Section Editors: Kerwyn C. Jones, MD, MS, and Martha M. Murray, MD

Contributing Authors:
Joseph Bernstein, MD, MS
Joseph A. Buckwalter, MS, MD
Creg A. Carpenter, MD
Andrew A. Freiberg, MD
Henry J. Mankin, MD
Jennifer Marler, MD
Joel L. Mayerson, MD
R. Alden Milam, IV, MD
Van C. Mow, PhD
Martha M. Murray, MD
Sonya Shortkroff, PhD

Approaching basic science can be daunting. without clinical experience to offer perspective, the novice student must acquire, assimilate andd apply information within a near vacuum.

And yet it must be done. As the word “basic” implies, this is a body of fundamental knowledge that must be mastered before you move on to advanced topics. So how can one effectively master basic science?

The best first step is reading. Some educators rec- ommend reading a little every day; others advocate reading in continuous thematic chunks. Whichever method you choose, the key is to make reading a con- stant part of your learning schedule, even when clini- cal responsibilities dominate your days. An excellent first source is a textbook that provides a good general overview supported by illustrative details. This should then be supplemented with more specialized texts and journal articles, particularly reviews.

Reading is only the first step; not all will be clear after the first pass through the material or even a sec- ond. The goal of reading is to give yourself a “prepared mind” (as Louis Pasteur put it), to make you ready for the real learning encounter: taking care of patients. As you progress through your clinical training, form con- nections between patient scenarios and basic scientif- ic causes. After examining patients, reinforce your clin- ical observations by rereading basic science material. You may, for example, see a patient with osteoarthritis of the knee. Observe that he is slightly bowlegged (a varus deformity), and note that his radiograph shows a white line in the tibia near the joint on the medial side, a find- ing that indicates subchondral sclerosis. Your reading will remind you that radiographs record density and that this white line therefore indicates an area of additional bone formation. Your basic science reading will also re- mind you of Wolff’s law: that bone grows in response to mechanical stress. Consequently, by recognizing the connection between varus alignment, abnormally high loads, and new bone formation, you can infer that the appropriate treatment for isolated medial compartment

arthritis may be to unload that stress with a brace or surgical realignment of the bone perhaps. As this ex- ample illustrates, clinical observations reinforce basic science reading, which in turn helps explain the clin- ical findings.

How much should you memorize? It’s hard to say. Because medicine is a practical art, you must collect facts. But go beyond that. Strive to discern relation- ships among facts and thereby identify patterns. For a useful and satisfying mental exercise, write a list of four or five topics on a blank sheet of paper and at- tempt to establish meaningful relationships among the entities based on scientific or clinical principles. Try, for instance, this list: osteoporosis, stress fractures, compartment syndrome, and long bone fractures. Af- ter reading, you may see the connection between os- teoporosis and stress fractures (both are characterized by perturbations of bone remodeling); stress fractures and compartment syndrome (both are conditions that can cause leg pain); compartment syndrome and long bone fractures (compartment syndrome being a dread- ed complication of fractures, typically from bleeding into the soft tissues); and last, fractures and osteoporo- sis (osteoporosis is a prime cause of fractures, espe- cially of the hip, wrist, and spine). Challenging your- self to make these connections will enhance your comprehension.

You may ask yourself the relevance of the basic science. A glib response is that your enlightenment begins when relevance is no longer in question. But until that point, it is fair to wonder whether the study of organs, cells, and molecules has much to do with clinical practice. The short answer is that almost every major improvement in prevention, diagnosis, and treatment has come from the translation of basic sci- ence into clinical medicine. So tackle the basic science section of this book with gusto. Even if you don’t fancy yourself a scientist, the basic science you study today may well be the basis of the clinical science you apply later in your career.

—Jaimo Ahn, PhD
—Joseph Bernstein, MD, MS

 

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Arachidonic acid – The substance that is a pre- cursor of inflammatory mediators such as prostaglandins and leukotrienes

Chemokines – An agent of the inflammatory process that attracts or recruits cells to the site

Cyclooxygenase pathway – One arm of the arachidonic acid cascade that leads to pro- duction of prostaglandins and thromboxanes

Cytokines – Proteins produced by a cell to modulate the actions of other cells; also known as messenger proteins

Growth factors – The molecules that stimulate cell growth or activation

Lipoxygenase pathway –  One arm of the arachidonic acid cascade that leads to pro- duction of leukotrienes and lipoxins

 Major histocompatibility complex (MHC) – A cluster of genes important in immune rec- ognition and signaling between cells of the immune system; also called human leukocyte antigen

Matrix metalloproteinases (MMP) – Agents of the inflammatory process that degrade the extracellular matrix

Phagocytosis – The process by which white blood cells ingest debris or micro- organisms

Endogenous Inhibitors
To regulate the inflammatory response, numerous endogenous agents have been em- ployed. IL-4 and IL-10 inhibit cytokine production. PGE2 can either stimulate or inhibit inflammation indirectly. Several other agents are competitive inhibitors of inflammation.  Read more

Inflammatory mediators often play important roles in the normal cell, regulating the synthesis and turnover of ECM, for ex- ample. Accordingly, blocking their production can have adverse effects on normal cell physiology. At best, inflammation can be controlled by modulating the production of these mediators.

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Inflammation may be initiated by either en- dogenous or exogenous factors. It can be an acute response to trauma (as in a ligament tear) or a chronic response (as in autoim- mune diseases such as RA). Infection and crystalline deposits also can provoke an in- flammatory response that will persist until the underlying cause is eliminated.

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The immune response to an antigen can be classified as humoral (antibody based) or cell mediated. Both processes require lympho- cytes and antigen-presenting cells (APCs), which may be lymphocytes, macrophages, or dendritic cells. Lymphocytes are de- scribed as B cells or T cells, a naming con- vention based on the site of their original differentiation—bone marrow (B cells) or thymus (T cells).5

Humoral immunity occurs through B cells, which produce soluble, membrane- bound immunoglobulin (antibody) for a spe- cific antigen. Cell-mediated immunity occurs through T cells that recognize an antigen when it is bound to a major histocompatibility complex (MHC) molecule, also termed a human leukocyte antigen (HLA). Thus, B cells are frequently the APCs to the T-cell receptors. Binding of the APCs with the T-cell receptors stimulates division of T cells into one of two types of helper cells (Th1 or Th2) and secretion of numerous cytokines that in- duce an inflammatory response (Fig. 3).

Stimulation of the immune response involves internalization of an anti- gen by macrophages. The antigen is then bound to a receptor (MHC II) and expressed on the cell surface.The CD4-expressing helperT cells are activated by receptor interaction with the antigen (2) if it is recognized as foreign. The activated CD4 cell (3) elaborates factors that stimulate B cells to express antibody and also inflammatory cytokines. B cells can differentiate into antibody- producing plasma cells or remain as memory cells. Similarly, the sensitized T cells can expand by proliferation and mediate cytotoxicity or be retained as memory cells.

There are two classes of MHC molecules (class I and II), both of which contain a large number of alleles (variable regions). Although MHC molecules bind antigens, they differ from B-cell receptors in that MHC molecules are expressed by a number of cell types. They also lack the specificity of the antibodies produced by B cells. Several chronic inflammatory diseases, such as RA, are associated with distinct alleles that may confer genetic predisposition to the disease. That the inflammation persists or recurs in these chronic diseases indicates that at- tempts to achieve homeostasis are impeded, possibly by a recurrent trigger.

In response to a trigger, such as an injury or an antigen, cells in affected tissue produce signals to initiate the infiltration of white blood cells (such as monocytes, granulocytes, and lymphocytes) to the site.

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Inflammation is characterized by erythema, warmth, pain, and edema. Acute in-flammation generally occurs in response to an injury or introduction of foreign mate- rial at a specific site and is an important part of wound healing.  Read more

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Acetylcholine – A key chemical mediator involved in neuromuscular synaptic transmission

Action potential – An electrical impulse generated by neurons

Concentric contraction – The shorten- ing of a muscle during activation

Dynamic strength – The magnitude of isotonic or isokinetic contraction

Eccentric contraction – The lengthen- ing of a muscle during activation

Endomysium – The connective tissue surrounding a muscle cell

Epimysium – The connective tissue surrounding the entire muscle

Isokinetic – Literally “same speed”; when applied to muscle action, it implies constant velocity of shortening

Isometric – Literally “same length”; when applied to muscle action, it implies that the muscle length is held constant

Isotonic – When applied to muscle action, it implies that the load is constant

Motor end plate (neuromuscular junction) – The synapse between a motor neuron and a muscle fiber

Motor unit – The motor nerve axon and the myofibers with which it contacts

Musculotendinous junction – The area of interface between a skeletal muscle and its tendon

Myoblasts – The embryonic cells that develop into skeletal muscle cells

Myofibers – The fibers that constitute a muscle

Perimysium – The connective tissue surrounding a fascicle

Sarcolemma – Muscle-cell membrane and its associated basement membrane

Sarcomeres – The fundamental components of the contracting unit of the myofibri

Sarcopenia – The loss of muscle mass and strength as a result of aging

Sarcoplasmic reticulum – A continuous branching network of membrane, which is a specialized form of endoplasmic reticulum unique to muscle

Schwann cell – A specialized support cell that encases nerve fibers

Static strength – The magnitude of isometric contraction

Stem cells – Cells with the unlimited ability of self-renewal and regeneration; serve to regenerate tissue

Synapse –  specialized site at which an electrical signal is transmitted chemically across a junction to produce a similar electrical impulse on the opposite side

Tenocytes – The cells in tendons