIOLOGY
      • Determinants of Bone Health19,20,51,52
        • Nutrition (see Chapter 41)
        • Vitamin D Requirements for Optimal Calcium Absorption and Bone Health54 (see later discussion)
        • Exercise
      • Gonadal Steroids (see Chapter 50)
      • Growth Hormone and Body Composition
      • Mineral Physiology
        • Calcium and Phosphorus
          • Metabolism
        • Magnesium
          • Metabolism
      • Hormone Physiology
        • Vitamin D54–56,65
          • Biochemistry and Metabolism
            • Fig. 33-2 Some common metabolites of cholecalciferol.
          • Mechanisms of Action54,66
            • Box 33-3 Target Organs for Calcitriol
            • Box 33-4 Primary Stimuli for Calcitriol Synthesis
            • Fig. 33-3 Interrelationships of serum calcium concentrations and parathyroid hormone (PTH) and calcitriol.
          • Regulation of Vitamin D Metabolism
        • Parathyroid Hormone74,75
          • Biochemistry and Metabolism
          • Mechanisms of Action
            • Fig. 33-4 Normal parathyroid hormone (PTH) physiology. PTH action increases serum calcium concentrations predominantly through its bone and kidney effects but reduces plasma phosphorous concentrations (P) by increasing excretion of renal phosphorus.
          • Perinatal PTH Homeostasis
        • PTH-Related Peptide77,78
          • Biochemistry and Metabolism
          • Mechanisms of Action
        • Calcitonin (CT)
          • Localization, Biochemistry, and Metabolism
          • Biological Effects
          • Regulation of CT Secretion79,80
            • BOX 33-3 KEY CONCEPTS
            • BOX 33-4 SECTION OBJECTIVES
            • Box 33-5 A Partial Differential Diagnosis of Osteopenia
              • Osteoporosis
                • Primary
                • Secondary
              • Osteomalacia
              • Osteitis Fibrosa
    • BONE DISORDERS
      • Osteoporosis22,86–90
        • Primary Osteoporosis
          • Table 33-1 Common Serum Abnormalities Associated with Metabolic Bone Disease
          • Table 33-2 Treatments That Increase the Risk of Secondary Osteoporosis
        • Secondary Osteoporosis
        • Senile Osteoporosis
          • Box 33-7 Calcium-Regulating Hormone Abnormalities Associated with Aging
          • Table 33-3 Disorders That Increase the Risk of Secondary Osteoporosis
          • Box 33-6 Risk Factors Associated with Low Bone Density and Fracture
        • Postmenopausal Osteoporosis
          • Fig. 33-5 Hypothesized pathogenesis of postmenopausal osteoporosis.
        • Idiopathic Juvenile Osteoporosis
        • Corticosteroid-Induced Osteoporosis98,99
        • Hyperthyroidism91
        • Hypogonadal States
        • Drugs
        • Diagnosis of Osteoporosis20,22,86–88
          • Box 33-8 Serum Tests to Rule Out Secondary Osteoporosis
          • Laboratory Tests to Rule Out Secondary Causes of Osteoporosis
        • Treatment for Osteoporosis53,62,104–108
          • Box 33-9 Current and Emerging Therapies for Osteoporosis
        • Bisphosphonates103
        • Hormone Replacement Therapy (HRT)105,106
        • Calcitonin
        • Parathyroid Hormone (PTH)75,104,113
        • Monitoring Osteoporosis and Treatment
          • Table 33-4 Biochemical Abnormalities Associated with Rickets
      • Osteomalacia
        • Vitamin D–Deficient Osteomalacia55,56,114
        • Osteomalacia Secondary to Gastrointestinal Disorders
        • Hepatic Rickets115
        • Osteomalacia Secondary to Anticonvulsant Medication92
        • Vitamin D–Dependent Osteomalacia (Types I and II)116
        • Vitamin D–Resistant Osteomalacia
        • Calcium Deficiency Rickets121
        • Hyperalimentation-Induced Osteopenia
        • Other Causes of Osteomalacia
        • Drug-Induced Osteomalacia123,124
      • Osteitis Fibrosa
        • Box 33-10 Pathological Forms of Renal Osteodystrophy
        • Fig. 33-6 Pathogenetic mechanism of secondary hyperparathyroidism in renal failure according to phosphate theory.
        • Fig. 33-7 Pathogenetic mechanism of secondary hyperparathyroidism in renal failure according to vitamin D theory.
      • Paget's Disease126–128
      • Heritable Bone Disease (Table 33-5)
        • Hypophosphatasia129
        • Osteogenesis Imperfecta130
          • Table 33-5 Common Genetic Diseases Associated with Bone and Mineral Disorders
        • Achondroplasia131,132
        • Osteopetrosis133
      • Albright Hereditary Osteodystrophy (AHO)134,135
        • BOX 33-4 KEY CONCEPTS
        • BOX 33-5 SECTION OBJECTIVES
    • CHANGE OF ANALYTE IN DISEASE
      • Biochemical Measurements of Bone Turnover
        • Urine Collagen Pyridinoline Cross-Linking Amino Acids
        • Urinary Telopeptides
      • Vitamin D
      • Parathyroid Hormone
        • Hypoparathyroidism
          • Primary Idiopathic Hypoparathyroidism
            • Box 33-11 Diseases and Conditions Associated With Changes in Serum Concentrations of Vitamin D Metabolites
          • Secondary Hypoparathyroidism
            • Fig. 33-8 In idiopathic hypoparathyroidism, decreased parathyroid hormone (PTH) results in decreased serum calcium, increased serum phosphorus, and decreased production of 1,25-dihydroxyvitamin D. In pseudohypoparathyroidism, although sufficient hormone is present, target organs are unresponsive and the biochemical result is similar. Inset, In pseudohypoparathyroidism, resultant low serum calcium concentrations serve as a stimulus to PTH production. Because parathyroid glands are intact, in contrast to idiopathic hypoparathyroidism, serum PTH concentrations will be elevated in an attempt to overcome target organ resistance and rectify hypocalcemia.
        • Hyperparathyroidism
          • Primary Hyperparathyroidism (PHPT)142
            • Table 33-6 Genetic Disorders of the Parathyroid Gland
          • Secondary Hyperparathyroidism
      • Calcium (see Methods on Evolve)
        • Hypercalcemia
          • Box 33-12 Causes of Hypercalcemia
          • Endocrine and Tumor-Related Hypercalcemia
          • Vitamin D–Related Disorders
          • Iatrogenic Causes
            • Box 33-13 Causes of Hypocalcemia
              • Vitamin D
              • Parathyroid
              • Calcitonin
              • Calcium
              • Magnesium
              • Phosphorus
          • Familial Form
        • Hypocalcemia
          • Hypomagnesemia
            • Table 33-7 Parathyroid Hormone–Vitamin D Axis Analytes in Hypercalcemia
            • Table 33-8 Parathyroid Hormone–Vitamin D Axis Analytes in Hypocalcemia
            • Box 33-14 Causes of Hypermagnesemia
      • Magnesium (see Methods on Evolve)
        • Hypermagnesemia
        • Hypomagnesemia and Magnesium Deficiency
      • Phosphate (see Methods on Evolve)
        • Hyperphosphatemia
          • Box 33-15 Causes of Hypomagnesemia
        • Hypophosphatemia
      • Calcitonin (CT)
        • Box 33-16 Diseases Associated with Abnormal Serum Calcitonin Concentrations
      • Alkaline Phosphatase (ALP) (see Methods on Evolve)
        • Box 33-17 Sources of Alkaline Phosphatase
        • Box 33-18 Bone Diseases Associated with Abnormal Serum Alkaline Phosphatase Concentrations
      • Osteocalcin
      • Hydroxyproline (HP)150
        • Box 33-19 Conditions Associated with Elevated Urinary Hydroxyproline Concentrations
        • BOX 33-5 KEY CONCEPTS
    • REFERENCES
    • BIBLIOGRAPHY
    • INTERNET SITES
    • Osteoporosis
    • Osteomalacia
    • Osteitis Fibrosa
  • Chapter 34 The Pancreas: Function and Chemical Pathology
    • Key Terms
    • Methods on Evolve
    • BOX 34-1 SECTION OBJECTIVES
    • ANATOMY
      • Fig. 34-1 Diagram of acinar cells and associated ductules. The exocrine acini terminate with a collection of acinar cells that contain zymogen granules; the latter contain the proenzymes and other digestive enzymes described in Fig. 34-3. Special cells line the ductules that secrete fluid and electrolytes, especially bicarbonate.
      • Fig. 34-2 Diagram of an islet of Langerhans. At least four types of cells secrete hormones into the blood. Most of these cells (beta-cells) produce insulin; only a small fraction are F-cells, which produce pancreatic polypeptide.
    • ENDOCRINE PHYSIOLOGY
    • EXOCRINE PHYSIOLOGY
      • Normal Pancreatic Exocrine Secretions
        • Table 34-1 Normal Pancreatic Islet Cell Hormones
      • Normal Pancreatic Fluid Secretions
      • Control of Exocrine Pancreatic Secretions
        • Fig. 34-3 The pancreatic enzymes and their conversion to active forms in the duodenum. Enzymes are stored in zymogen granules that reach the pancreatic duct by exocytosis. Upon reaching the duodenum, proenzymes are converted to their active form by enterokinase and by active trypsin.
        • Table 34-2 Factors That Control Normal Exocrine Pancreatic Secretions
        • BOX 34-1 KEY CONCEPTS
        • BOX 34-2 SECTION OBJECTIVES
    • PATHOLOGICAL CONDITIONS
      • Endocrine Pancreatic Disorders
        • Diabetes Mellitus
      • Exocrine Pancreatic Disorders
        • Inflammatory or Necrotic Pancreatic Injury
          • Acute Pancreatitis
            • Table 34-3 Proposed Events in the Development of Acute Pancreatitis
            • Box 34-1 Causes of Acute Pancreatitis
          • Chronic Pancreatitis
            • Table 34-4 Ranson's Laboratory Indicators of Severity in Acute Pancreatitis*
            • Box 34-2 Diseases Associated With Secondary Pancreatitis
          • Cystic Fibrosis
          • Pancreatic Insufficiency
            • Box 34-3 Causes of Acinar Cell Loss
      • Pancreatic Neoplasms
        • Adenocarcinoma
        • Islet Cell Tumors
        • Insulinoma
        • Glucagonoma
        • Somatostatinoma
        • PPoma
        • Gastrinoma, VIPoma
          • BOX 34-2 KEY CONCEPTS
    • EXOCRINE PANCREATIC TESTS
      • Tests on Feces
      • Indirect Tests of Pancreatic Function
    • CHANGE IN ANALYTES WITH DISEASE
      • Amylase and Lipase
      • Cancer Markers
      • Endocrine Tumor Markers
        • Insulin
        • Glucagon
          • BOX 34-3 KEY CONCEPTS
    • REFERENCES
    • INTERNET SITES
  • Chapter 35 Gastrointestinal Function and Digestive Disease
    • Key Terms
      • Methods on Evolve
      • Fig. 35-1 Diagram of gastrointestinal tract.
      • BOX 35-1 SECTION OBJECTIVES
    • ANATOMY AND FUNCTION
      • Fig. 35-2 Diagram of stomach.
      • Fig. 35-3 Schema demonstrating various stimuli of stomach and duodenum.
    • DIGESTION
      • Carbohydrate Digestion
      • Protein Digestion
      • Fat Digestion
        • Fig. 35-4 Structures of functional components of small intestine.
        • Table 35-1 Chemical Processes for Digestion of Food
    • ABSORPTION
      • Carbohydrate Absorption
      • Protein Absorption
      • Fat Absorption (see also Chapter 37)
      • Water and Sodium Absorption
      • Calcium and Iron Absorption
        • BOX 35-1 KEY CONCEPTS
        • BOX 35-2 SECTION OBJECTIVES
    • HORMONE PHYSIOLOGY
      • Gut Hormone Structure and Functions
      • Gastrin
      • Cholecystokinin (CCK)
        • Table 35-2 Major Intestinal Hormones
      • Secretin
      • Vasoactive Intestinal Polypeptide
      • Glucagon-Like Peptides
        • BOX 35-2 KEY CONCEPTS
        • Box 35-1 Factors Contributing to Ulcers
        • BOX 35-3 SECTION OBJECTIVES
    • PATHOLOGICAL CONDITIONS
      • Stomach Diseases
        • Ulcers
        • Stomach Cancer
        • Zollinger-Ellison Syndrome
        • Pernicious Anemia and other Causes of Vitamin B12 Malabsorption
      • Small Intestine Diseases
        • Malabsorption Syndromes
        • Celiac Disease (Celiac Sprue)
        • Lactose Intolerance and Other Carbohydrate Malabsorption Disorders
        • Carcinoid Syndrome
      • Large Intestine Diseases
        • Diarrhea
        • Colorectal Cancer
        • Inflammatory Bowel Disease
          • BOX 35-3 KEY CONCEPTS
          • BOX 35-4 SECTION OBJECTIVES
    • GASTROINTESTINAL FUNCTION TESTS
      • Helicobacter pylori Diagnostic Tests
      • Fat Absorption Tests (see Evolve)
        • Fat Screening
      • D-Xylose Absorption Test (see Methods on Evolve)
      • Lactose Tolerance Test
        • BOX 35-4 KEY CONCEPTS
        • BOX 35-5 SECTION OBJECTIVES
    • CHANGE OF ANALYTE IN DISEASE (Table 35-3)
      • Malabsorption Testing
        • Screening Approach
      • Evaluation of Diarrhea
        • Occult Blood in Stool
          • Table 35-3 Change of Analyte and Function Tests in Disease
        • Carcinoembryonic Antigen
          • BOX 35-5 KEY CONCEPTS
    • REFERENCES
    • INTERNET SITES
    • MEN 1
    • Ulcers
    • Malabsorption
    • Celiac Disease
    • Lactose Intolerance
    • Carcinoid Disease
  • Chapter 36 Cardiac and Muscle Disease
    • Key Terms
      • Methods on Evolve
      • BOX 36-1 SECTION OBJECTIVES
    • MUSCLE ANATOMY AND FUNCTION
      • Types of Muscle
        • Table 36-1 Characteristics of Myofibrillar Proteins
      • Proteins Involved in Muscle Contraction (Table 36-1)
        • Fig. 36-1 Schematic representation of the spatial configuration of myosin, actin, tropomyosin, and the troponin complex in the presence and absence of calcium ions. A, In the absence of calcium ions, the long tropomyosin molecule is bound to the myosin-binding site on the actin filament (large spheres representing actin monomers polymerize to form the actin filament). B, Calcium ions (Ca2+), upon their release from the sarcoplasmic reticulum, bind to the troponin C subunit of the troponin complex (total ion current [TIC] spherical complex with Ca2+-binding site on the C subunit); subsequent conformational changes increase the affinity of the troponin T subunit for the tropomyosin molecule. The troponin-tropomyosin-Ca2+ complex triggers movement of the tropomyosin molecule away from the myosin-binding site on the actin filament. Adenosine-5′-triphosphate (ATP) binds to a site on the myosin head domain and, upon hydrolysis to adenosine-5′-diphosphate (ADP) and inorganic phosphate (Pi), triggers a conformational change that allows the myosin head to move along the actin filament in the direction of the Z line (not shown).
      • The Neuromuscular Connection
      • Mechanism of Contraction
        • BOX 36-1 KEY CONCEPTS
    • ANATOMY AND FUNCTION OF THE HEART
    • ENERGY METABOLISM
    • ENERGY DEMANDS OF DIFFERENT MUSCLE TYPES
      • Skeletal Muscle
      • Cardiac Muscle
      • Smooth Muscle
        • BOX 36-2 KEY CONCEPTS
        • BOX 36-2 SECTION OBJECTIVES
    • PATHOLOGICAL CONDITIONS
      • Cardiac Disorders
        • Ischemic Heart Disease
        • Effects of Occlusion on Myocardium
        • Acute Coronary Syndromes (ACS)
        • Congestive Heart Failure (CHF)
        • Cardiomyopathy
        • Arrhythmias
        • Congenital and Valvular Heart Disease
      • Skeletal Muscle Disorders
        • Anterior Root and Peripheral Nerve Involvement
        • Disorders of Muscle Fibers: Muscular Dystrophies
        • Disturbances of the Neuromuscular Junction
          • BOX 36-3 KEY CONCEPTS
          • BOX 36-3 SECTION OBJECTIVES
    • FUNCTION TESTS
    • DRUG THERAPY
      • Glycosides
      • Antiarrhythmic Drugs
    • CHANGE OF ANALYTE IN DISEASE
      • Myocardiocyte Biomarkers
        • Fig. 36-2 Relative marker increase after myocardial infarction. Markers are expressed as multiples of the upper limit of the reference interval. Therefore, the relative increase varies, depending on the normal reference interval used. The time scale above (x-axis) is not linear.
        • Definition of Myocardial Infarction (MI)
        • Cardiac Biomarkers in MI
        • Recommendations for the Use of Cardiac Biomarkers in Coronary Disease
        • Diagnostic Use of Cardiac Troponin T (cTnT) and Cardiac Troponin I (cTnI)
        • cTnI
        • cTnT
        • cTnI Versus cTnT
        • Myoglobin
        • CK and CK Isoenzymes in Conditions Other Than MI
        • Caveats for Diagnostic Performance of Cardiac Biomarkers for MI
        • B-type Natriuretic Peptide, or Brain Natriuretic Peptide (BNP)
          • BOX 36-4 KEY CONCEPTS
    • BIBLIOGRAPHY
    • INTERNET SITES
    • Guidelines for MI
  • Chapter 37 Coronary Artery Disease: Lipid Metabolism
    • Key Terms
      • Abbreviations
      • Methods on Evolve
      • BOX 37-1 SECTION OBJECTIVES
    • PART 1: Lipids
    • NORMAL PHYSIOLOGY OF LIPIDS
      • Lipid Composition of Foods
      • Fat Digestion, Absorption, and Metabolism of Lipids
        • Intraluminal Phase
        • Absorptive Phase
          • Fig. 37-1 Cholesterol absorption pathway. ABCA1, ATP binding cassette transporter A1; ABCG5/G8, ATP binding cassette transporter G5/G8; ACAT, acyl-coenzyme A:cholesterol acyltransferase; ApoA-I, apolipoprotein A-I; ASBT, apical sodium-dependent bile acid transportor; B48, apolipoprotein B-48; CE, cholesteryl ester; CM, chylomicron; FA, fatty acid; MTP, microsomal triglyceride transfer protein; NPC1L1, Niemann-Pick C-1–like 1; TG, triglyceride;, biliary cholesterol;, dietary cholesterol;, dietary triglyceride;, plant sterols;, bile acids;, fatty acids.
        • Transport Phase
          • Fig. 37-2 Origin and catabolic pathway of chylomicron and very-low-density lipoprotein (VLDL). End product of chylomicron is chylomicron remnant; end product of VLDL is LDL. Chol, Cholesterol; PL, phosphatidyl lecithin; TG, triglyceride.
        • Role of Liver in Metabolism of Lipids
          • BOX 37-1 KEY CONCEPTS
          • BOX 37-2 SECTION OBJECTIVES
    • CHOLESTEROL METABOLISM
      • Biological Functions
        • Fig. 37-3 Chemical structure of cyclopentanoperhydrophenanthrene ring. This common four-ring structure is the basic structure of all steroids.
      • Physiology
        • Fig. 37-4 Scheme of dynamics of cholesterol metabolism.
      • Synthesis
        • Fig. 37-5 Scheme of low-density lipoprotein (LDL) uptake and catabolism by a cell. Mechanism not only clears LDL from circulation but also aids in regulation of cholesterol synthesis and storage. High-density lipoprotein (HDL) plays an integral role in removing cellular cholesterol, esterifying free cholesterol in blood, and transporting cholesterol to the liver for catabolism. ACAT, Acyl-CoA:cholesterol acyltransferase; EC, cholesteryl ester; HMG-CoA reductase, 3-hydroxy-3-methylglutaryl-coenzyme A reductase; LCAT, lecithin:cholesterol acyltransferase; PL, phospholipid; RER, rough endoplasmic reticulum; SER, smooth endoplasmic reticulum.
      • Catabolism
        • Fig. 37-6 Metabolic pathway of cholesterol synthesis, emphasizing negative feedback end-product inhibition by cholesterol on the rate determining enzyme HMG-CoA reductase.
      • Expected Cholesterol Values
        • Box 37-1 National Institutes of Health National Cholesterol Education Program Adult Treatment Panel III8 Guidelines
          • Optimal Fasting Levels
          • Near or Above Optimal Fasting Levels
          • Borderline High Fasting Levels
          • High Fasting Levels
          • Very High Fasting Levels
        • Box 37-2 Risk Factors Associated With the Development of Coronary Heart Disease
          • Major
          • Other
          • Negative Risk Factors
        • Genetics
        • Age
        • Sex
        • Diet
        • Obesity
        • Physical Activity
        • Hormones
        • Primary Disease States
    • TRIGLYCERIDE METABOLISM
      • Biological Functions
      • Physiology
      • Synthesis
      • Catabolism
      • Expected Triglyceride Values
        • Box 37-3 Factors That Contribute to Elevated Serum Triglycerides
        • BOX 37-2 KEY CONCEPTS
        • BOX 37-3 SECTION OBJECTIVES
    • PART 2: Apolipoproteins
      • Apolipoprotein A
        • Table 37-1 Physical and Chemical Descriptions of Plasma Lipoproteins in Humans
        • Table 37-2 Characteristics and Functions of Serum Apolipoproteins
      • Apolipoprotein B
      • Apolipoprotein C
      • Apolipoprotein E
      • Apolipoproteins as Markers of Cardiovascular Disease Risk
        • BOX 37-3 KEY CONCEPTS
        • BOX 37-4 SECTION OBJECTIVES
    • PART 3: Lipoproteins
      • Fig. 37-7 Scheme of HDL (high-density lipoprotein), a lipoprotein complex showing polar outer surface and a core filled with neutral lipids.
      • Fig. 37-8 Overview of major types of lipoproteins, showing some basic chemical and physical properties. alpha, α-Lipoprotein; beta, β-lipoprotein; chylo, chylomicrons; preBeta, a very-low-density lipoprotein; Sf, Svedberg flotation rate.
    • CLASSIFICATION OF LIPOPROTEINS
      • Chylomicrons
      • Very-Low-Density Lipoprotein
      • Low-Density Lipoprotein
      • High-Density Lipoprotein
      • Other Lipoproteins
        • IDL
        • Lp(a)
        • Lipoprotein X
    • LIPOPROTEIN METABOLISM
      • Fig. 37-9 Exogenous lipoprotein transport pathway. B48, Apolipoprotein B-48; C-II, apolipoprotein C-II; CE, cholesteryl ester; CM, chylomicron; CM-Rem, chylomicron remnant; E, apolipoprotein E; FC, free cholesterol; LPL, lipoprotein lipase; LDLR, LDL receptor; LRP, LDL receptor–related protein; TG, triglyceride.
      • Fig. 37-10 Endogenous lipoprotein transport pathway. B100, Apolipoprotein B-100; C-III, apolipoprotein C-III; CE, cholesteryl ester; E, apolipoprotein E; FC, free cholesterol; HL, hepatic lipase; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; LPL, lipoprotein lipase; SR-A, scavenger receptor type A; VLDL, very-low-density lipoprotein.
      • Fig. 37-11 Reverse cholesterol transport pathway. ABCA1, ATP binding cassette transporter A1; A-I, apolipoprotein A-I; B100, apolipoprotein B-100; CE, cholesteryl ester; FC, free cholesterol; LCAT, lecithin:cholesterol acyltransferase; LDLR, low-density lipoprotein receptor; TG, triglyceride.
      • Chylomicrons
      • Very-Low-Density Lipoprotein
      • Intermediate-Density Lipoprotein
      • Low-Density Lipoprotein
      • High-Density Lipoprotein
        • BOX 37-4 KEY CONCEPTS
        • BOX 37-5 SECTION OBJECTIVE
    • PART 4: Pathological Disorders
    • HYPERLIPIDEMIA
    • HYPERLIPOPROTEINEMIA
    • METABOLIC SYNDROME
      • Table 37-3 Causes of Secondary Hyperlipoproteinemia
      • Box 37-4 Features Characteristic of Metabolic Syndrome
    • GENETIC DYSLIPOPROTEINEMIAS
      • Familial Hyperchylomicronemia
      • Familial Lipoprotein Lipase Deficiency
        • Fig. 37-12 Summary of six types of hyperlipoproteinemias. Abbreviations as in Fig. 37-8.
        • Table 37-4 Genetic Dyslipidemias
      • ApoC-II Deficiency
      • Familial Hypertriglyceridemia
      • Monogenic Hypercholesterolemia
        • Familial Hypercholesterolemia
        • Familial Defective ApoB-100
        • Familial Combined Hyperlipidemia
        • Familial Dysbetalipoproteinemia
      • Monogenic Hypocholesterolemia
        • Familial Hypobetalipoproteinemia
        • Abetalipoproteinemia
      • Chylomicron Retention Disease
      • Familial Hypoalphalipoproteinemia
      • Tangier Disease
    • TRANSFORMATION OF HYPERLIPIDEMIA TO HYPERLIPOPROTEINEMIA
      • From Lipids to Lipoproteins: Laboratory Considerations
      • Secondary Hyperlipoproteinemia
        • BOX 37-5 KEY CONCEPTS
        • BOX 37-6 SECTION OBJECTIVES
    • CLINICAL IMPLICATIONS OF HYPERLIPIDEMIA
      • Coronary Artery Disease
        • Box 37-5 Primary and Secondary Risk Factors Associated With Coronary Heart Disease
          • Primary
          • Secondary
        • Risk Factors Associated With CAD
          • Fig. 37-13 Diagram of a healthy blood vessel (artery) with normal integrity of the intima, media, and adventitia.
    • ATHEROSCLEROTIC PLAQUE FORMATION
      • Fig. 37-14 The three stages of atherogenesis: formation of the fatty streak, fibrous plaque, and complicated lesion. Note the development and accumulation of foam cells in the fatty streak, accumulation of smooth muscle cells in the fibrous plaque, and formation of calcification, ulceration, thrombosis, and hemorrhage in the advanced or complicated lesion.
      • Fig. 37-15 Formation of the foam cell: macrophage uptake (ingestion) of modified low-density lipoprotein (LDL) by the modified LDL receptor pathway, which results in the development of large fat-laden droplets. This process of foam cell formation is the hallmark of fatty streak development in atherogenesis.
      • Fig. 37-16 Modification of low-density lipoprotein (LDL). Entrapped native LDL (in the subendothelial space) can undergo two types of modification: derivatization (malondialdehyde attachment to or glycosylation of apoB-100) or oxidation (degradation of apoB-100 by superoxides).
      • BOX 37-6 KEY CONCEPTS
      • BOX 37-7 SECTION OBJECTIVES
      • Change of Analyte in Disease: Therapeutic Guidelines and Treatment
        • Fig. 37-17 Hypothesis of the multiple roles of oxidized low-density lipoprotein (LDL) in atherogenesis.
        • Table 37-5 Classifications of Risk in Adults Based on Low-Density Lipoprotein Cholesterol
        • Table 37-6 NCEP ATP III Risk Classification for HDL Cholesterol Levels
        • Table 37-7 Recommendations from the NCEP for Children and Adolescents
        • Box 37-6 Major Therapeutic Modalities
          • Therapeutic Lifestyle Changes
          • Pharmaceuticals
          • Cholesterol absorption inhibitors
        • Fig. 37-18 Algorithm of coronary heart disease risk assessment, treatment, and monitoring using the National Cholesterol Education Program (NCEP) Adult Treatment Panel III guidelines8 for primary prevention in adults with and without evidence of coronary heart disease (CHD). Initial classification of risk is based on nonfasting results of both total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) concentrations. RF, Risk factor.
        • Fig. 37-19 Algorithm of coronary heart disease (CHD) risk assessment, treatment, and monitoring for primary and secondary prevention of CHD in adults with and without evidence of CHD. Classification of risk is based on fasting results on low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG) concentrations, and other risk factors. Monitoring of LDL cholesterol response to therapy should be evaluated 6, 12, and 16 to 24 weeks after initiation of therapy. If the initial goal is to reduce the risk for acute pancreatitis, rapid reduction of triglycerides by diet is required; triglyceride monitoring should be done within a few days. RE, Risk equivalent; RF, risk factor; TLC, therapeutic lifestyle changes.
        • Table 37-8 Three Categories of Risk That Modify LDL Cholesterol Goals
        • Table 37-9 Comparison of LDL Cholesterol and Non-HDL Cholesterol Goals for Three Risk Categories
        • Table 37-10 National Cholesterol Education Program Recommendations for Triglyceride Classification of Risk
        • BOX 37-7 KEY CONCEPTS
    • REFERENCES
    • INTERNET SITES
      • General
      • Biochemistry of Lipids and Lipoproteins
      • Diagnosis and Treatment/Adult Treatment Panel/National Institutes of Health Sites
      • Atherosclerosis
  • Chapter 38 Diabetes Mellitus
    • Key Terms
    • Methods on Evolve
    • BOX 38-1 SECTION OBJECTIVES
    • DIABETES
      • BOX 38-1 KEY CONCEPTS
      • Fig. 38-1 A through E, The insulin signaling pathway. Insulin binds to the α-unit of the insulin receptor, thus beginning a cascade of phosphorylations that leads to the transport of glucose transporter protein-4 (GLUT-4) from vesicles in the cytoplasm to the plasma membrane. GLUT-4 binds with glucose and transports it to the cytoplasm, where it is phosphorylated to form glucose 6-phosphate. See text for details.
      • BOX 38-2 SECTION OBJECTIVES
    • GLUCOSE: PROPERTIES AND METABOLISM
      • Definition
      • Function
      • Insulin Signaling Pathway
      • Principal Glucose Metabolic Pathways
        • Fig. 38-2 The five principal pathways of glucose metabolism: glycolysis, tricarboxylic acid pathway, glycogenesis, hexose monophosphate shunt, and the uronic acid pathway.
      • Aerobic Glycolysis
        • Glycolysis
        • Tricarboxylic Acid Cycle
        • Electron Transport Chain (Oxidative Phosphorylation)
      • Anaerobic Glycolysis
        • Alternate Energy Sources
      • Glycogenesis, Glycogenolysis, and Gluconeogenesis
        • Glycogen
          • Fig. 38-3 Two stages of glycolysis. First stage proceeds from glucose to formation of 1,3-diphosphoglycerate and consumes 2 mol of adenosine triphosphate (ATP). Second stage proceeds from 1,3-diphosphoglycerate to pyruvate and produces 4 mol of ATP. Glycolysis therefore results in net gain of 2 mol of ATP per mole of glucose. The synthesis of 2,3-DPG by the Rapoport-Luebring cycle is important for the regulation of oxygen transport.
        • Glycogenesis
          • Fig. 38-4 Tricarboxylic acid cycle produces CO2 and water from pyruvate, fatty acids, and amino acids, which enter the cycle at the points indicated. Hydride ions (H−) are produced and used in the oxidative phosphorylation process to produce adenosine triphosphate (ATP) from adenosine diphosphate (ADP) and inorganic phosphate.
          • Fig. 38-5 Glycogen is a 1 to 4 million Dalton polysaccharide composed of glucose units in 1,4- and 1,6-glycosidic linkage. The 1,6-bonds produce branches at intervals of approximately 10 glucose units.
        • Glycogenolysis
          • Fig. 38-6 Glycogen, the storage molecule for glucose, is synthesized from glucose-1-phosphate through a process called glycogenesis (left side). Glycogenolysis releases glucose units from glycogen. Debranching is the first step in glycogenolysis (right side).
        • Gluconeogenesis
          • Fig. 38-7 Pathways involved in gluconeogenesis from amino acids, fatty acids, glycerol, and lactate. This pathway shares many of the enzymes of glycolytic and tricarboxylic acid pathways. Gluconeogenesis provides glucose whenever scarcity of glucose occurs, and whenever lactate accumulates. ALT, Alanine transaminase; LD, lactate dehydrogenase; PC, pyruvate carboxylase.
      • Hormone Regulation of Glucose Metabolism
        • Fig. 38-8 Amino acid sequence of human preproinsulin. The series of enzymatic cleavages of preproinsulin (site 1) to proinsulin and of proinsulin (sites 2 and 3) to insulin are described in text.
        • Insulin
        • Glucagon and Cortisol
          • Table 38-1 Metabolic Action of Insulin
        • Epinephrine
        • Incretins
        • Other Hormones
      • Glucose Metabolism in Diabetes Mellitus
        • Metabolic Processes in the Normal Individual
        • Metabolic Processes in the Person With Diabetes15,20
          • Fig. 38-9 Oral glucose tolerance test (OGTT, see p. 746). Response of person with diabetes to OGTT is compared with normal response. In diabetic individuals, the glucose curve is elevated and delayed. In normal response, a peak is reached after 30 minutes and returns to baseline value after 2 hours. Those with type 1 diabetes produce a nearly flat insulin curve after glucose load. If there is a peak, it occurs late (later than 1 hour). In type 2 diabetes, insulin response often is exaggerated, the peak is late, and the return to baseline value is later than 3 hours.
          • BOX 38-2 KEY CONCEPTS
          • BOX 38-3 SECTION OBJECTIVE
    • CLASSIFICATION OF DIABETES MELLITUS
      • Type 1 Diabetes
      • Type 2 Diabetes
      • Secondary Diabetes
        • Table 38-2 Classification of Diabetes and Other Categories of Glucose Intolerance
      • Impaired Glucose Tolerance
      • Gestational Diabetes
        • Table 38-3 Genetic Changes Related to Diabetes Mellitus
        • BOX 38-3 KEY CONCEPTS
        • BOX 38-4 SECTION OBJECTIVES
    • PATHOGENESIS OF DIABETES MELLITUS
      • Introduction
      • Genetic Factors (Type 2 Diabetes)
      • Genetic Factors (Type 1 Diabetes)
      • Viruses
        • BOX 38-4 KEY CONCEPTS
        • BOX 38-5 SECTION OBJECTIVES
    • COMPLICATIONS OF DIABETES MELLITUS
      • Retinopathy
      • Neuropathy
      • Angiopathy
      • Nephropathy
        • Fig. 38-10 Pathways involved in keto acid metabolism. Accumulation of keto acids, acetoacetate, and β-hydroxybutyrate is a principal feature of diabetic ketoacidosis. The metabolic pathway leading from acetyl-CoA to acetoacetate and β-hydroxybutyrate is accelerated in diabetes because of free fatty acid mobilization.
      • Infection
      • Hyperlipidemia and Atherosclerosis
      • Diabetic Ketoacidosis (DKA)
        • Keto Acid Metabolism
        • Keto Acids and Insulin
        • Diagnosis of Ketoacidosis
        • Lactic Acidosis
      • Hyperglycemic Hyperosmolar Nonketotic Coma
      • Hypoglycemia
        • Box 38-1 Causes of Fasting Hypoglycemia
        • Effects of Diabetes on the Fetus (see also Chapters 44 and 45)
      • Other Complications of Diabetes
        • BOX 38-5 KEY CONCEPTS
        • BOX 38-6 SECTION OBJECTIVE
    • PATHOGENESIS OF DIABETIC COMPLICATIONS
      • Protein Glycation
      • Sorbitol Accumulation
        • BOX 38-6 KEY CONCEPTS
        • BOX 38-7 SECTION OBJECTIVES
    • FUNCTION TESTS
      • Postprandial Plasma Glucose
      • Oral Glucose Tolerance Test
        • Factors Affecting Glucose Tolerance
          • Table 38-4 Comparison of the Criteria for Evaluation of Oral Glucose Tolerance Test Using 75 G or 100 G Glucose Challenges
      • Fasting Blood Glucose
      • O'Sullivan-Mahan Glucose Challenge Test and Carpenter-Coustan OGTT for Gestational Diabetes
      • Intravenous Glucose Tolerance Test
        • BOX 38-7 KEY CONCEPTS
        • BOX 38-8 SECTION OBJECTIVES
    • CHANGE OF ANALYTE IN DISEASE
      • Fasting Plasma Glucose
        • Box 38-2 Conditions and Diseases that Often Cause Both Hyperglycemia and Glucosuria or Glycosuria in the Absence of Hyperglycemia
          • Hyperglycemia and Glucosuria
          • Glucosuria and Normal Plasma Glucose
      • Urinary Glucose
      • Self-Monitoring and Bedside Monitoring of Blood Glucose81
      • Glycated Hemoglobin82–89
      • Insulin
      • Keto Acids
      • Urinary Protein91–94
      • Lactic Acid
      • Hydrogen Ion (pH)
      • Electrolytes
      • Osmolality
      • Body Fluid Volume
      • Anion Gap
      • Blood Urea Nitrogen (BUN)
      • Lipids
        • BOX 38-8 KEY CONCEPTS
        • BOX 38-9 SECTION OBJECTIVES
    • SCREENING
    • TREATMENT
      • Type 1 Diabetes Mellitus
      • Type 2 Diabetes Mellitus
        • BOX 38-9 KEY CONCEPTS
    • REFERENCES
    • INTERNET SITES
  • Chapter 39 Iron and Porphyrin Metabolism
    • Key Terms
      • Methods on Evolve
      • BOX 39-1 SECTION OBJECTIVES
    • PART 1: Iron Metabolism
    • DISTRIBUTION AND FUNCTION
    • METABOLISM
      • Table 39-1 Iron Distribution and Function in a Normal Male Adult
      • Absorption
        • Fig. 39-1 Iron absorption. Dietary iron is reduced from Fe3+ to Fe2+ at the apical surface of intestinal epithelial cells by a ferric reductase enzyme (known as duodenal cytochrome b, or DcytB). Ferrous iron then is taken into cells by a divalent metal transporter (DMT1). Within the cell, iron may be stored as ferritin, or it may be transported through the basolateral surface to enter the circulation. The basolateral transporter, called ferroportin, works in combination with hephaestin, a copper-containing protein that oxidizes Fe2+ back to Fe3+.
        • Fig. 39-2 Delivery of iron to cells. Iron-loaded transferrin (Fe2-Tf) binds to transferrin receptors (TfR) on the cell surface. A portion of the cell membrane then is pinched off to form an endosome, a self-enclosed fragment of the membrane with the Fe2-Tf-TfR complex inside. Protons (H+) are pumped into the endosome, releasing iron from transferrin. Iron is transported out of the acidified endosome and into the cytoplasm, where it can enter the mitochondria for heme synthesis or can be stored as ferritin. The endosome then fuses with the cell membrane, and iron-free apotransferrin (Apo-Tf) is released into the extracellular space.
      • Red Blood Cell Turnover
      • Transport and Cell Uptake
        • Fig. 39-3 Regulation of iron. Iron may enter the circulation from intestinal cells (absorbed iron) or from macrophages (turnover of red blood cells). Hepcidin, a small polypeptide hormone that regulates the flow of iron from these cells into plasma, is produced in the liver. Several proteins involved in iron metabolism, including HFE, are thought to modulate hepcidin production and release.
      • Storage
      • Control of Iron Balance
        • BOX 39-1 KEY CONCEPTS
        • Table 39-2 Laboratory Measurements of Iron Status
        • BOX 39-2 SECTION OBJECTIVES
    • PATHOLOGICAL CONDITIONS
      • Iron Deficiency
      • Iron Overload
        • Hereditary Hemochromatosis
          • Table 39-3 Hereditary Disorders Causing Iron Overload
        • Acquired Hemochromatosis
          • BOX 39-2 KEY CONCEPTS
          • BOX 39-2 SECTION OBJECTIVES
    • CHANGE OF ANALYTE IN DISEASE
      • Complete Blood Count (CBC)
      • Serum Iron, TIBC, and Transferrin Saturation
      • Serum Ferritin
      • Free Erythrocyte Protoporphyrin
      • Molecular Genetics
        • BOX 39-3 KEY CONCEPTS
        • BOX 39-4 SECTION OBJECTIVES
    • PART 2: Heme Synthesis and the Porphyrias
    • STRUCTURE AND FUNCTION
      • Fig. 39-4 Chemical structures of pyrrole and the porphyrin ring. One of the pyrrole units within the porphyrin ring appears in boldface.
    • METABOLISM
      • Synthetic Pathway
        • Fig. 39-5 Initial steps in porphyrin synthesis. The difference between the type I and type III isomers of uroporphyrinogen is indicated by the bolded side chains. Only the type III isomer is a precursor of heme. A, Acetate; P, propionate.
        • Fig. 39-6 Latter half of the heme biosynthetic pathway. Note the difference in structure between a porphyrinogen and a porphyrin (compare protoporphyrinogen IX to protoporphyrin IX). M, Methyl; P, propionate; V, vinyl.
      • Regulation
        • Fig. 39-7 Distribution of the porphyrin pathway between mitochondria and cytosol.
        • BOX 39-4 KEY CONCEPTS
        • BOX 39-5 SECTION OBJECTIVES
    • PATHOLOGICAL CONDITIONS
      • Neurological Porphyrias
        • Table 39-4 Biochemical and Clinical Features of the Neurological Porphyrias
        • Acute Intermittent Porphyria
        • Variegate Porphyria
        • Hereditary Coproporphyria
        • ALA Dehydratase Deficiency
          • Table 39-5 Biochemical and Clinical Features of the Cutaneous Porphyrias
      • Cutaneous Porphyrias
        • Porphyria Cutanea Tarda
        • Protoporphyria
        • Congenital Erythropoietic Porphyria
      • Secondary Disorders of Porphyrin Metabolism
        • Lead Poisoning
          • Table 39-6 Laboratory Diagnosis of the Porphyrias
        • Iron Deficiency
        • Coproporphyrinuria
          • BOX 39-5 KEY CONCEPTS
          • BOX 39-6 SECTION OBJECTIVES
    • CHANGE OF ANALYTE IN DISEASE
      • Porphobilinogen (PBG)
      • Delta-Aminolevulinic Acid (ALA)
      • Urine Porphyrins
      • Fecal Porphyrins
      • Red Blood Cell Porphyrins
      • Enzyme Assays
      • Molecular Genetics
        • BOX 39-6 KEY CONCEPTS
    • BIBLIOGRAPHY
      • Iron Metabolism
      • Heme Synthesis and the Porphyrias
    • INTERNET SITES
      • Porphyria
      • Iron Metabolism
      • Hemochromatosis
  • Chapter 40 Hemoglobin
    • Key Terms
      • Methods on Evolve
      • BOX 40-1 SECTION OBJECTIVES
    • STRUCTURE AND FUNCTION OF HEMOGLOBIN
      • Genetics
      • Structure
        • Fig. 40-1 The β-globin chain showing helical and nonhelical segments. The helical segments are labeled A through H, whereas nonhelical segments are designated NA for those residues between the N terminus and the A helix, CD for residues between the C and D helices, and so forth.
      • Ontogeny
        • Fig. 40-2 Diagrammatic representation of the tertiary structure of the hemoglobin molecule, showing the location of variant hemoglobins that impart physical instability to the molecule. Each chain carries an iron-containing porphyrin derivative called heme, a ferriprotoporphyrin IX in which one iron atom is bound in the center of the porphyrin ring. The FG corner is shown and represents an important area of the molecule that regulates oxygen binding and release. 2,3-Biphosphoglycerate (2,3-BPG), an important oxygenregulating enzyme, is located in the central clear area of the molecule.
        • Fig. 40-3 Quaternary structure of hemoglobin. The α1- and β2-chains are in the foreground, and α1β2 contact is at the center.
        • Fig. 40-4 Developmental switching of globin synthesis and the globin chain composition of human hemoglobins. Switching of gene expression within the β-like and α-like gene clusters leads to the synthesis of different hemoglobins within the embryo, fetus, infant, and adult. Top, The globin gene–containing chromosomes and their contributions to the hemoglobin molecules of the embryo, fetus, and adult. Bottom, Embryonic ɛ- and ζ-chains rapidly disappear and are replaced by fetal γ-and adult α-chains. γ-Chain synthesis peaks at mid gestation and reaches its adult level at 6 months of age. A progressive rise in β-chain synthesis is seen from the first trimester to its peak at 6 to 12 months of age. Small amounts of synthesized δ-chain peak at about 12 months.
        • BOX 40-1 KEY CONCEPTS
    • NORMAL HEMOGLOBIN BIOCHEMISTRY
      • Assembly of Hemoglobin
      • Functional and Structural Interrelationships
        • Hemoglobin and Oxygen: The Oxygen Dissociation Curve
          • Fig. 40-5 Oxygen dissociation curves of normal human hemoglobin. Heavy middle line, Dissociation curve of normal adult blood (temperature 37°C, pH 7.4, PCO2 35 mm Hg). Dots, P50 values, partial pressure of oxygen (27 mm Hg) at which hemoglobin solution is 50% oxyhemoglobin and 50% deoxyhemoglobin. If temperature increases, pH decreases, or carbon dioxide tension (PCO2) increases, the curve shifts to the right. This shift increases the release of oxygen from hemoglobin at given oxygen tension by decreasing its oxygen affinity. If temperature decreases, pH rises, or carbon dioxide tension decreases, the oxygen dissociation curve moves to the left. This shift increases the oxygen-binding capacity of hemoglobin at given oxygen tension, resulting in a decrease in oxygen release.
      • Oxygen Affinity and Transport
        • Bohr Effect
      • 2,3-Biphosphoglycerate
      • Other Chemical Derivatives of Hemoglobin
        • Hemoglobin A1
        • Carbaminohemoglobin
        • Carboxyhemoglobin
        • Methemoglobin
        • Hemichromes
        • Sulfhemoglobin
          • BOX 40-2 SECTION OBJECTIVES
    • NORMAL HUMAN HEMOGLOBINS (Table 40-1)
      • Hemoglobin A (α2β2)
      • Hemoglobin A2 (α2δ2)
        • Table 40-1 Normal Human Hemoglobins
      • Fetal Hemoglobin (α2γ2)
    • PATHOLOGICAL CONDITIONS
      • Hemoglobinopathies
      • Structural Hemoglobin Variants (see Chapter 5)
        • Nomenclature
      • Classification
        • Molecular Mechanisms Responsible for Structural Hemoglobin Variants
        • Clinical Consequences of Structural Alterations of Hemoglobin Molecules
          • Hemolytic Anemias
          • Cyanosis
          • Erythrocytosis
          • Hypochromic Anemias
        • Electrophoretic and Chromatographic Behavior of Hemoglobins
        • Sickle Cell Disorders: Sickle Hemoglobin
          • Table 40-2 Varying Clinical Severity of the Different Sickle Syndromes
        • Molecular Mechanism of Sickling
        • Pathophysiology of Sickle Cell Disease
        • Sickle Cell Trait (HbAS)
        • Sickle Cell Anemia (HbSS)
          • Box 40-1 Acute Clinical Manifestations of HbSS
            • Hematological
            • Vasoocclusive
          • Fig. 40-6 Restriction endonuclease polymorphisms in the β-globin cluster. Top, Arrows point to the cleavage sites for each of the enzymes. Bottom, Haplotypes defined by patterns of cleavage typical of the regions in which each haplotype is most prevalent.
        • Sickle Cell–HbC Disease
      • HbC Trait (Hgb AC)
        • Hemoglobin C Disease (HbCC)
        • Hemoglobin E Trait (HbAE) and Disease (HbEE)
        • Unstable Hemoglobin Disorder
    • THALASSEMIAS24–28
      • Definitions
      • Classification
        • α-Thalassemias
          • Table 40-3 Laboratory Findings in α-Thalassemias
        • β-Thalassemias25,26
        • Thalassemias and Hemoglobinopathies
        • Hereditary Persistence of Fetal Hemoglobin (HPFH)
        • Methemoglobinemia31,32
          • Acquired Methemoglobinemia32
          • Hereditary Methemoglobinemia
            • BOX 40-2 KEY CONCEPTS
            • BOX 40-3 SECTION OBJECTIVES
            • Table 40-4 Reference Intervals for Hemoglobin in Grams per Deciliter in “Apparently Healthy” Subjects, White and Black
    • CHANGE OF ANALYTE IN DISEASE
      • Interpretation of Hemoglobin Values
        • HbF
        • Hb A1c
        • Carboxyhemoglobin (CO-Hb)
      • Oxygen Saturation
      • 2,3-Biphosphoglycerate
      • Other Hemoglobins
      • Other Related Biochemical Findings
      • Use of Hemogram Results to Differentiate Iron Deficiency from Thalassemias
        • BOX 40-3 KEY CONCEPTS
    • REFERENCES
    • BIBLIOGRAPHY
    • INTERNET SITES
  • Chapter 41 Human Nutrition
    • Key Terms
      • Methods on Evolve
      • BOX 41-1 SECTION OBJECTIVES
    • NUTRIENT CLASSES
      • Table 41-1 Basic Classes of Nutrients
      • Energy Requirements3–6
        • Box 41-1 Observations Associated With the Hypermetabolic State
      • Carbohydrates (see Chapter 38)
      • Proteins
        • Requirements
          • Table 41-2 Daily Recommended Dietary Allowance for Protein and for Some Minerals and Trace Elements for Various Ages
          • Box 41-2 Essential Amino Acids
        • Nitrogen Balance
      • Lipids
      • Minerals1–3
        • Table 41-3 Major Role of Macrominerals and Associated Abnormalities
      • Fiber
        • BOX 41-1 KEY CONCEPTS
        • BOX 41-2 SECTION OBJECTIVES
    • MALNUTRITION1–5
      • Types of Malnutrition10
        • Table 41-4 WHO Classification of Marasmus
        • Box 41-3 Characteristics of Kwashiorkor
        • Protein Malnutrition—Kwashiorkor
        • Protein-Energy Malnutrition—Marasmus
          • Box 41-4 Consequences of Malnutrition and Undernutrition
        • Undernutrition
        • Micronutrient Deficiency12
        • Obesity13–15
      • General Populations
        • World Population17–19
          • Box 41-5 Medical Consequences of Obesity
          • PEM
          • Undernutrition
          • Micronutrient Deficiency
            • Box 41-6 Conditions Associated With Undernutrition or Malnutrition
          • Obesity20
        • American Population
          • Malnutrition
          • Obesity20,21
      • Institutionalized Populations
        • Box 41-7 Medical Consequences of Protein-Calorie Malnutrition in Institutionalized Individuals
      • Drug-Nutrient Interactions
        • Table 41-5 Examples of Drugs That Are Vitamin Antagonists*
        • Table 41-6 Some Classes or Individual Drugs That Influence Mineral Status
        • Box 41-8 Populations at High Risk for Drug-Nutrient Interactions
        • BOX 41-2 KEY CONCEPTS
        • BOX 41-3 SECTION OBJECTIVES
        • Box 41-9 Conditions for Which Enteral Nutrition Is Indicated
    • THERAPEUTIC NUTRITION SUPPORT1–3,31
      • Enteral Feeding
        • Box 41-10 Clinical States of Patients Likely to Benefit from Parenteral Nutrition
      • Parenteral Nutrition (PN)
      • Dietary Therapy
    • NUTRITION AND INBORN ERRORS OF METABOLISM1,32–34
    • BIOCHEMICAL PARAMETERS USED TO MONITOR NUTRITIONAL STATUS
      • General Detection and Monitoring of PEM9,36
        • Box 41-11 Anthropometric Measurements
        • Box 41-12 Properties of an Ideal Nutritional Marker
      • Refeeding Syndrome37,38
      • Nitrogen Balance
      • Protein Synthesis
        • Table 41-7 Laboratory Tests to Monitor Response to Nutrient Supplements
        • Table 41-8 Proteins Used in Nutrition Assessment
        • BOX 41-3 KEY CONCEPTS
    • REFERENCES
    • INTERNET SITES
      • General
      • World Malnutrition
      • Obesity
      • Drug-Nutrient Interactions
      • Enteral Feeding
      • Genetic Disease
      • Refeeding Syndrome
  • Chapter 42 Trace Elements
    • Key Terms
    • Methods on Evolve
    • BOX 42-1 SECTION OBJECTIVES
    • CLASSIFICATION1
      • Box 42-1 Dietary Reference Intakes (DRI) Definitions
      • Table 42-1 Recommended Daily Dietary Allowances Established for Zinc, Iodine, and Selenium (the RDA for Iron is Included for Comparison)
      • Table 42-2 Biological Roles of Essential Trace Elements and Associated Abnormalities
      • BOX 42-1 KEY CONCEPTS
      • BOX 42-2 SECTION OBJECTIVES
    • ESSENTIAL TRACE ELEMENTS
      • Chromium (Cr)2–8
        • Biochemistry
          • Table 42-3 Suggested Reference Intervals for Essential Trace Elements
        • Clinical Significance
          • Table 42-4 Acceptable and Toxic Reference Ranges for Toxic Trace Metals
        • Toxicity
        • Food Sources
      • Method8
      • Reference Intervals
      • Copper (Cu)9–16
        • Biochemistry
        • Clinical Significance
          • Table 42-5 Genetic Changes Associated With Disease
        • Food Sources of Copper
        • Methods16
        • Reference Intervals
      • Fluorine (F)17–21
        • Biochemistry
        • Clinical Significance
        • Requirement
        • Food Sources
        • Toxicity
        • Method
        • Reference Intervals21
      • Iodine (I)22–24
        • Biochemistry
        • Clinical Significance22,24
        • Requirements
        • Food Sources
        • Toxicity
        • Methods
        • Reference Intervals23
      • Manganese (Mn)25–29
        • Biochemistry
        • Clinical Significance
        • Requirement
        • Food Sources
        • Toxicity
        • Method
        • Reference Intervals
      • Molybdenum (Mo)30–34
        • Biochemistry
        • Clinical Significance
        • Requirement
        • Food Sources
        • Toxicity
        • Method
        • Reference Interval
      • Selenium (Se)35–44
        • Biochemistry35–38
        • Clinical Significance
        • Requirement
        • Food Sources
        • Toxicity
        • Method44
        • Reference Intervals
      • Zinc (Zn)45–52
        • Biochemistry
        • Clinical Significance47,48
        • Requirement
        • Food Sources
        • Toxicity52
        • Method
        • Reference Intervals
          • BOX 42-2 KEY CONCEPTS
          • BOX 42-3 SECTION OBJECTIVES
    • TOXIC TRACE METALS
      • Aluminum (Al)53–59
        • Basis for Toxicity
        • Serum Levels and Indications for Treatment
        • Method
        • Arsenic (As)60–66
        • Basis for Toxicity
        • Treatment66
        • Method
      • Cadmium (Cd)67–73
        • Basis for Toxicity
        • Clinical Significance
        • Treatment
        • Method
      • Lead (Pb)74–82
        • Basis for Toxicity
        • Clinical Significance of Lead Toxicity
        • Blood-Lead Levels
        • Treatment
        • Method
      • Mercury (Hg)86–92
        • Basis for Toxicity86,87
        • Clinical Significance
        • Treatment
        • Method100
        • Levels in Biological Samples
    • CONSIDERATIONS IN ASSESSING TRACE ELEMENT STATUS IN HUMANS
      • BOX 42-3 SECTION OBJECTIVES
    • REFERENCES
      • Classification of Trace Elements
      • Essential Trace Elements: Chromium
      • Copper
      • Fluorine
      • Iodine
      • Manganese
      • Molybdenum
      • Selenium
      • Zinc
      • Toxic Trace Metals: Aluminum
      • Arsenic
      • Cadmium
      • Lead
      • Mercury
    • INTERNET SITES
      • General
      • Arsenic
      • Cadmium
      • Chromium
      • Copper
      • Wilson's Disease
      • Menkes' Syndrome
      • Fluoride
      • Iodine
      • Manganese
      • Lead
      • Mercury
      • Selenium
      • Zinc
  • Chapter 43 Vitamins
    • Key Terms
      • Methods on Evolve
      • BOX 43-1 SECTION OBJECTIVES
    • GENERAL CONSIDERATIONS
      • Recommended Dietary Allowances and Intakes
        • Vitamin Deficiencies
          • Table 43-1 Genetic Changes Associated With Disease
          • Table 43-2 Vitamin Functions and Symptoms of Deficiency or Toxicity
          • BOX 43-1 KEY CONCEPTS
          • BOX 43-2 SECTION OBJECTIVES
    • FAT-SOLUBLE VITAMINS
      • Fig. 43-1 Structures of vitamin A compounds.
      • Table 43-3 Concentration or Excretion Rates Associated With Classical Vitamin Deficiency Symptoms*†
      • Vitamin A and Carotenoids
        • Metabolism
        • Function (see Table 43-2)
        • Clinical and Chemical Deficiency Signs
        • Pathophysiology
        • Therapeutic Uses and Toxicity
      • Vitamin E
        • Fig. 43-2 Vitamin E α-tocopherol.
        • Metabolism
        • Function
        • Clinical Deficiency Signs (see Table 43-2)
        • Chemical Deficiency Signs
        • Pathophysiology
        • Toxicity
      • Vitamin K
        • Fig. 43-3 Structures of vitamin K forms.
        • Metabolism
        • Function
        • Clinical Deficiency Signs (see Table 43-2)
        • Chemical Deficiency Signs
        • Pathophysiology
      • Vitamin D (see Chapter 33)
        • BOX 43-2 KEY CONCEPTS
        • BOX 43-3 SECTION OBJECTIVES
    • WATER-SOLUBLE VITAMINS
      • Box 43-1 B Vitamin Group
      • Ascorbic Acid (Vitamin C)
        • Box 43-2 Symptoms of Scurvy
        • Fig. 43-4 Structures of ascorbic acid and dehydroascorbate.
        • Metabolism
        • Function
        • Clinical and Chemical Deficiency Signs
        • Pathophysiology
        • Toxicity and Therapeutic Uses
      • Riboflavin (Vitamin B2)
        • Fig. 43-5 Riboflavin and its active cofactor forms.
        • Metabolism
        • Function
          • Fig. 43-6 Vitamin B6 forms and major metabolites.
        • Clinical and Chemical Deficiency Signs
        • Pathophysiology
      • Pyridoxine (Vitamin B6)
        • Metabolism
        • Function
        • Clinical and Chemical Deficiency Signs
          • Fig. 43-7 Role of vitamin B6 in tryptophan metabolism. NAD, Nicotinamide adenine dinucleotide; NADP, nicotinamide adenine dinucleotide phosphate; PLP, pyridoxal phosphate.
        • Pathophysiology
      • Niacin (Vitamin B3)
        • Metabolism
        • Function
        • Clinical and Chemical Deficiency Signs
      • Thiamine (Vitamin B1)
        • Metabolism
          • Fig. 43-8 Cofactor forms and metabolites derived from niacin or tryptophan.
          • Fig. 43-9 Thiamine and its cofactor forms.
        • Function
        • Clinical Deficiency Signs
        • Chemical Deficiency Signs
        • Pathophysiology
      • Biotin (Vitamin H)
        • Fig. 43-10 Biotin and its active form.
        • Metabolism
        • Function
        • Clinical and Clinical Deficiency Signs
        • Pathophysiology
      • Pantothenic Acid (Vitamin B5)
        • Metabolism
        • Function
        • Clinical and Chemical Deficiency Signs
        • Pathophysiology
      • Cobalamin (Vitamin B12)
        • Fig. 43-11 Pantothenic acid and its active cofactors.
        • Absorption
          • Fig. 43-12 Active vitamin B12 forms in humans: R = CH3 (methylcobalamin) and R = 5′Deoxyadenosine (deoxyadenosylcobalamine).
          • Fig. 43-13 Structure of folic acid.
        • Functions
          • Fig. 43-14 Absorption of dietary vitamin B12: R, Haptocorrin; IF, intrinsic factor; P, exogenous binding proteins.
        • Diagnostic Testing and Deficiency
          • Fig. 43-15 One-carbon transfer with the use of folic acid forms as cofactors. DHF, Dihydrofolate; DNA, deoxyribonucleic acid; dUMP, deoxyuridine monophosphate; FIGLU, formimino-L-glutaric acid; F-THF, folinic acid; MeB12, methylcobalamin; 5-MeTH, N5-methyltetrahydrofolate; THF, tetrahydrofolate; TMP, thymidine monophosphate.
        • Pathophysiology
        • Treatment
      • Folic Acid (Vitamin B11)
        • Metabolism
        • Function
        • Clinical and Chemical Deficiency Signs
        • Pathophysiology
        • Therapeutic Uses
      • Carnitine
        • Metabolism
        • Function
          • Fig. 43-16 L-Carnitine and fatty acid esters.
        • Clinical and Chemical Deficiency Signs
        • Pathophysiology
          • Fig. 43-17 Carnitine transport of acyl groups.
          • BOX 43-3 KEY CONCEPTS
          • BOX 43-4 SECTION OBJECTIVES
    • VITAMIN SUPPLEMENTATION IN DISEASE PREVENTION: THE BUSINESS OF MULTIVITAMIN SUPPLEMENTATION
      • BOX 43-4 KEY CONCEPTS
    • REFERENCES
    • INTERNET WEBSITES
  • Chapter 44 Pregnancy and Fetal Development
    • Key Terms
      • Methods on Evolve
      • BOX 44-1 SECTION OBJECTIVES
    • ANATOMICAL AND PHYSIOLOGICAL INTERACTION OF MOTHER AND FETUS
      • Fertilization and Implantation of the Ovum
        • Fig. 44-1 Attachment of blastocyst to endometrial wall.
      • Fetal Growth and Nutrition
      • Role of Placenta in Gas Exchange
      • Formation of Amniotic Fluid
        • Table 44-1 Amniotic Fluid Volume in Normal Pregnancy
        • BOX 44-1 KEY CONCEPTS
        • BOX 44-2 SECTION OBJECTIVES
    • BIOCHEMISTRY OF AMNIOTIC FLUID6
      • Water, Electrolytes, and Nitrogenous Products
      • Proteins
      • Hormones
        • Box 44-1 Hormones Identified in Amniotic Fluid
          • Proteins and Polypeptides
          • Steroids
          • Prostaglandins
        • BOX 44-2 KEY CONCEPTS
        • BOX 44-3 SECTION OBJECTIVES
    • MATERNAL BIOCHEMICAL CHANGES DURING PREGNANCY
      • Human Chorionic Gonadotropin
        • Fig. 44-2 Mean (±SE) maternal serum human chorionic gonadotropin (hCG) concentrations throughout normal pregnancy.
        • Fig. 44-3 Representation of the structures of human chorionic gonadotropin (hCG) and related molecules in the placenta, blood, and urine.
        • Fig. 44-4 Structures of the three clinically relevant estrogens.
      • Estrogens
        • Fig. 44-5 Schema of fetoplacental unit. DHEA, Dehydroepiandrosterone; 16α-OH-DHEA, 16α-hydroxydehydroepiandrosterone.
        • Fig. 44-6 Mean (solid line) and estimated 5th and 95th percentiles (shaded areas) for plasma unconjugated estriol during normal pregnancy. Estriol patterns from three actual pregnancy conditions are shown.
      • Thyroid
      • Serum Lipids
      • Serum Proteins and Liver Function
      • Proteinuria
      • Glucosuria
        • BOX 44-3 KEY CONCEPTS
        • BOX 44-4 SECTION OBJECTIVES
    • FETAL BIOCHEMICAL CHANGES DURING PRENATAL DEVELOPMENT
      • Liver Function
        • Fig. 44-7 Median and 95th percentile of α-fetoprotein (AFP) in maternal serum.
      • Renal Function
        • Fig. 44-8 Distribution and regression curve of amniotic fluid creatinine concentration in milligrams per deciliter.
      • Lung Development
        • Fig. 44-9 Composition (by weight percent) of human surfactant. PC-sat, Saturated phosphatidylcholine; PC-unsat, unsaturated phosphatidylinositol; PE, phosphatidylethanolamine; PG, phosphatidylglycerol; PI, phosphatidylinositol; PS, phosphatidylserine. Proteins include 3.8% surfactant protein (SP)-A (SP-B and SP-C detected but not quantified).
        • Fig. 44-10 Lecithin, sphingomyelin, and lecithin/sphingomyelin ratios in amniotic fluid during normal pregnancy.
      • Hemoglobin
        • Fig. 44-11 Illustration of surfactant metabolism. The anabolic synthetic and secretory pathways link with the alveolar transformation of lamellar bodies to tubular myelin that forms the functional surfactant monolayer. During the newborn period, most surfactant is taken up by type II pneumocytes and is recycled.
        • Fig. 44-12 Relationship between hemoglobin types and developmental stages in early human life. Dashed lines and hatched area, Expected development.
        • Fig. 44-13 Developmental changes in hematopoietic sites, red blood cell morphology, and hemoglobin types.
      • Bilirubin
        • BOX 44-4 KEY CONCEPTS
        • BOX 44-5 SECTION OBJECTIVES
    • PATHOLOGICAL CONDITIONS ASSOCIATED WITH PREGNANCY AND PERINATAL PERIOD
      • Placental Disorders
      • Ectopic Pregnancy
      • Preterm Delivery
        • Box 44-2 Risk Factors Associated With Preterm Birth
          • Maternal
          • Fetal
          • Infectious
      • Preeclampsia
      • Maternal Diabetes (also see Chapter 38)
      • Intrahepatic Cholestasis of Pregnancy
      • Fetal Lung Immaturity
      • Fetal Hemolytic Disorders (Rh Isoimmunization)
      • Neural Tube Defects
      • Down Syndrome
      • Recurrent Pregnancy Loss
        • BOX 44-5 KEY CONCEPTS
        • BOX 44-6 SECTION OBJECTIVES
    • CHANGE OF ANALYTE IN DISEASE
      • Human Chorionic Gonadotropin
      • Estriol
      • Fetal Fibronectin
      • Tests of Fetal Lung Maturation
        • Biochemical Assays
        • Biophysical Assays
      • Tests for Hemolytic Disease (Isoimmunization)
      • Cord Blood/Venous Bilirubin
        • Fig. 44-14 Spectrum of bilirubin in amniotic fluid. Dashed line, Absorbance at 450 nm.
        • Fig. 44-15 Relationships of absorbance at 450 nm, gestational age of amniotic fluid associated with fetal anemia, and suggested clinical measurement. OD, Optical density (absorbance).
        • Box 44-3 Bilirubin Values Typically Associated With Pathological Causes
      • Glucose Screening and Monitoring (see also pp. 746 and 747)
      • Renal Function Tests (see also p. 580)
      • α-Fetoprotein
      • Screening for Down Syndrome in the First and Second Trimesters
      • Magnesium
      • Bile Acids
        • BOX 44-6 KEY CONCEPTS
    • REFERENCES
    • INTERNET SITES
  • Chapter 45 The Newborn
    • Key Terms
      • Methods on Evolve
    • THE NEWBORN
      • BOX 45-1 SECTION OBJECTIVES
    • PHYSIOLOGICAL CHANGES ASSOCIATED WITH TRANSITION FROM INTRAUTERINE TO EXTRAUTERINE STATE
      • Cardiorespiratory Adaptation
        • Table 45-1 Chemistry Testing in Neonates: Expected Reference Intervals (Normal Values) Relative to Adults
        • Table 45-2 Fetal and Neonatal Body Composition
      • Fluid, Electrolyte, and Mineral Homeostasis (see Chapters 28, 30, and 33)
      • Gastrointestinal Functions (see Chapters 31, 34, and 35)
      • Hematological and Immune Systems (see Chapter 40)
      • Endocrine Functions (see Chapters 48 and 49)
      • Blood-Brain Barrier (see Chapter 47)
        • BOX 45-1 KEY CONCEPTS
        • BOX 45-2 SECTION OBJECTIVES
    • PATHOLOGICAL CONDITIONS IN NEONATAL MEDICINE
      • Table 45-3 Major Concerns in Neonatal Medicine
      • Box 45-1 Pathological Causes of Hyper-unconjugated Bilirubinemia
      • Neonatal Jaundice (see p. 591, Chapter 31)
        • Box 45-2 Pathological Causes of Cholestasis and Hyper-conjugated Bilirubinemia
      • Disorders of Fluid and Electrolyte Homeostasis
        • Box 45-3 Risk Factors That May Affect Phototherapy Intervention
      • Disorders of Glucose Regulation
        • Box 45-4 Causes of Neonatal Hypoglycemia
      • Calcium and Phosphate Disorders
      • Thyroid Disorders
      • Adrenal Disorders
      • Neonatal Infections
      • Neurological Disorders
      • Hematological Disorders
      • Cardiovascular Disorders
      • Distinct Problems of Small-for-GestationalAge (SGA) and Large-for-Gestational-Age (LGA) Infants
      • Distinct Problems of Preterm Neonates
        • Electrolyte Disorders
        • Nutritional Disorders
        • Respiratory Disorders
        • Necrotizing Enterocolitis (NEC)
        • Anemia of Prematurity
        • Neonatal Jaundice
          • BOX 45-2 KEY CONCEPTS
          • BOX 45-3 SECTION OBJECTIVES
    • LABORATORY REQUIREMENTS FOR NEWBORN CARE
      • Sample Volume and Sample Collection
        • Fig. 45-1 Expected blood and plasma volumes for preterm neonates, term neonates, and adults, respectively.
        • Box 45-5 Neonatal Sample Considerations
          • Collection Consideration
            • Line Samples: Infection Control
            • Heelstick Capillary Samples
          • Laboratory Considerations
        • Box 45-6 Alternative Laboratory Monitoring Techniques for Neonates in Critical Care
          • Transcutaneous
          • Blood Gases: Whole blood analysis
          • Point-of-Care Testing
        • Box 45-8 Instrumentation Considerations for Testing of Neonatal Plasma/Serum Samples
        • Box 45-7 Factors Affecting Whole Blood Tests in Neonates
      • Metabolic Diseases (see Chapter 52)
        • Table 45-4 Special Samples for Neonatal Assessment
        • BOX 45-3 KEY CONCEPTS
    • REFERENCES
    • INTERNET SITES
  • Chapter 46 Extravascular Biological Fluids
    • Key Terms
      • Methods on CD-ROM
      • BOX 46-1 SECTION OBJECTIVES
    • SEROUS FLUIDS
      • Formation
        • Normal Formation
          • Fig. 46-1 Relationships of serous membranes, body cavities, and viscera. The heart is enclosed within the pericardial sac. The outer layer of pericardium is called the parietal pericardium. Lining the exterior surface of the heart is the visceral pericardium, which also is called the epicardium. Parietal peritoneum lines the wall of the abdominal cavity. Visceral peritoneum invests stomach, liver, and intestines. The peritoneal cavity is the space between the two layers of peritoneum.
        • Abnormal Formation
          • Fig. 46-2 Pleural fluid is formed at the parietal pleura because net forces for flow of fluid out of the systemic capillaries exceed net colloid osmotic pressures. Fluid moves toward the visceral pleura, where net colloid osmotic pressure exceeds outward forces because of low hydrostatic pressure in pulmonary capillaries. Lymphatics play a role in absorption of water, protein, and particulate matter. COP, Colloid osmotic pressure; HP, hydrostatic pressure.
          • BOX 46-1 KEY CONCEPTS
          • Table 46-1 Causes of Effusions
          • BOX 46-2 SECTION OBJECTIVES
      • Change of Analyte in Disease
        • Transudates and Exudates
        • Glucose
          • Table 46-2 Diagnostic Criteria for Transudates and Exudates in Pleural Fluid
        • pH
        • Lipid
          • Box 46-1 Laboratory Analysis of a Pleural Fluid
        • Analytes as Markers for Organs and Disease
          • Fig. 46-3 Chemical determinations of body fluids as markers for specific organ involvement.
          • BOX 46-2 KEY CONCEPTS
          • BOX 46-3 SECTION OBJECTIVES
    • SYNOVIAL FLUID (SYNOVIA)
      • Fig. 46-4 Diagram of normal synovial joint.
      • Normal Synovial Fluid
      • Change of Analyte in Disease
        • Table 46-3 Physical and Chemical Characteristics of Normal Synovia
        • Table 46-4 Pathological Classification of Synovial Fluids
        • Table 46-5 Genetic Changes With Disease
        • BOX 46-3 KEY CONCEPTS
    • OTHER BODY FLUIDS
    • REFERENCES
    • INTERNET SITES
  • Chapter 47 Nervous System
    • Key Terms
      • Methods in Evolve
    • BASIC NEUROANATOMY
      • Fig. 47-1 Scheme of functional or motor control areas of the brain (right hemisphere, medial view). 1, Cerebellum; 2, medulla oblongata; 3, spinal cord; 4, pituitary gland: a, anterior lobe; b, posterior lobe; 5, frontal lobe; 6, parietal lobe; 7, occipital lobe; 8, corpus callosum; 9, thalamus; 10, pons; 11, cerebrum; 12, pineal body; 13, fornix; 14, third ventricle; and 15, fourth ventricle.
      • Fig. 47-2 Scheme of brain showing relationships of ventricles and subarachnoid space with rest of brain.
      • BOX 47-1 SECTION OBJECTIVES
    • PHYSIOLOGY AND BIOCHEMISTRY
      • Formation of Cerebrospinal Fluid
        • Fig. 47-3 Scheme of meninges. Arrangement may be compared with that of an underground parking garage. Dura and arachnoid form the roof with pia membrane as the floor. Cerebrospinal fluid (CSF) flows in the subarachnoid space.
      • Blood-Brain Barrier
      • Functions of Cerebrospinal Fluid
      • Composition of Cerebrospinal Fluid
        • Box 47-1 Characteristics of Normal Spinal Fluid
      • Brain Metabolism
      • Neurotransmitter Systems
        • Fig. 47-4 Norepinephrine (N) neuron, synapse, and postsynaptic connections. MAO, Monoamine oxidase.
        • Fig. 47-5 Enzymatic pathway for synthesis of dopamine and norepinephrine.
        • Norepinephrine
        • Dopamine
        • Acetylcholine
        • Serotonin (5-Hydroxytryptamine, 5-HT)
        • GABA (γ-Aminobutyric Acid)
        • Glutamate
        • Other Neurotransmitters
          • BOX 47-1 KEY CONCEPTS
          • BOX 47-2 SECTION OBJECTIVES
    • PATHOLOGICAL CONDITIONS: NEUROLOGICAL
      • Coma
        • Table 47-1 Some Causes of Coma and Altered Mental States
      • Intracranial Bleeding
      • Inflammatory Diseases
        • Box 47-2 CSF Abnormalities Associated With MS
      • Infectious Diseases
        • Table 47-2 CSF Findings in CNS Infections
      • Ischemia
      • Stroke
      • Diffuse Cerebral Ischemia and Hypoxia
      • Neuromuscular Diseases (see also Chapter 36)
      • Neoplastic and Paraneoplastic Syndromes
      • Epilepsy
      • Intoxication With Drugs and Poisons
      • Metabolic Diseases
      • Endocrine Diseases
        • Adrenal Disease
        • Hypothyroidism
      • Neuropathic Pain
        • Table 47-3 Drugs for Neuropathic Pain
        • Neurogenetics
          • Table 47-4 Opioid Analgesics Used in Treating Pain
          • BOX 47-2 KEY CONCEPTS
          • Table 47-5 Genetic Bases of Some Important Neurological Diseases
          • BOX 47-3 SECTION OBJECTIVES
    • PATHOLOGICAL CONDITIONS: PSYCHIATRIC
      • Schizophrenia
        • Description
        • Pathophysiology
        • Treatment
      • Affective Disorders
        • Description
        • Pathophysiology
        • Treatment
          • Table 47-6 Site of Action of Some Antidepressants
      • Anxiety Disorders
        • Description
        • Pathophysiology
        • Treatment
          • BOX 47-3 KEY CONCEPTS
          • BOX 47-4 SECTION OBJECTIVES
    • CHANGE OF ANALYTE IN DISEASE: NONDRUG ANALYTES (Table 47-7)
      • Appearance of Cerebrospinal Fluid
        • Table 47-7 Change of Analyte in CNS Disease
      • Proteins of Cerebrospinal Fluid
      • γ-Globulin Synthesis
      • Oligoclonal Bands
      • Glucose in Cerebrospinal Fluid
      • Thyroid Function Tests
      • Toxicology Screen
        • BOX 47-4 KEY CONCEPTS
        • BOX 47-5 SECTION OBJECTIVES
    • CHANGE OF ANALYTE IN DISEASE: THERAPEUTIC DRUG MONITORING
      • Antiepileptic Drugs
        • Table 47-8 Commonly Used Antiepileptic Drugs
      • Antipsychotic Drugs
      • Antidepressant Drugs
        • Tricyclic Antidepressants
          • Fig. 47-6 A, Sigmoidal relationships between clinical response and imipramine plus desipramine plasma levels. B, Curvilinear relationship between clinical response and nortriptyline plasma levels.
          • Table 47-9 Antidepressant Medications
        • Monoamine Oxidase Inhibitors
      • Anxiolytics
      • Mood Stabilizers
        • BOX 47-5 KEY CONCEPTS
    • BIBLIOGRAPHY
    • INTERNET SITES
  • Chapter 48 General Endocrinology
    • Key Terms
      • Methods on Evolve
      • BOX 48-1 SECTION OBJECTIVES
    • FUNDAMENTALS OF ENDOCRINOLOGY
      • The Chemical Nature of Hormones
        • Fig. 48-1 Location of endocrine glands.
      • Mechanisms of Hormone Action
        • Steroid Hormones
          • Fig. 48-2 Current proposed mechanism of action of steroid hormones (estrogens, androgens, progesterone, glucocorticoids, aldosterone). Steroids (S) diffuse across the plasma membrane and bind to a cytosolic or nuclear protein receptor (R). Steroid binding activates the receptor complex (S-R), which then translocates to the nucleus of the cell, where it interacts with chromatin at a specific binding site on DNA called the steroid response element. This binding activates the transcription of specific genes involved in steroid hormone action. Transcription of messenger RNA then takes place with the eventual synthesis of specific proteins by cells that are linked to steroid hormone action.
          • Fig. 48-3 Current proposed mechanism of action of peptide hormones. Peptide hormones bind to a specific receptor on the external domain of the plasma membrane. Hormone binding causes activation of a G-protein complex in the cell membrane that is coupled to and activates the enzyme adenylate cyclase. When the catalytic component of adenylate cyclase is activated, adenosine triphosphate (ATP) is converted into cyclic adenosine monophosphate (cAMP), which in turn activates cAMPdependent protein kinase, resulting in protein phosphorylation and expression of the peptide hormone effect.
          • Table 48-1 Steroid and Peptide Hormones
        • Peptide Hormones
      • Regulatory Control of Hormone Synthesis and Release
        • Feedback Control Mechanism
          • Fig. 48-4 Regulatory feedback loops of the hypothalamic-pituitary–target organ axis. The hypothalamus receives neural and sensory input to produce pituitary hormone–releasing and inhibitory peptides and factors. The pituitary responds by releasing trophic hormones that act on specific endocrine glands or tissues to promote primary gland hormone synthesis and release. The secretory hormone from the endocrine organ negatively feeds back to the higher centers of control to maintain a homeostatic balance of hormone in the circulation.
        • Control of Hormone Availability
        • Catabolism-Peptide Hormones
          • Fig. 48-5 The regulatory feedback loop of the hypothalamic-pituitary-adrenal axis. Several neurotransmitters, including acetylcholinesterase (ACh), 5-hydroxytryptamine (5-HT), norepinephrine (NE), and the cytokine interleukin-1 (IL-1), have a positive effect on the release of corticotropinreleasing hormone (CRH) from the hypothalamus. Gamma-aminobutyric acid (GABA) has a negative influence. Stress and circadian rhythm also influence the release of CRH from the hypothalamus. Both CRH and arginine vasopressin (AVP) stimulate the pituitary to release adrenocorticotropic hormone (ACTH), which in turn stimulates the adrenal gland to synthesize and release three major classes of hormones (aldosterone [ALD], cortisol [CPF], and dehydroepiandrosterone [DHEA]). Cortisol is the only adrenal steroid to feed back negatively to the hypothalamic-pituitary axis to control its own biosynthetic rate.
          • Fig. 48-6 The regulatory feedback loop of the hypothalamic-pituitary–growth hormone axis. Growth hormone release from the pituitary is driven primarily by growth hormone–releasing hormone (GH-RH) from the hypothalamus. GH-RH release from the hypothalamus is influenced positively by alpha-adrenergic and dopaminergic drugs, and by stress, sleep patterns, and exercise. Growth hormone acts on the liver to produce somatomedin-C, or insulin-like growth factor (IGF-I). This factor in turn negatively feeds back to the hypothalamic-pituitary axis to maintain homeostatic control over growth hormone secretion.
          • Fig. 48-7 The regulatory feedback loop of the hypothalamic-pituitary-gonadal axis. Biogenic amine and peptidergic neurons in the hypothalamus respond to neural and sensory input from the brain to elicit the release of gonadotropin hormone (luteinizing hormone–releasing hormone [LH-RH]). This input can be visual and olfactory in origin and occurs in a pulsatile fashion. Stress can override these inputs in a negative fashion. LH-RH in turn acts on the pituitary to synthesize and release the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH). In the female, FSH causes ovarian follicular development and the production of estradiol (E2), whereas LH causes corpus luteum development and the secretion of progesterone. Estradiol feeds back both negatively and positively to the hypothalamic-pituitary axis to control the menstrual cycle and LH secretion. FSH release feedback control is orchestrated by an ovarian peptide called inhibin. In the male, FSH causes testicular spermatogenesis, whereas LH stimulates testosterone production by the testes. Testosterone negatively feeds back to the hypothalamic-pituitary axis to control LH release, whereas a testicular peptide, inhibin, feeds back to control FSH release.
          • Fig. 48-8 The regulatory feedback loop for prolactin secretion. Prolactin release from the pituitary is under tonic inhibitory control by hypothalamusderived dopamine, or prolactin inhibitory factor (PIF). Thyrotropin-releasing hormone (TRH) in turn is stimulatory to prolactin release. Prolactin release is affected by many factors that influence dopamine release. Drugs, estrogen, and stress are overriding factors that can produce an augmentation in prolactin release from the pituitary. Estrogen can directly sensitize the pituitary to release prolactin.
          • Fig. 48-9 The regulatory feedback loop of the hypothalamic-pituitary-thyroid axis. The hypothalamus secretes thyrotropin-releasing hormone (TRH) to stimulate the synthesis and release of thyroid-stimulating hormone (TSH) from the pituitary. TSH in turn stimulates the thyroid gland to grow, vascularize, and produce the thyroid hormones tetraiodothyronine (T4) and triiodothyronine (T3). T3 is formed primarily from T4 outside the thyroid gland. T4 (through hypothalamic and pituitary conversion to T3) and T3 (directly) feed back to the hypothalamic-pituitary axis to maintain a homeostatic balance of circulating thyroid hormone.
      • Sequestration: Free and Bound Transport of Steroid and Thyroid Hormones
        • Table 48-2 Hormone Transport Proteins
        • Free and Protein-Bound Hormone Transport
          • Fig. 48-10 Free and weakly bound testosterone. Testosterone circulates while bound to two proteins: a specific binding protein, sex hormone–binding globulin (SHBG), and albumin. Only a small fraction of testosterone circulates in a free state. Total testosterone levels reflect the combination of SHBG-bound, albumin-bound, and free testosterone. The bioavailable form of circulating testosterone, the form that “sees” the tissue receptor, is composed of the free fraction and that portion that is bound to albumin. Thus bioavailable testosterone is the biologically active form of the hormone that is found in the circulation.
      • Local Hormone and Growth Factor Action
        • BOX 48-1 KEY CONCEPTS
        • Fig. 48-11 Local and systemic modalities of hormone and growth factor action. Hormones (H) are the chemical messengers that are released into the circulation by endocrine glands to effect a response.
        • BOX 48-2 SECTION OBJECTIVE
    • THE HYPOTHALAMIC-PITUITARY AXIS
      • Hypothalamus
      • Neurohypophysis
        • Fig. 48-12 Sinusoidal portal system of the pituitary gland.
      • Adenohypophysis
        • BOX 48-2 KEY CONCEPTS
        • Table 48-3 Human Hypothalamic Neurosecretory Factors
        • BOX 48-3 SECTION OBJECTIVES
    • PATHOLOGICAL CONDITIONS
      • Table 48-4 Genetic Causes of Pituitary Disease
      • Box 48-1 Disorders of the Hypothalamic-Pituitary Axis
        • Hypopituitarism
        • Hyperpituitarism
      • Pituitary Hormone Deficiency
      • Pituitary Hormone Excess
        • Primary Hyperpituitarism
        • Secondary Hyperpituitarism
          • BOX 48-3 KEY CONCEPTS
          • BOX 48-4 SECTION OBJECTIVES
    • TESTS OF HYPOTHALAMIC AND PITUITARY FUNCTION
      • ACTH Excess
        • Dexamethasone Suppression Tests (see p. 1016)
        • Inferior Petrosal Sinus Sampling (http://www.cushings-help.com/petrossal.htm)
      • GH Excess
        • Oral Glucose Tolerance Test
      • GH Deficiency
        • Insulin Challenge Test
      • Secondary Hypogonadism
        • LH-RH Challenge
          • BOX 48-4 KEY CONCEPTS
    • CHANGE OF ANALYTE IN DISEASE
      • Prolactin
      • ACTH
      • Growth Hormone
      • TSH
      • FSH/LH
        • BOX 48-5 KEY CONCEPTS
    • BIBLIOGRAPHY
    • INTERNET SITES
  • Chapter 49 Thyroid
    • Key Terms
      • Methods on Evolve
    • ANATOMY
      • BOX 49-1 SECTION OBJECTIVES
    • PHYSIOLOGY
      • Synthesis and Secretion of Thyroid Hormones
      • Synthesis and Storage of Thyroglobulin
        • Fig. 49-1 Thyroid gland structure consists of follicular cells (A) that enclose colloid (B) and parafollicular C-cells (D) in the interstitium (C). E, Venule; F, capillary.
        • Iodine Uptake and Incorporation into Thyroglobulin
        • Thyroid Hormone Secretion
          • Fig. 49-2 Chemical structure of thyroid hormones and iodinated precursors and metabolites.
          • Fig. 49-3 Thyroid cell. Schema depicting stages of thyroid hormonogenesis and intrathyroidal iodine metabolism. A, Iodine transport; B, thyroglobulin (TG) synthesis; C, iodide organification; D, intrathyroglobulin oxidative coupling; E, storage. F, endocytosis; G, hydrolysis; H, hormone secretion; I, intrathyroidal deiodination; J, recycling. Steps influenced by the thyroid-stimulating hormone (TSH) are indicated by the symbol ⊕.
      • Regulation of Thyroid Hormone Secretion
        • Hypothalamic-Pituitary-Thyroid Axis (HPTA) and Its Regulation
          • Fig. 49-4 Hypothalamic-pituitary-thyroid axis (HPTA). Stimulatory, ⊕, or inhibitory, effect of agent.
          • Fig. 49-5 The relationship between TSH and FT4 concentrations in individuals with stable thyroid status and normal hypothalamic-pituitary-thyroid function.
      • Transport of Thyroid Hormones
      • Mechanism of Action of Thyroid Hormones
      • General Metabolic and Physiological Effects of Thyroid Hormones
      • Deiodinases and the Metabolism of Thyroid Hormones
        • Table 49-1 Basic Physiological Effects of Thyroid Hormone and Their Relationship With Syndromes of Thyroid Dysfunction
        • BOX 49-1 KEY CONCEPTS
        • Fig. 49-6 Metabolic pathways of thyroid hormone. 1, Biological effects through binding to intracellular receptors; 2, main deiodinative pathway for thyroxine (T4); 3, conversion of T4 into triiodothyronine (T3); 4, conversion of T4 to reverse triiodothyronine (rT3); 5, serial deiodinations of T3 and rT3; 6, deamination and decarboxylation pathway; 7, conjugative pathway.
        • BOX 49-2 SECTION OBJECTIVES
    • PATHOLOGICAL CONDITIONS
      • Hyperthyroidism
        • Box 49-1 Causes of Hyperthyroidism
        • Graves' Disease
        • Nodules
        • Thyroiditis
          • Box 49-2 Types of Thyroiditis
            • Autoimmune
            • Infectious/Postviral
            • Other
        • Other Causes of Thyrotoxicosis
        • Subclinical Hyperthyroidism
        • Laboratory Findings (see Table 49-2)
          • Table 49-2 Changes in Thyroid Function Tests in Different Disease States
        • Treatment
      • Hypothyroidism
        • Hashimoto's Thyroiditis
          • Box 49-3 Causes of Hypothyroidism
            • Primary Hypothyroidism
            • Central (Secondary or Tertiary) Hypothyroidism
            • Thyroid Hormone Resistance
        • Other Causes of Hypothyroidism
        • Congenital Hypothyroidism
        • Secondary Hypothyroidism
        • Subclinical Hypothyroidism
        • Thyroid Hormone Resistance
        • Laboratory Findings (see Table 49-2)
        • Treatment
      • Goiter
      • Solitary Nodule
      • Thyroid Cancer
        • Useful Tests in Thyroid Nodules and Thyroid Cancer
      • Multiple Endocrine Neoplasia Syndromes
      • Drugs That Affect Thyroid Function
        • Interferon-Alpha
        • Amiodarone
          • Table 49-3 Drugs That Affect Thyroid Function and Thyroid Function Tests
          • Box 49-4 Classification of Multiple Endocrine Neoplasia
            • MEN 1
            • MEN 2A
            • MEN 2B
        • Lithium
        • Sunitinib
        • Antithyroid Drugs (Methimazole, Carbimazole, Propylthiouracil)
        • Other Causes
      • Pregnancy and Thyroid Function
      • Thyroid Function in the Fetus and Newborn (see Chapter 45)
      • Screening
        • Genetics and Thyroid Disease
      • Thyroid Function in Nonthyroidal Illness (Euthyroid-Sick Syndrome)
        • BOX 49-2 KEY CONCEPTS
        • BOX 49-3 SECTION OBJECTIVES
    • THYROID FUNCTION TESTING
      • Static Tests of Thyroid Function
        • TSH
        • Total Thyroid Hormones
        • Free Thyroid Hormones
        • Thyroid Antibodies
          • Anti-Thyroid Peroxidase Antibodies (Anti-TPO Antibodies, Previously Called Antimicrosomal Antibodies)
          • Anti-Thyroglobulin Antibodies (Anti-Tg Ab)
          • Thyroglobulin (Tg)
          • Thyroid Receptor Antibodies (TR Ab)
      • Dynamic Tests of Thyroid Function
        • TRH Stimulation Test
        • rTSH Stimulation Test for Identifying Residual Malignant Thyroid Cancer Tissue
          • BOX 49-3 KEY CONCEPTS
          • BOX 49-4 SECTION OBJECTIVES
    • CHANGE OF ANALYTE IN DISEASE
      • TSH
      • Serum Total T4
      • Serum Total T3
      • Estimates of Free Thyroid Hormone Concentration
        • Box 49-5 Causes of Abnormalities in Thyroxine-Binding Globulin (TBG)
          • Quantitative
          • Qualitative
      • T3 Resin Uptake
      • Calculated Free Thyroid Hormone Indices
      • Free Thyroid Hormones
      • Thyroid Antibodies
        • Anti-TPO Ab
        • Tg-Ab
        • Tg
        • Thyroid Receptor Antibodies (TR-Ab)
      • Discordance Between fT4 and TSH Concentrations
      • Recommendations for Thyroid Testing
      • TSH Reference Intervals
        • Box 49-6 Causes of Discordance Between TSH and fT4
          • Increased TSH Without Low fT4
          • Subnormal TSH Without Increased fT4
        • BOX 49-4 KEY CONCEPTS
        • Fig. 49-7 Logit probability (log odds) for development within twenty years of hypothyroidism with increasing values of TSH as measured at first survey in 912 female survivors.
    • REFERENCES
  • Chapter 50 The Gonads
    • Key Terms
      • Methods on Evolve
      • BOX 50-1 SECTION OBJECTIVE
    • NORMAL OVARY AND OVARIAN FUNCTION
      • Early Development of the Ovary
        • Fetal Ovary
        • Childhood and Premenarchal Ovary
      • Ovary of the Reproductive Years
        • Structural Organization of the Mature Ovary
          • BOX 50-1 KEY CONCEPTS
          • BOX 50-2 SECTION OBJECTIVES
          • Fig. 50-1 Diagram of ovary, showing sequential development of a follicle and formation of corpus luteum. Section of wall of a mature follicle is enlarged at upper right.
        • The Hypothalamic-Pituitary-Ovarian Axis: An Overview
          • Fig. 50-2 Diagram of hypothalamic-pituitary-ovarian axis. FSH, Follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; +, positive effect; −, negative effect.
        • Ovarian Steroid Hormones
        • Estrogens
          • Fig. 50-3 Principal pathways of steroid hormone biosynthesis in the human ovary. Although each cell type of the ovary contains the complete enzyme complement required for the formation of estradiol from cholesterol, the amounts of the various enzymes and consequently the predominant hormones formed differ among cell types. The major enzyme complements for the corpus luteum, theca, and granulosa cells are shown in brackets; these cells produce predominantly progesterone and 17-hydroxyprogesterone (corpus luteum), androgen (theca), and estrogen (granulosa). The major sites of action of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in mediating this pathway are shown by the horizontal arrows. The dotted line emphasizes that the metabolism of 17-hydroxyprogesterone is limited in the human ovary.
        • Progestagens
        • Androgens
        • Biosynthesis of Ovarian Steroid Hormones
        • Transport of Steroid Hormones
        • Mechanisms of Action of Steroid Hormones
        • Metabolism of Ovarian Hormones
        • Nonsteroidal Hormones
          • BOX 50-2 KEY CONCEPTS
          • BOX 50-3 SECTION OBJECTIVES
      • The Menstrual Cycle
        • Fig. 50-4 Hormonal, ovarian, endometrial, and basal body temperature changes and relationships throughout the normal menstrual cycle. E2, Estradiol; FSH, follicle-stimulating hormone; LH, luteinizing hormone; P, progesterone.
        • Follicular Phase
        • Ovulation
        • Luteal Phase
        • The Effect of Ovarian Hormones on the Uterus/Endometrium
        • Premenstrual Syndrome
        • Dysmenorrhea
      • The Menopause
        • BOX 50-3 KEY CONCEPTS
        • BOX 50-4 SECTION OBJECTIVES
    • PATHOLOGICAL STATES
      • Amenorrhea
        • Disorders of the Outflow Tract or Uterus
          • Box 50-1 Causes of Amenorrhea
            • Disorders of the Outflow Tract or Uterus
            • Disorders of the Ovary (Primary Hypogonadism)
            • Disorders of the Anterior Pituitary (Secondary Hypogonadism)
            • Central Nervous System Disorders
          • Fig. 50-5 Clinical approach to the investigation of amenorrhea. DUB, Dysfunctional uterine bleeding; FSH, follicle-stimulating hormone; fT4, free thyroxine; hCG, human chorionic gonadotropin; LH, luteinizing hormone; MRI, magnetic resonance imaging; PRL, prolactin; TSH, thyroid-stimulating hormone.
        • Disorders of the Ovary
        • Disorders of the Anterior Pituitary
          • Box 50-2 Pituitary Disorders Associated With Estrogen Deficiency and Amenorrhea
        • Central Nervous System Disorders
      • Dysfunctional Uterine Bleeding
      • Polycystic Ovary Syndrome
      • Other Disorders Associated With Androgen Excess
        • Box 50-3 Causes of Hirsutism
      • Ovarian Hyperfunction
        • BOX 50-4 KEY CONCEPTS
        • BOX 50-5 SECTION OBJECTIVES
    • NORMAL TESTES AND TESTICULAR FUNCTION
      • Early Development
      • The Mature Testes
        • Structural Organization
          • Fig. 50-6 A, Human testis, epididymis, and vas deferens showing efferent ducts leading from the rete testis to the caput epididymis and the cauda epididymis, continuing to become the vas deferens. B, Cross section through a seminiferous tubule showing central lumen, seminiferous epithelium, and interstitial space containing Leydig cells. C, Anatomical relationships in the seminiferous epithelium between germ cells (spermatogonia, spermatocytes, and spermatids), Sertoli cells, peritubular myoid cells, and Leydig cells.
        • The Hypothalamic-Pituitary-Testicular Axis: An Overview
        • Testosterone Synthesis and Secretion
        • Testosterone Transport
        • Extraglandular Metabolism of Androgens
        • The Androgen Receptor
          • BOX 50-5 KEY CONCEPTS
          • BOX 50-6 SECTION OBJECTIVES
    • PATHOLOGICAL STATES
      • Hypogonadism
        • Box 50-4 Causes of Male Hypogonadism
          • Primary Hypogonadism
          • Secondary Hypogonadism
        • Disorders of the Testes—Primary Hypogonadism
          • Fig. 50-7 Clinical approach to the investigation of male hypogonadism.
        • Secondary Hypogonadism—Hypogonadotropic Hypogonadism
      • Testicular Hyperfunction
      • Erectile Dysfunction
        • BOX 50-6 KEY CONCEPTS
        • BOX 50-7 SECTION OBJECTIVES
    • CHANGE OF ANALYTE IN DISEASE: EVALUATION OF THE INFERTILE COUPLE
      • Evaluation of Infertility
        • Fig. 50-8 Causes of infertility.
        • Fig. 50-9 Evaluation of the infertile couple. DHEA-S, Dihydroepiandrosterone sulfate; FSH, follicle-stimulating hormone; LH, luteinizing hormone; PCOS, polycystic ovarian syndrome; PRL, prolactin; T, testosterone; TSH, thyroid-stimulating hormone; USS, ultrasound scan.
      • Female Infertility
        • Box 50-6 Causes of Fallopian Tube Damage
        • Box 50-5 Causes of Female Infertility
        • Box 50-7 Causes of Male Infertility
      • Male Infertility
        • Testosterone
      • Infertility Treatment
        • Ovulation Induction
        • Assisted Reproduction
          • BOX 50-6 KEY CONCEPTS
    • BIBLIOGRAPHY
    • INTERNET SITES
  • Chapter 51 Adrenal Hormones and Hypertension
    • Key Terms
      • Methods on Evolve
    • PART 1: The Adrenal Hormones
    • ANATOMY
      • Fig. 51-1 Adrenal gland anatomy and histology.
      • BOX 51-1 SECTION OBJECTIVES
    • PHYSIOLOGY
      • Fig. 51-2 Structures of adrenocortical hormones.
      • Box 51-1 Physiological Functions of Cortisol
        • Effects on Intermediary Metabolism
        • Effects on Protein Metabolism
        • Effects on Blood Pressure
        • Effects on Immunological and Inflammatory Responses
        • Miscellaneous
      • Glucocorticoids
        • Intermediary Metabolism
        • Blood Pressure
        • Immune Function
        • Miscellaneous Functions
      • Mineralocorticoids
      • Adrenal Androgens
      • Catecholamines
        • BOX 51-1 KEY CONCEPTS
        • BOX 51-2 SECTION OBJECTIVES
    • BIOSYNTHESIS
      • Adrenocorticosteroids
        • Fig. 51-3 Principal pathways of adrenal steroidogenesis. CYP11A1, mitochondrial cholesterol desmolase, catalyzes the side-chain cleavage of cholesterol. 3β-HSD, 3-β-hydroxysteroid dehydrogenase bound to the endoplasmic reticulum, also catalyzes Δ5-Δ4 isomerase activity. CYP17 is responsible for both 17β-hydroxylase activity and 17,20-lyase activity, which cleave off the remaining side chain at the C-17 position. CYP21A2, 21-hydroxylase, catalyzes 21-hydroxylation of progesterone, and 17-hydroxyprogesterone. CYP11B1, 11β-hydroxylase, catalyzes 11 hydroxylation. CYP11B2, aldosterone synthase, catalyzes 18-hydroxylation and 18-methyloxidation. 11β-HSD 2, 11β-hydroxysteroid dehydrogenase type 2, which is mainly expressed in renal distal tubules, catalyzes the conversion of cortisol to cortisone, therefore inactivates the mineralocorticoid activity of cortisol. 11β-HSD 1, 11β-hydroxysteroid dehydrogenase type 1, which is expressed mainly in liver, reactivates cortisone to cortisol.
      • Catecholamines
        • BOX 51-2 KEY CONCEPTS
        • Fig. 51-4 Synthesis of medullary hormones. PNMT, Phenylethanolamine N-methyl-transferase; SAH, S-adenosyl homocysteine; SAM, S-adenosylmethionine.
        • BOX 51-3 SECTION OBJECTIVES
    • TRANSPORT AND CATABOLISM
      • Adrenocorticosteroids
      • Catecholamines
        • Fig. 51-5 Metabolism of medullary hormones (see text for description of abbreviations).
        • BOX 51-3 KEY CONCEPTS
        • BOX 51-4 SECTION OBJECTIVES
    • CONTROL AND REGULATION
      • Glucocorticoids
      • Mineralocorticoids
        • Fig. 51-6 Control and metabolism of glucocorticoids.
        • Fig. 51-7 Variation of serum cortisol concentration during 24-hour period in normal individual.
        • Renin-Angiotensin
          • Fig. 51-8 Control and metabolism of aldosterone.
        • Potassium and ACTH
        • Natriuretic Peptides
      • Adrenal Androgens
      • Catecholamines
        • BOX 51-4 KEY CONCEPTS
        • BOX 51-5 SECTION OBJECTIVES
    • PATHOLOGICAL CONDITIONS
      • Disorders of the Adrenal Cortex
        • Hyperadrenalism
          • Cushing's Syndrome
            • Box 51-2 Major Causes and Clinical Features of Cushing's Syndrome
              • Causes
              • Iatrogenic
              • Clinical Features
          • Hyperaldosteronism
            • Box 51-3 Major Causes and Clinical Features of Primary Hyperaldosteronism (Conn's Syndrome)
              • Causes
              • Clinical Features
        • Congenital Adrenal Hyperplasia
        • Hypoadrenalism
          • Addison's Disease
            • Box 51-4 Major Causes and Clinical Features of Primary Adrenal Insufficiency
              • Causes
              • Clinical Features
      • Disorders of the Adrenal Medulla: Pheochromocytoma
        • Box 51-5 Major Causes and Clinical Features of Pheochromocytoma
          • Causes
          • Clinical Features
        • BOX 51-5 KEY CONCEPTS
    • CHANGE OF ANALYTE IN DISEASE (see Table 51-1)
      • Hyperadrenalism
        • Cushing's Syndrome
          • BOX 51-6 SECTION OBJECTIVES
          • Table 51-1 Change of Analyte With Diseases
          • Miscellaneous Tests for the Investigation of Cushing's Syndrome
        • Primary Hyperaldosteronism
          • Fig. 51-9 Laboratory protocol for the investigation of Cushing's syndrome. See text for details.
          • Oral Salt Loading Test
          • Intravenous Saline Infusion Test
          • Fludrocortisone Suppression Test
            • Fig. 51-10 Laboratory protocol for the investigation of a patient with suspected primary hyperaldosteronism (Conn's syndrome).
      • Congenital Adrenal Hyperplasia
      • Hypoadrenalism, or Primary Adrenal Insufficiency (Addison's Disease)
      • Pheochromocytoma
        • Fig. 51-11 Laboratory protocol for the investigation of Addison's disease. Please note that secondary adrenal insufficiency is unlikely to occur with hyperkalemia.
        • Investigation of the Adrenal Incidentaloma
          • BOX 51-6 KEY CONCEPTS
          • BOX 51-7 SECTION OBJECTIVES
    • PART 2: Hypertension
    • DEFINITION AND CRITERIA
      • Table 51-2 Classification of Hypertension (JNC VII)*†
    • FACTORS REGULATING NORMAL BLOOD PRESSURE
      • Table 51-3 Factors That Regulate Blood Pressure
    • PATHOLOGICAL CONDITIONS
      • Table 51-4 Principal Causes of Hypertension
      • Secondary Hypertension
        • Renal Disease
        • Renovascular Hypertension
        • Drug-Induced Hypertension
        • Coarctation of the Aorta
        • Endocrine Causes of Hypertension
    • COMPLICATIONS OF HYPERTENSION
    • CHANGE OF ANALYTE WITH DISEASE
      • Box 51-6 Complications of Hypertension
      • Box 51-7 Minimum Evaluation of the Hypertensive Individual
      • Urinalysis
      • Sodium
      • Potassium
      • Creatinine
      • Calcium
        • Table 51-5 Causes of Hypertension and Hypokalemia Characterized by Plasma Renin Activity (PRA) and Aldosterone Levels (ALDO)
      • Uric Acid
      • Glucose
      • Lipid Profile (Total Cholesterol, HDL Cholesterol, LDL Cholesterol, and Triglyceride)
      • Electrocardiogram
      • Chest X-Ray Film
    • SECONDARY STUDIES
      • BOX 51-7 KEY CONCEPTS
    • BIBLIOGRAPHY
      • General
      • Mineralocorticoids
      • Glucocorticoids
      • Adrenal Androgens
      • Adrenal Incidentalomas
      • Congenital Adrenal Hyperplasia
      • Catecholamines and Pheochromocytoma
      • Hypertension
      • INTERNET SITES
  • Chapter 52 Diseases of Genetic Origin
    • Key Terms
      • BOX 52-1 SECTION OBJECTIVES
    • PRINCIPLES OF GENETICS
    • CATEGORIES OF GENETIC DISORDERS
      • Fig. 52-1 Pedigree demonstrating autosomal dominant inheritance.
      • Fig. 52-2 Pedigree demonstrating autosomal recessive inheritance.
      • Fig. 52-3 Pedigree demonstrating X-linked recessive inheritance.
      • Fig. 52-4 Pedigree demonstrating X-linked dominant inheritance.
      • Table 52-1 Common Single Gene Disorders
      • BOX 52-1 KEY CONCEPTS
      • BOX 52-2 SECTION OBJECTIVES
      • Variations in Mendelian Inheritance
        • Table 52-2 Common Chromosomal Disorders
        • Table 52-3 Common Chromosomal Microdeletion Syndromes
      • Imprinting and Epigenetic Disorders
        • Fig. 52-5 Pedigree demonstrating mitochondrial inheritance.
    • GENOMIC VARIATION
      • Chromosomal Aberrations
      • DNA Sequence Variations: Mutations and Polymorphisms
        • Nucleotide Substitutions, Insertions, and Deletions
          • BOX 52-2 KEY CONCEPTS
          • BOX 52-3 SECTION OBJECTIVES
    • MAPPING AND IDENTIFICATION OF DISEASE GENES
    • GENETIC TESTING
      • Diagnostic Genetic Testing
        • Cytogenetic Testing
          • Fig. 52-6 Karyotype of a normal 46,XY male. The G-band technique was performed to stain the chromosomes.
          • Fig. 52-7 Diagram illustrating the fluorescent in situ hybridization (FISH) technique.
      • Molecular Genetic Testing (see Chapter 13)
        • Mutation Screening
        • Testing for a Specified Sequence Change
        • Testing for DNA Methylation Patterns
        • Testing for Trinucleotide Repeat Disorders
        • Population Screening
      • Carrier Genetic Testing
      • Predictive Genetic Testing
        • Box 52-1 Disorders Commonly Included in Newborn Screening Programs*
          • Fatty Acid Oxidation Disorders
          • Organic Acid Disorders
          • Amino Acid Disorders
          • Other Metabolic Disorders
          • Endocrinopathies
          • Other Disorders
      • Prenatal Testing
    • TREATMENT OF GENETIC DISORDERS
      • Bone Marrow and Hematopoietic Stem Cell Transplantation
      • Replacement Therapy
      • Gene Therapy
        • BOX 52-3 KEY CONCEPTS
        • BOX 52-4 SECTION OBJECTIVE
    • ACCESS TO GENETIC RESOURCES
      • Box 52-2 Examples of Information Available on the Online Mendelian Inheritance in Man (OMIM) Website34
      • Fig. 52-8 A screen capture from the Online Mendelian Inheritance in Man (OMIM) website, from which one can search for specific diseases or classes of diseases. In this example, the disease group “lipidoses” is entered.
      • Fig. 52-9 A screen capture of the partial search result. Fabry's disease is one of the results. Detailed information may be obtained by clicking on the Online Mendelian Inheritance in Man (OMIM) number associated with Fabry's disease.
      • BOX 52-4 KEY CONCEPTS
      • Fig. 52-10 A screen capture of detailed information obtained by clicking on the Fabry's disease Online Mendelian Inheritance in Man (OMIM) number.
    • REFERENCES
  • Chapter 53 Neoplasia
    • Key Terms
      • Methods on Evolve
    • CANCER INCIDENCE IN THE UNITED STATES
      • BOX 53-1 SECTION OBJECTIVES
    • CANCER: NATURE OF THE DISEASE
      • Table 53-1 Estimated Rates of Cancer Death in 2008 in the United States by Site and Sex
      • Etiology
        • Cancer as a Multi-Step Process
        • Onocogenes6,7
          • Table 53-2 Classes of Oncogenes and Their Derived Protein Products
        • Apoptosis
        • Expression of the Cancer Phenotype: From Transformation to Cancer
      • Diversity of Cancer Cells
        • Variation of Gene Expression
      • Clinical Manifestations
      • Time as a Factor: Cancer as a Long-Term Process
        • Box 53-1 Examples of Angiogenic Factors
      • Invasion by Cancer Cells of Surrounding Tissue
      • Models of Carcinogenesis
        • Linear Model of Carcinogenesis: Colorectal Cancer Model of Tumorigenesis
        • The APC/Beta-Catenin Pathway
        • The DNA Mismatch Repair Pathway
        • Stochastic Model for Carcinogenesis
        • Factors Identified in Promotion of Metastasis
          • BOX 53-1 KEY CONCEPTS
          • BOX 53-2 SECTION OBJECTIVES
    • OVERVIEW OF ROLES OF LABORATORY TESTS
      • Detection (Screening)16
      • Confirmation
      • Classification and Staging
      • Monitoring
    • DEFINITION OF THE IDEAL TUMOR MARKER
      • BOX 53-2 KEY CONCEPTS
      • BOX 53-3 SECTION OBJECTIVES
    • CHANGE OF ANALYTE IN DISEASE
      • Classes of Biochemicals Used as Tumor Markers
      • Oncofetal Antigens
        • Carcinoembryonic Antigen
          • Table 53-3 Classes of Biochemicals Used as Tumor Markers
        • α-Fetoprotein
        • Carbohydrate Antigen 15-3 and 27-29
        • Carbohydrate Antigen 19-9
        • Carbohydrate Antigen 125
        • TA90
      • Hormones
        • Human Chorionic Gonadotropin
          • Table 53-4 WHO Classification of Germ Cell Tumors and Associated Tumor Markers
        • Calcitonin
        • Thyroglobulin
      • Cellular Markers
        • Table 53-5 Phenotypic Heterogeneity of ALL
    • TUMOR MARKERS FOR SPECIFIC MALIGNANCIES
      • Prostate Cancer
      • Breast Cancer
        • Steroid Receptor Analysis
        • HER-2 (c-erbB-2)
        • Carbohydrate Antigen 15-3 and 27-29
        • Genetic Screening for Breast Cancer
        • Assessment of Circulating Tumor Cells55,57
      • Lung Cancer58
        • Neuron-Specific Enolase
      • Colorectal Cancer59
        • Carcinoembryonic Antigen (CEA)
        • Occult Blood Test
      • Bladder Cancer61
      • Monoclonal Gammopathies62
        • Table 53-6 International Guidelines for the Classification of Multiple Myeloma (MM) and Monoclonal Gammopathy of Undetermined Significance (MGUS)
        • Table 53-7 Distribution of Clinical Diagnoses in 1026 Patients With a Monoclonal Protein Detected at the Mayo Clinic in 1992
        • Table 53-8 Classification of MM Based on Monoclonal Protein Production from the UK MRC Multiple Myeloma Trials
        • Identification of M-Proteins
        • Quantitation of Immunoglobulins
        • Free Light Chains
          • BOX 53-3 KEY CONCEPTS
    • INVESTIGATION OF NEW CANDIDATE TUMOR MARKERS
      • Table 53-9 Microarray Applications in Cancer Diagnostics
    • PHARMACOGENOMICS IN CANCER CHEMOTHERAPY
    • REFERENCES
    • INTERNET SITES
  • Chapter 54 Laboratory Evaluation of the Transplant Recipient
    • Key Terms
      • Methods on Evolve
    • BACKGROUND
      • BOX 54-1 SECTION OBJECTIVES
    • PRETRANSPLANT EVALUATION
      • Deceased Donors
        • Table 54-1 Surrogate Laboratory Measures of Healthy Organ Function
        • Table 54-2 United Network for Organ Sharing: Mandatory Laboratory Testing of the Potential Deceased Donor*
      • Live Donors
        • Kidney
        • Liver
          • Table 54-3 Pretransplantation Evaluation of the Renal Recipient
      • Recipient
        • Box 54-1 Recipient Contraindications to Renal Transplantation
      • Pretransplant Immunological Testing
        • BOX 54-1 KEY CONCEPTS
        • BOX 54-2 SECTION OBJECTIVES
    • POST-TRANSPLANT EVALUATION
      • Immunological Monitoring
        • Peritransplant and Post-Transplant Immunological Testing
        • Post-Transplant Immunological Testing
        • Allograft Function
          • Kidney
          • Pancreas
          • Liver
          • Heart
          • Lung
          • Intestines
        • Infection
        • Recurrent Disease and Co-Morbid Conditions
          • BOX 54-2 KEY CONCEPTS
          • BOX 54-3 SECTION OBJECTIVES
    • PHARMACOLOGICAL MONITORING
      • Corticosteroids
      • Antimetabolites
        • Azathiopurine
        • Mycophenolic Acid
      • Calcineurin Inhibitors
      • mTOR Inhibitors
        • Sirolimus, Rapamune, Rapamycin
      • Antibody Preparations
        • Polyclonal Antibodies
        • Monoclonal Antibodies
          • BOX 54-3 KEY CONCEPTS
          • BOX 54-4 SECTION OBJECTIVES
    • MONITORING TRANSPLANT OUTCOMES
      • Transplant Rejection: Types and Mechanisms
        • Table 54-4 Transplant Rejection Types Based on Time of Onset
      • Monitoring Rejection
        • Box 54-2 Infectious Agents Commonly Seen in Transplant Recipients
    • COMPLICATIONS OF OVER-IMMUNOSUPPRESSION
      • Infection
        • Cytomegalovirus (CMV)
          • Table 54-5 World Health Organization Classification of Post-Transplant Lymphoproliferative Disorder
        • Polyomavirus Infection (BKV)
        • Post-Transplant Lymphoproliferative Disorder
      • Recurrent Disease or Exacerbation
        • Autoimmune Recurrence
        • Post-Transplant Cardiovascular Disease
          • BOX 54-4 KEY CONCEPTS
    • BIBLIOGRAPHY
    • INTERNET SITES
  • Chapter 55 Toxicology
    • Key Terms
      • Methods on Evolve
      • BOX 55-1 SECTION OBJECTIVES
    • INTRODUCTION TO TOXICOLOGY
      • BOX 55-1 KEY CONCEPTS
      • BOX 55-2 SECTION OBJECTIVES
    • THE POTENTIAL FOR TOXICITY
      • The Dose Makes the Poison
        • Fig. 55-1 Dose-response curve. Results of therapeutic and toxic effects on a population. ED50, Effective dose for 50% of the population.
        • Table 55-1 Approximate LD50 of Selected Chemicals
      • Physical Characteristics of a Toxin
      • Stereochemistry and Chiral Pharmacology
        • Fig. 55-2 Stereochemistry: enantiomers. The enantiomeric pairs for lactic acid and methamphetamine are shown. When solutions of these are placed in plane polarized light, the d or (+) forms rotate the light to the right, whereas the l or (−) forms rotate the light to the left.
        • Table 55-2 Comparison of Pharmacological and Toxicological Differences Between Enantiomeric Pairs
      • Mechanisms of Organ Toxicity
        • Fig. 55-3 Site of toxicity for various agents.
        • BOX 55-2 KEY CONCEPTS
        • Table 55-3 Relationship Between Route of Exposure and LD50, mg/kg
        • BOX 55-3 SECTION OBJECTIVES
    • EXPOSURES, KINETICS, AND GENES
      • Routes of Exposure
      • Duration and Frequency of Exposure
      • Toxicokinetics and Toxicogenetics
        • Table 55-4 Common Drugs and Toxins Metabolized Via the Cytochrome P-450 Isoenzymes
      • Interactions Between Toxins
        • Table 55-5 Genes and Their Protein Products Responsible for Increased Toxicity
        • BOX 55-3 KEY CONCEPTS
        • BOX 55-4 SECTION OBJECTIVES
    • TOXICOLOGY IN THE CLINICAL SETTING
      • Table 55-6 The Most Common Toxic Syndromes
      • Fig. 55-4 Comparison of poisonings in adults and children.
      • Table 55-7 Examples of Poisons and Antidotes
      • BOX 55-4 KEY CONCEPTS
      • BOX 55-5 SECTION OBJECTIVES
    • THE TOXICOLOGY LABORATORY
      • Choosing Samples and Methods
        • BOX 55-5 KEY CONCEPTS
        • BOX 55-6 SECTION OBJECTIVES
    • MEDICOLEGAL CHALLENGES
      • BOX 55-6 KEY CONCEPTS
      • BOX 55-7 SECTION OBJECTIVES
    • BIOLOGICAL AND CHEMICAL AGENTS OF MASS DESTRUCTION
    • THE TOXICITY OF NATURAL PRODUCTS
      • BOX 55-7 KEY CONCEPTS
      • BOX 55-8 SECTION OBJECTIVES
    • KEY TOXINS ENCOUNTERED IN THE LABORATORY
      • Analgesics
        • Fig. 55-5 Biological and chemical warfare. AchE, Acetylcholinesterase; GI, gastrointestinal;↑↑, increased; GC, gas chromatography; GC/MS, gas chromatography–mass spectrometry; ELISA, enzyme-linked immunosorbent assay; mtb, metabolite; RIA, radioimmunoassay; resp., respiratory. *For biological agents, the site of action, toxic effects, assessment of exposure, and treatment are discussed for the designated agent.
        • Table 55-8 Herbals of Toxicological Importance
        • Fig. 55-6 Metabolic pathway for acetaminophen. The metabolic pathways for acetaminophen are shown. Under therapeutic conditions in which CYP2E1 is not induced and glutathione stores are adequate, ≈55% of the drug is metabolized to the glucuronide metabolite, ≈30% to the sulfate metabolite, and ≈6% to the NAPQI metabolite. NAPQI is conjugated rapidly to glutathione and eliminated. CYP2E1, Cytochrome P-450 isoenzyme 2E1; NAPQI, N-acetyl-p-benzoquinone imine; UDPGT, uridine diphosphoglucuronosyl transferase.
        • Fig. 55-7 Plasma acetaminophen concentration in relation to time after acute overdose. Liver damage is likely to be severe above the upper line, severe to mild between the lines, and clinically insignificant under the lower line.
        • BOX 55-8 KEY CONCEPTS
        • BOX 55-9 SECTION OBJECTIVES
    • DRUGS OF ABUSE
      • Table 55-9 Drugs of Abuse in Urine (DAU)
      • Amphetamines
      • Barbiturates
      • Benzodiazepines
      • Cannabinoids
      • Cocaine
      • Opioids
      • Phencyclidine
      • Club Drugs
        • Table 55-10 Pharmacological and Testing Aspects of Club Drugs
        • BOX 55-9 KEY CONCEPTS
        • BOX 55-10 SECTION OBJECTIVES
    • GASES
    • METALS
      • Table 55-11 Toxicity of Heavy Metals
    • PESTICIDES
    • VOLATILES
      • BOX 55-10 KEY CONCEPTS
    • REFERENCES
    • INTERNET RESOURCES
  • Chapter 56 Addiction and Substance Abuse
    • Key Terms
      • Methods on Evolve
      • BOX 56-1 SECTION OBJECTIVE
    • THE ADDICTION PROCESS
      • BOX 56-1 KEY CONCEPTS
      • BOX 56-2 SECTION OBJECTIVES
    • THEORIES TO EXPLAIN ADDICTION
      • Box 56-1 Withdrawal Symptoms
        • Alcohol and Sedatives
        • Tobacco
        • Stimulants and Cocaine
        • Opiates
        • Caffeine
        • Marijuana
    • PREVALENCE OF ADDICTION AMONG VARIOUS GROUPS
      • Table 56-1 Prevalence of U.S. Alcohol and Drug Use by Age Group in 2006 (percentage of population) in National Survey on Drug Use and Health
      • Table 56-2 Examples of Medical Pathophysiology Associated With Chronic Abuse*
      • BOX 56-2 KEY CONCEPTS
      • BOX 56-3 SECTION OBJECTIVES
      • Box 56-2 Diagnostic Criteria of Substance Dependence
    • DIAGNOSIS OF SUBSTANCE ABUSE, SUBSTANCE DEPENDENCE, AND ADDICTION
    • RECOVERY AND THE TREATMENT PROCESS
      • BOX 56-3 KEY CONCEPTS
      • BOX 56-4 SECTION OBJECTIVES
    • THE PREEMPLOYMENT OR RANDOM DRUG SCREEN
    • WHY INDIVIDUALS FAIL DRUG SCREENS
    • CHANGE OF ANALYTE IN DISEASE
      • BOX 56-4 KEY CONCEPTS
    • REFERENCES
    • INTERNET SITES
• Back Matter
  • Appendix A Buffer Solutions*
    • REFERENCES
    • TABLE REFERENCES
  • Appendix B Preparation of Buffer Solutions
  • Appendix C Concentrations of Common Acids and Bases*
  • Appendix D Major Plasma Proteins*
  • Appendix E Conversions Between Conventional and SI Units
  • Appendix F Conversions Between Conventional and SI Units for Specific Analytes
  • Inside Back Cover

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