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Flashcards in Musculoskeletal Deck (52)
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Neuromuscular transmission I

The sequence of events by which a signal is transmit- ted from nerve to striated muscle is the pivotal process in the physiology of the locomotor system. The basic mechanisms involved are the same as those utilised in synaptic transmission in general. The neuromuscular junction or motor end-plate is a chemical synapse between the motor axon and the skeletal muscle fibre. The myelinated axon of the alpha motor neuron is the ‘final common pathway’ in the neurophysiology of motor activity. Each skeletal muscle has its own particular set of innervating motor neurons, called the motor neuron pool, whose cell bodies lie in lamina IX of the ventral horn of the spinal cord or in the cra- nial nerve motor nuclei. Each muscle cell (a fibre is an elongated cell) has only one neuromuscular junc- tion, but each alpha motor neuronal axon innervates a number of fibres. The alpha motor neuron and the fibres it innervates constitute the motor unit.


Neuromuscular transmission II

Just proximal to the neuromuscular junction the axon loses its myelin sheath and divides to form the axon terminals. Each axon terminal lies in a synaptic trough on the surface of its target muscle cell (fibre), separated from the postjunctional membrane of the muscle cell by the synaptic cleft. The passage of an action potential down the axon leads to depolarisation of the presynaptic terminal membrane. This depolar- isation opens voltage-gated calcium (Ca) channels, allowing extracellular Ca to flow down its electro- chemical gradient into the axon terminal. The increase in intracellular Ca concentration stimulates synaptic vesicles, containing acetylcholine (ACh), to fuse with the presynaptic membrane and release ‘quanta’ of ACh into the synaptic cleft.


Neuromuscular transmission III

The ACh is synthesised in the motor neuron from acetyl CoA produced in the neuron and choline taken up actively by the neuron from the extracellular fluid. This choline is largely recycled from metabolised ACh. The ACh diffuses across the cleft and combines chemically with the receptor proteins in the postjunctional membrane. These proteins are integral parts of the membrane, constituting nico- tinic cholinergic receptors. As a result of this chemical combination, ligand-gated ion channels open so that there is transiently increased permeability both to Na and K. The net inward ionic current leads to a tran- sient local depolarisation of the postjunctional mem- brane, the end-plate potential (EPP). This itself is non-propagating, but sets up local electrotonic depo- larising currents in the adjacent muscle cell membrane (sarcolemma). When these currents reach threshold, an action potential (AP) propagates along the muscle fibre and initiates muscle contraction via the excitation-contraction coupling mechanism to be described below.


Neuromuscular transmission IV

The size of the typical EPP is several times greater than the minimum necessary to initiate an AP in the muscle. The size of an AP in nerve and in muscle, cannot vary (all-or-nothing principle), but its frequency can, leading to summation and subsequently to a tetanic response. The number of motor units recruited can also vary. The released ACh is constantly being hydro- lysed in the synaptic cleft into acetate and choline: the process is catalysed by the enzyme acetylcholinesterase, which occurs in high concentration at the normal post- junctional membrane. Small spontaneous releases of ACh also occur, without axonal stimulation, causing miniature depolarisations of the postjunctional mem- brane (miniature end-plate potentials, (MEPP)).


Neuromuscular V

It is important to understand the way in which this process can be modified, both pharmacologically and by disease. Transmission can be altered in a number of ways. Non-depolarising drugs such as curare, a plant alphatoxin, work by binding to the receptor protein and blocking transmission. This causes longer-term paralysis than do the depolarisers, such as succinylcho- line, which bind to the receptor and cause temporary depolarisation. These different forms of action are util- ised in anaesthesia. The action of such drugs can be reversed by neostigmine, which blocks the action of acetylcholinesterase and thus promotes transmission. In the disease myasthenia gravis, circulating antibodies to the cholinergic receptor proteins are present.


Muscle structure I

In terms of connective tissue architecture, each muscle has an almost fractal structure, in that each level of magnitude replicates the next (Fig. 12.40). The whole muscle consists of numerous bundles (fasciculi) of fibres. The fibres are bound together by endomysium and the fasciculi by perimysium. The whole muscle is enclosed in a sheath of epimysium. Each fibre is an elongated multinucleate cell bounded by a limiting membrane, the sarcolemma.

Within each cell lie further ‘bundled’ structures, the myofibrils, which contain the interdigitating contractile elements actin (‘thin fila- ments’) and myosin (‘thick filaments’). Thin filaments also contain small proportions of two other proteins, tropomyosin and troponin (see below). Each thick fila- ment is surrounded by six thin filaments arranged hex- agonally. The myofilaments lie within the cytoplasm of the cell, and are organised into serially repeating units or sarcomeres, giving the familiar striped or striated appearance on light microscopy.


Muscle structure II

The transverse components of the sarcomeres are cytoskeletal elements, anchoring the contractile proteins and connecting them to the sarcolemma to enable contraction of the whole fibre. The bundles of myofibrils are separated by the complex membranous network of the sarcoplasmic reticulum and by other intracellular organelles, notably mitochondria. Calcium is specifically stored within the reticulum, bound to the protein calseques- trin; muscle cells are too large to rely on the diffusion of calcium from the extracellular pool. The membrane of the reticulum is in structural continuity with the sarcolemma via a system of membranous T-tubules. Thus the whole of the sarcolemma and reticulum can become electrically activated as the AP is propagated.


Muscle structure III

Calcium stored within the reticulum acts as the second messenger in the process of excitation-contraction coupling. When the AP reaches and depolarises the T-tubular membrane, voltage-gated Ca channels are opened in the contiguous reticulum, releasing Ca into the cytoplasm surrounding the myofibrils. This calcium binds to troponin, a protein bound to the actin, causing it to change its molecular conformation, dis- place a second actin-bound protein (tropomyosin) and expose binding sites on the actin for the attachment of the adjacent myosin filaments.

Conformational change in the myosin, when bound to the actin, produces the sliding movement which is magnified into contraction of the fibre and thus of the muscle. While the cytoplas- mic Ca concentration is high, the contraction continues: its duration is determined by the rate of return of the Ca into the sarcoplasmic reticulum.


Muscle structure IV

The cycle of changes in the binding region of the myosin filament which produces the change of shape is called the cross-bridge cycle. The process is power- ed by the hydrolysis of ATP to ADP, and is cyclical because of the alternating and differing levels of affin- ity for myosin of ATP and ADP. The ADP is rephos- phorylated to form more ATP as the cycle progresses.

There are three possible biochemical pathways for this phosphorylation, in muscle as in all other cells. These pathways are oxidative phosphorylation, glycolysis, and direct phosphorylation. The first of these relies on the oxidation of imported substrates such as carbo- hydrates and fatty acids, occurs in the mitochondria, and requires the presence of a copious capillary blood supply and an oxygen-binding protein (myoglobin).

The second, a much more rapid process, is anaerobic and involves the breakdown of locally stored glycogen via the pyruvate cycle, with lactate as the main ‘waste’ product. The third process, direct phosphorylation of ADP, utilises locally-stored creatine phosphate; it is not directly synthetic, and serves as a rapid and quickly available ‘holding mechanism’ until one or both of the other, synthetic, processes come into play.


Tissue level: fibre type and metabolism

Skeletal muscle contains two main cell (fibre) types, each specialised for a particular work rate and power output. The difference between types is determined by the rate at which ATP is used, this in turn being decided by the type of myosin isoenzyme present in the cell. Those which work more slowly and are adapted for sustained (low fatigue), lower power con- traction utilise mainly oxidative phosphorylation, and so are well vascularised and contain much myoglobin, accounting for their ‘red’ colour. Those which work fastest, and are adapted for rapid and high powered work, rely on anaerobic glycolysis, have fewer capil- laries and less myoglobin, and are thus ‘white’ fibres. They fatigue quickly as the intramuscular glycogen is used up and lactate concentration rises.


Muscle fibre types and function I

Type I: slow, red, oxidative fibres;

TypeII A: an intermediate group of fibres,whichutilise oxidative glycolysis as well as anaerobic processes

Type II B: fast, white, anaerobic glycolytic fibres.
Humans have a good balance of these fibre types; cats have mainly fast fibres, dogs mainly slow. Fibre types are never mixed within motor units.

Each unit contains either slow or fast fibres. Slow units have small motor neurons and few fibres. The axons are slower conducting but the neurons are relatively more excitable, and are recruited first and act frequently. Fast units have large, fast conducting axons but less excitable cell bodies, and contain many muscle fibres. They are recruited in maximal efforts of short dur- ation (rapid fatiguability).


Muscle fibre types and function II

Controlled variation in the number and type of motor unit recruited, and in the frequency of stimulation, allows gradation of the power of contraction over a wide range. The relative
proportions of each type of fibre within individual muscles vary with the overall function of the muscle, postural muscles having mainly Type I units.

Exercise and training do not cause motor units to change in type, though proportions may change and individual fibres may increase in size and strength as more con- tractile filaments are synthesised. Disuse and dener- vation both lead to muscle atrophy. The regeneration pattern in terms of unit type is determined by the level of recruitment (frequency of activation).


Muscle contraction: isotonic and isometric

Muscles may contract in two functionally different ways: isotonically and isometrically. Isotonic contraction involves change in muscle length with constant load. This change in length does not have to be a decrease: when the external force exceeds that gener- ated by the muscle, the muscle may lengthen as it contracts.

In molecular terms, the stretched cross-bridges are unable to change their conformation to produce shortening. Bonds are broken and reform, almost in ratchet fashion. This type of contraction – eccentric contraction – has great potential for muscle injury.


Muscle contraction: Eccentric

A common example of eccentric contraction is the simply tested action of biceps brachii during controlled active elbow extension with gravity: biceps is ‘paying out rope’ to prevent a sudden extension of the elbow. Triceps, the prime elbow extensor, remains flaccid. More commonly, muscle shortens as it contracts, tension being proportional to load: this is concentric contraction. A muscle may also contract isometri- cally, developing tension without changing its length: this happens if a load is applied which is greater than the muscle can lift.

Muscles cannot generate force at the limits of their length: this fact supports the sliding- filament theory of muscle action. As in any machine, the energy cost of muscle action can be expressed in terms of its efficiency of action. This is the ratio of the mechanical work performed to the (chemical) energy produced by the hydrolysis of ATP. The maximal efficiency of this process occurs in partially loaded muscle and is about 45%, but loss of energy as heat and in other energy-consuming reactions within the muscle reduces the overall efficiency to 20–25%.


Fracture healing

The process of fracture healing involves the recruit- ment of bone-forming cell precursors (osteoprogeni- tors) to the fracture site, the induction and activation of these precursors to differentiate into cartilage- and bone-forming cells (osteoinduction), and the presence of an osteoconductive surface or template on which this new bone can be produced (the various types of ‘callus’). The process is best learned as a series of coordinated temporal stages whose progression is determined by numerous factors both local and sys- temic. The stages as classically described are based on light-microscopic histological appearances, but more recent approaches involve biochemical cascades, cell population kinetics and considerations of local strain environment. The process is regulated and coord- inated, with a timescale which appears predetermined for each particular limb and bone.


Histological stages of fracture healing

The classical histological stages of fracture healing are:
• haematoma formation;
• inflammation – the blood clot is organised to form
granulation tissue;
• callus formation:
— primary, highly cellular soft callus formed mainly from uninjured periosteum a little distant from the fracture ends (where the bone is dead);
— external bridging callus, formed mainly by locally induced osteoprogenitors in the ‘fracture gap’; and
— late medullary callus, formed mainly within the medullary cavity at the fracture
• conversion of callus to woven bone: bridging callus passes from granulation tissue through a cartilaginous or chondroid stage. The chondroid material is converted to woven bone by a process of endochondral ossification. Bone is also formed in the healing fracture by intramembranous ossification, both from the periosteum and in the
• medulla consolidation and remodelling of the woven bone
• (‘osteoid’) into lamellar bone; and
reconstitution of the medullary canal and recovery of the shape of the bone.


Factors affecting fracture healing

The following can all be considered as aspects of the fracture environment.

General: the patient and local or systemic disease
• age – children heal faster than adults;
• state of nutrition and general health;
• the presence of infection at the fracture;
• pre-existing abnormal bone at the fracture
(‘pathological fracture’). This may be genetically determined (e.g. osteogenesis imperfecta) or the result of acquired conditions (e.g. malignant disease, metabolic bone disease).

Local anatomical environment
• site – upper limb bones heal faster than lower
• blood supply – soft-tissue attachments
• the proximity of the bone ends – the amount of
bone loss; soft-tissue interposition
• whether the fracture surfaces are intra-articular
• nerve supply


Condition of tendons and tendon repair

Again the local anatomy and the mechanical environ- ment are of paramount importance. The relationship of the tendons to their sheaths, synovial and fibrous, and to their sources of blood supply, and the occur- rence of specialised histological regions (e.g. fibrocarti- lage) within particular tendons should be borne in mind when considering their pathology. Conditions other than trauma which commonly affect tendons include pyogenic infections of their sheaths, and inflammatory disease both systemic and local. Rheumatoid arthritis often involves tendons, especially in the hands and feet. Synovial inflammation and proliferation may combine with local bony attrition to cause tendon rupture.

Disproportion between flexor tendons and their fibrous sheaths in the hand leads to the ‘triggering’ phenom- enon. Trauma to tendons may be open or closed, acute or chronic, single or repetitive. Overuse injury (repetitive strain injury (RSI)) falls into the latter category.


Open tendon injury

Open tendon injury is most commonly seen in the hand. The prognosis for successful function after repair of such injuries is affected by the anatomical ‘zone’ of the hand within which the injury occurs as well as by the quality of the surgical repair. Anatomical zones are described both for flexor and extensor tendons: their extent is largely determined by changes in the relation- ship of the tendon to its synovial and fibrous sheaths. Postoperative adhesions commonly cause poor results.

Both early active and passive movement of the repaired tendon are advocated to improve the functional result. Such increase in mobility may, however, be obtained at the expense of strength of the repair. The process of tendon repair involves scar formation: the extent of this scar must be minimised.


Postop tendon repair recovery

As in most wound healing, the process has inflammatory, proliferative and organisational stages. The cell populations involved, fibroblasts and macrophages, originate within the ten- don itself. Synovial healing must also occur: sheaths must be accurately and separately repaired to ensure optimal return of function and tendon excursion. The same considerations apply when tendon grafts are inserted, though here the problem of vascularisation is greater than in primary repair. Tendon repairs are weakest a week or so after surgery. Though most of the strength is regained in three to four weeks, it is not maximal until six months after surgical repair.



Acute osteomyelitis is a disease of growing bones or in immunosuppressed or diabetic adults. It is usually due to Staphylococcus aureus and rarely due to streprococci, pneumococci, haemophilus or Salmonella. The infection usually starts at the vascular metaphysis of a long bone or the centre of a short bone. Common sites include the lower end of the femur, upper end of the tibia, humerus, radius, ulnar and vertebral bod- ies. Suppuration occurs and pus under tension causes bone necrosis.

The classical sequence of changes in osteomyelitis is as follows:

• transient bacteremia, e.g. Staphylococcus aureus;
• focus of acute inflammation in metaphysis of bone;
• necrosis of bone fragments forming the
• reactive new bone forms, i.e. the involucrum; and
• if untreated sinuses form draining pus to the skin
surface via cloacae.

Osteomyelitis may also follow penetrating injury of bone; surgical invention must be included here (joint replacement, internal fixation of fractures).

Chronic osteomyelitis may follow acute osteomyelitis but is more common following surgery for a compound fracture, especially when foreign material is implanted. It may be chronic from the outset, e.g. tuberculosis, syphilis (tertiary) or mycotic infections. Tuberculosis is the most common.


Acute pyogenic arthritis

Most cases of septic arthritis are the result of bacter- ial infection. This is usually blood borne infection, especially in infants. Staphylococci, streptococci and gonococci may be causative organisms. It may arise following osteomyelitis where the metaphysis is intrac- apsular, e.g. hip joint.

In adults, septic arthritis may be seen in diabetes mellitus, the immunologically compromised (HIV), drug abusers, patients with rheumatoid arthritis in which there may already be joint damage prior to infection and after joint surgery.

Tuberculous infection of bone and joint remains very common in the developing world and its pres- ence is increasing again elsewhere as HIV, social depri- vation and anti-tuberculous drug resistance spread. A multiplicity of rarer pathogens from fungi to anaer- obes and protozoa may also cause bone and joint infections, particularly in the immunocompromised subject.

Viral infections of bone have also been described; it has been suggested that the commonly- seen Paget’s disease of bone is caused by a slow virus.



Osteoarthritis is a manifestation of degenerative change: the prevalence of primary osteoarthritis increases with age. Secondary osteoarthritis occurs after pre-existing joint damage (e.g. following trauma or infection). The primary lesion in osteoarthritis is now thought to be failure of cartilage repair in stressed areas of the joint. Whether the initial failure lies in the chondrocytes or in the extracellular matrix, and, if the latter, whether in its proteoglycan/hyaluronan or in its collagenous component, is not yet established. Local enzyme dysfunction and abnormal cytokines have also been implicated. Subchondral bone changes are generally thought to be secondary to changes in the articular cartilage, but primacy of the bone changes has been proposed by some.

In summary, the main pathological features are:

• cartilage breakdown with failure of repair in stressed areas, giving the clinical appearance of fibrillation, loss of radiographic ‘joint space’ and leading ultimately to exposure of bone (eburnation);

• subchondral bone sclerosis with cyst formation;

• proliferation and remodelling of cartilage and
bone in unstressed areas, presenting as osteophyte
formation; and

• capsular thickening and fibrosis, contributing to
joint stiffness.
The pain of osteoarthritis probably arises from the capsule and from the exposed or damaged bone. Articular cartilage is not innervated.


Rheumatoid arthritis I

Rheumatoid arthritis is a common, systemic progressive and often disabling chronic inflammatory disorder. Pathological changes are not restricted to joints only. Joints tend to be involved symmetrically, the small joints of the hands and feet usually being affected first. More proximal joints, particularly the knees, shoulders and elbows, may also be involved. The cervical spine may be affected, leading to instability and neurological changes.

Females are affected more commonly than males. It may occur in all age groups and children may be affected (Still’s disease). There is a slight familial ten- dency especially in severe forms. Up to 75% of patients are HLA-DR4ve. Most adults have circulating auto- antibodies (rheumatoid factor) directed against autol- ogous immunoglobulins. It is a multi-system disease characterised by chronic inflammatory granulomatous lesions (rheumatoid nodules).


Rheumatoid arthritis II

In affected synovial joints, the proliferative syn- ovium or pannus extends over and erodes the articu- lar cartilage, with evidence both of acute and chronic inflammation. Genetic factors are involved in the pathogenesis of the disease, though the primary event is likely to be the activation of helper T (CD4) cells by an as yet unknown microbial pathogen. These activated cells produce cytokines which activate and perpetuate the process of inflammation within the joint, and also activate the B cell system to produce rheumatoid factors. Antibodies in synovial fluid form immune complexes which produce local tissue dam- age by a Type III hypersensitivity reaction. Secondary osteoarthritic changes may also occur.


Rheumatoid arthritis III

Rheumatoid disease exhibits several extra articular features. These are:

• subcutaneous rheumatic nodules;
• anaemia;
• lymphadenopathy and splenomegaly;
• pericarditis;
• dry eyes and mouth (Sjögren’s syndrome);
• uveitis and scleritis;
• vasculitis;
• pulmonary changes (nodules, interstitial fibrosis);
• amyloidosis.


Bone tumours I

These may be either benign or malignant. Secondary tumours are much more common than primary. Secondary occur from the lung, breast, prostate, thyroid and kidney. Primary tumours are rare and account for only 0.5% of all cancer deaths. Overall they have a bad
prognosis and affect patients in a younger age group. The management of suspected primary bone tumours is a specialist multi-disciplinary task and may involve discussion with national tumour centres, where there are orthopaedic surgeons, radiologists and histopathol- ogists with sufficient experience of these lesions.
Bones contain many different tissues, all of which may undergo neoplastic change. The simplest general classification of bone tumours divides them first into benign and malignant groups, organized according to tissue of origin of the tumour (Box 12.1).


Bone tumours: Benign: Osteochondroma

The two commonest benign tumours of bones are osteochondroma (exostosis) and chondroma (enchon- droma) which account for over 50% of all benign bone tumours.

Patients with osteochondromas are usually under 20-years-old. An osteochondroma is a cartilage-capped bony outgrowth which tends to develop near the epi- physes of limb bones, although they can form in any bone that develops from cartilage. Solitary lesions tend to be benign. In diaphyseal aclasis there are multiple cartilage-capped exostoses and there is a risk of devel- oping malignancy. Malignancy should be suspected if any lesion is 2cm or continues to grow after puberty.


Bone tumours: Benign: Chondroma (enchondroma)

Chondromas arise within the medullary cavity of the bones of the hands and feet and because of this are usually known as enchondromas. They occur in patients aged 20–50 and are more common in males. Enchondromatosis (Ollier’s disease) is multiple enchondromas and there is a risk of chondrosarcoma developing.


Bone tumours: Benign: Osteoma

Osteoma (‘ivory’ osteoma)
This is a growth from the surface of bone. It is com- mon on the surface of the vault of the skull. A smooth, non-tender mound develops which rarely causes symptoms.