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Introduction to the Viruses In 1898, Friedrich Loeffler and Paul Frosch found evidence that the cause of foot-and-mouth disease in livestock was an infectious particle smaller than any bacteria. This was the first clue to the nature of viruses, genetic entities that lie somewhere in the grey area between living and non-living states.

Viruses depend on the host cells that they infect to reproduce. When found outside of host cells, viruses exist as a protein coat or capsid, sometimes enclosed within a membrane. The capsid encloses either DNA or RNA which codes for the virus elements. While in this form outside the cell, the virus is metabollically inert; examples of such forms are pictured below.

Viral micrographs : To the left is an electron micrograph of a cluster of influenza viruses, each about 100 nanometers (billionths of a meter) long; both membrane and protein coat are visible. On the right is a micrograph of the virus that causes tobacco mosaic disease in tobacco plants.

When it comes into contact with a host cell, a virus can insert its genetic material into its host, literally taking over the host's functions. An infected cell produces more viral protein and genetic material instead of its usual products. Some viruses may remain dormant inside host cells for long periods, causing no obvious change in their host cells (a stage known as the lysogenic phase). But when a dormant virus is stimulated, it enters the lytic phase: new viruses are formed, self-assemble, and burst out of the host cell, killing the cell and going on to infect other cells. The diagram below at right shows a virus that attacks bacteria, known as the lambda bacteriophage, which measures roughly 200 nanometers.

Viruses cause a number of diseases in eukaryotes. In humans, smallpox, the common cold, chickenpox, influenza, shingles, herpes, polio, rabies, Ebola, hanta fever, and AIDS are examples of viral diseases. Even some types of cancer -- though definitely not all -- have been linked to viruses.

Viruses themselves have no fossil record, but it is quite possible that they have left traces in the history of life. It has been hypothesized that viruses may be responsible for some of the extinctions seen in the fossil record (Emiliani, 1993). It was once thought by some that outbreaks of viral disease might have been responsible for mass extinctions, such as the extinction of the dinosaurs and other life forms. This theory is hard to test but seems unlikely, since a given virus can typically cause disease only in one species or in a group of related species. Even a hypothetical virus that could infect and kill all dinosaurs, 65 million years ago, could not have infected the ammonites or foraminifera that also went extinct at the same time.

On the other hand, because viruses can transfer genetic material between different species of host, they are extensively used in genetic engineering. Viruses also carry out natural "genetic engineering": a virus may incorporate some genetic material from its host as it is replicating, and transfer this genetic information to a new host, even to a host unrelated to the previous host. This is known as transduction, and in some cases it may serve as a means of evolutionary change -- although it is not clear how important an evolutionary mechanism transduction actually is.

The image of influenza virus was provided by the Department of Veterinary Sciences of the Queen's University of Belfast. The tobacco mosaic virus picture was provided by the Rothamstead Experimental Station. Both servers have extensive archives of virus images.

The Institute for Molecular Virology of the University of Wisconsin has a lot of excellent information on viruses, including news, course notes, and some magnificent computer images and animations of viruses.

The Cells Alive! website includes information on the sizes of viral particles and an article on the mechanisms of HIV infection.

INSTITUTE FOR ANIMAL HEALTH good science, useful science home back to scientists Robert Koch - advancing the field of bacteriology return to top major accomplishments key dates

Koch’s main contribution was to the field of bacteriology where he did more to advance the world’s understanding of microbes as causes of disease than any other scientist (with perhaps the exception of Louis Pasteur). Koch developed new techniques and adapted old techniques to new uses. With his students, he created the majority of techniques for the modern study of bacteria. Koch established the new fields of medical bacteriology, public health and hygiene. Advances in the control of infectious disease build on Koch’s seminal work on germ theory and disease. Between 1876 and 1899 most of the major bacterial pathogens were isolated and characterised and most of the discoverers were German or German influenced, Koch played a major role in this.

Koch was a first rate experimenter, making careful and patient observations, working hard and with keen insight. His motto ‘nunquam otiosus’ (never idle) and his saying ‘Nicht locker lassen’ (never give up) exemplified the energy and determination he put into his research.

Major accomplishments

Put the germ theory of disease on an experimental footing Koch’s postulates Developed the plate technique for the pure culture of bacteria - an essential technique for the fields of bacteriology and genetics of bacteriology Perfected technique of microscopic observation of bacteria, which led to the development of the field of microscopic pathology. Made the first photomicrographs of bacteria Developed the slide technique for studying bacterial cultures Determined the lifecycle of the anthrax bacillus and the importance of endospores Discovered the tubercle bacillus Isolated the bacterium causing cholera Defined essential procedures and methodology in disinfection and sterilisation Observed tuberculin sensitivity, which became the foundation of cellular immunology Discovered that water filtration would control cholera Identified the carrier state Developed policies on public health and hygiene Described the aetiology of wound infection Founded the important school of bacteriology Made significant contributions to tropical medicine

Key Dates

return to top 11 December 1843 Heinrich Herrmann Robert Koch born in Claustal, a small mining town in the Harz Mountains, Lower Saxony, Germany. His father, Herrmann Koch, was a mining administrator and later to be head of the mine. His mother was called Mathilde Juliette Henriette Biewend. 1862 Left school with good but not outstanding grades and went to Gottingen University to train to be a teacher but soon changed to study medicine. By the age of 22 had 2 substantial research papers 1866 Graduated as a doctor and became a medical assistant at Hamburg General Hospital where he showed an interest in research carrying out careful microscopical examinations of pathological material and first became acquainted with the disease cholera. 1866-1868 Held position in an institution for education and care of retarded children at Langenhagen near Hannover and started his own medical practise 1867 Married Emmy (Adolfine Josefine ) Fraatz 6 September 1868 Daughter, Gertrud, born June, 1868 Set up medical practise in Braetz July, 1869 Set up medial practise in Rakwitz 1870 Outbreak of Franco-German war. Koch volunteers as physician in a battlefield hospital where he had experience of typhoid fever and battle wounds. 1871 Returns to Rakwitz 1872 Passes exams to become District Medical Officer and takes up post at Wollstein where he also sets up his own practise. 1873 Starts to study anthrax 1875 Attends scientific and medical meetings and visits laboratories. Returns determined to make a scientific contribution of his own. Develops artificial culture medium (aqueous humour of cattle eyes) for growth of anthrax bacterium and identifies spore formation. In 1 month he has worked out the life cycle of the anthrax bacterium (Bacillus anthracis) and explained the significance of the spores allowing the organism to remain alive in the soil. 1877 Produces first photographs of bacteria by adapting light microscope and developing the slide technique and staining methods. 1872-1879 Demonstrates that different septic conditions arising from wounds are due to different organisms. July 1879 Becomes City Medical Officer for Breslau and tries to set up own practise but fails. October 1879 Moves back to Wollstein. July 1880 Moves to Berlin as Head of a newly established laboratory of bacterial research. At the age of 37 this is the beginning of his true career. 1880- Possibly Koch’s greatest contribution to the development of bacteriology and microbiology as independent sciences was his introduction of pure culture technique using solid or semi solid media. This technology led to the isolation and characterisation of the causal organisms of almost all bacterial diseases which affected humans.

Others had already shown that microorganisms could be grown on the surface of cut potatoes or solid media made from starch paste, egg albumin, bread and meat. But pathogenic bacteria will not grow on potatoes so he took nutrient media in which they do grow and solidified that with gelatin – nutrient gelatin. However this does not remain solid at the temperature for bacterial growth or in summer heat. On the advice of an associate (Walther Hesse) he replaced gelatin with agar as suggested by Hesse’s wife who had used it for fruit jellies! 1882 After developing new staining and culture techniques Koch announces the discovery of the tubercle bacillus, the bacterium responsible for tuberculosis. Kaiser Wilhelm appoints Koch ‘Imperial Privy Councillor’ 1883 –1884 Koch leads German team to study cholera in Egypt. He identifies an organism that he is sure is the cause of the disease but cannot infect experimental animals with it so doubts remain. However he does demonstrate that the disease is transmitted through contaminated drinking water and this is a major factor used in control of the disease. On his return to Germany he is received by the Kaiser and Chancellor Otto von Bismarck, presented with a medal in his honour and, as the ‘Bacillus Father’, celebrated throughout he German Empire. 1885 Becomes Professor of Hygiene at Friedrich-Wilhelm University, Berlin 1890 Publishes his ‘postulates’. These are the steps or procedures to prove that a specific microbe is the cause of a specific infectious disease. They are: 1. The organism must be constantly present. 2. The organism must be isolated and grown in pure culture, 3. Pure cultures of the organism must induce the disease when given to an experimental animal, 4. The same organism is recovered August 1890 Koch implies he has found a cure for tuberculosis and sufferers from around the world flock to Berlin to be cured. Arthur Conan Doyle, a physician as well as the creator of Sherlock Holmes, was sent to visit Koch in Berlin by the Review of Reviews to write a report on the treatment. Koch is awarded the Grand Cross of the Red Eagle by the German Emperor and given the freedom of Berlin. 1891 Koch realises that the basis for the ‘cure’, an extract of the tubercle bacterium he calls tuberculin, is not a remedy at all. This material stimulates a reaction in patients infected with the tubercle bacillus and his paper on the subject is the first description of the cellular immune response. Tuberculin becomes a useful diagnostic reagent. 1896 Koch visits South Africa where he makes important contributions to the study of malaria, sleeping sickness and many viral diseases of livestock, including rinderpest. 1898 Confirms the findings of Sir Ronald Ross that mosquitoes are responsible for the transmission of malaria. Later develops methods using quinine for eradicating malaria. 1901 Koch is awarded the Harben medal for his work on tuberculosis. 1902 In a stroke of genius he correctly explained the reason behind continued outbreaks of typhoid fever, after the contaminated water supply had been eliminated, as being due to human ‘carriers’ – that is people who are infected with the bacterium and can infect others but who themselves remain healthy. 1903 Goes to Rhodesia to study a disease called Rhodesian redwater. He demonstrates this is due to a protozoan parasite. 1904 Officially retires but continues to work in Africa. 1905 Goes on to Stockholm to receive the Nobel Prize for medicine. 27 May 1910 Koch dies of a heart attack in Baden Baden

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SHOULDER (see also Anatomy of the Joints) The shoulder girdle is the attachment of the upper extremity to the trunk. It consists of two bones: the scapula (shoulder blade) and the clavicle (collarbone). Along with the humerus (upper arm bone), these bones form the framework of the shoulder (Figures 38 & 39). The upper end or head of the humerus is shaped like a hemisphere (actually, somewhat less than half a sphere). Adjacent to the humeral head are two bony prominences, the greater and lesser tuberosities. Between the two tuberosities (on the anterolateral aspect of the humerus) runs the bicipital groove. The scapula is a flat, triangular bone that lies over the posterior surface of the rib cage. At its upper lateral corner is a cuplike depression (the glenoid fossa) which forms a socket for the head of the humerus (Figure 37). This glenohumeral joint is the one that is commonly referred to as "the shoulder". The posterior surface of the scapula is divided by a nearly horizontal ridge of bone, the scapular spine. The spine extends laterally to form a projection (the acromion) which overhangs the glenoid fossa. The anterior surface of the scapula, just medial to the glenoid fossa, has a beaklike projection (the coracoid process) that acts as an attachment for muscles and ligaments. The clavicle is shaped like a rod with a slight S curve; it extends from the base of the neck to the shoulder. Medially it is connected to the upper part of the sternum (breastbone), at the sternoclavicular joint. Laterally it is connected to the acromion of the scapula, at the acromioclavicular joint. The sternoclavicular joint is the only bony connection between the shoulder girdle and the trunk. The scapula is connected to the trunk indirectly through the acromioclavicular (AC) joint; otherwise, the scapula is attached to the trunk only by muscles. During scapular movements (e.g., shrugging; elevating the arm overhead), the AC joint permits the clavicle to glide and rotate on the scapula. The AC joint is bound together by the acromioclavicular and coracoclavicular ligaments. The glenohumeral joint is a ball-and-socket type joint similar to that of the hip (see Anatomy of the Joints). However, unlike the hip, the socket is shallow. This allows great freedom of movement in all directions, but at the cost of stability. The glenoid fossa is deepened somewhat by a fibrous lip or labrum. The labrum is actually a fold of the joint capsule, which encloses the entire joint from the glenoid to the neck of the humerus. The anterior part of the joint capsule is reinforced by several additional folds or thickenings known as the glenohumeral ligaments. Other ligaments are located outside the capsule; these include the coracoacromial and coracohumeral ligaments. The coracoacromial ligament stretches between the acromion and the coracoid process, forming a roof over the head of the humerus, the coracoacromial arch. In addition to protecting and stabilizing the joint, it plays an important role in the mechanics of shoulder movement (discussed below). There are numerous bursae in the region of the shoulder (Figure 42). The bursae most commonly involved in pathology are the subacromial bursa (located between the acromion and the joint capsule) and subdeltoid bursa (between the deltoid muscle and the joint capsule). Other large bursae include the subscapular and subcoracoid bursae. The subscapular bursa usually communicates with the joint cavity; the subcoracoid bursa sometimes does so. The subacromial and subdeltoid bursae do not communicate with the joint cavity, but often connect with each other (Figures 40 & 41). Movement at the glenohumeral joint can take place in all directions: flexion (raising the arm in front) and extension (raising the arm in back); abduction (raising the arm outward to the side) and adduction (bringing the arm in to the side); internal and external rotation; and circumduction (a combination of all of these). Each movement is brought about by different groups of muscles. The deltoid is the muscle that covers the point of the shoulder. It originates on the clavicle and on the scapular spine and acromion; it inserts into the lateral side of the humerus. The deltoid abducts the glenohumeral joint; however, by itself it can abduct the humerus to an angle of only 90o (relative to the scapula). At that point, the greater tuberosity of the humerus comes up against the coracoacromial arch. In order to abduct further, the head of the humerus must be externally rotated so that the tuberosity is turned out of the way. Rotation of the humerus is accomplished by a group of four muscles, subscapularis, supraspinatus, infraspinatus, and teres minor, collectively called the rotator cuff. These muscles originate on different parts of the scapula, and insert like a cuff around the perimeter of the humeral head, where their tendons blend with the joint capsule. In addition to externally and internally rotating the humerus, the rotator cuff helps stabilize the joint during abduction by pulling the humeral head into the glenoid fossa. With external rotation, the glenohumeral joint can be abducted to an angle of about 120o before the humeral head once more impinges on the coracoacromial arch. Further elevation of the arm requires rotation of the scapula (counterclockwise as viewed from behind, so that the glenoid fossa tilts upward). This provides an additional 60o of elevation, for a total of 180o (arm straight overhead). Scapular rotation is accomplished by the trapezius and serratus anterior muscles. (Trapezius originates on the cervical and thoracic spine, and inserts on the scapula. Serratus anterior originates on the anterior rib cage and inserts on the scapula.) During the first 15-20o of abduction, movement takes place almost exclusively at the glenohumeral joint. With further abduction, the scapula comes into play; both glenohumeral and scapular movement then take place simultaneously. Since the scapula and clavicle are connected, when the scapula rotates the clavicle also moves, at both the sternoclavicular and acromioclavicular joints. Muscles that flex the glenohumeral joint include pectoralis major (originating on the clavicle, sternum, and rib cartilages; inserting on the humerus) and coracobrachialis (originating on the coracoid process; inserting on the humerus). Muscles that extend the humerus include latissimus dorsi (originating in the thoracolumbar region and on the pelvis; inserting on the humerus) and teres major (originating on the scapula; inserting on the humerus). Both pectoralis major and latissimus dorsi also adduct and internally rotate the humerus. Another muscle that is anatomically related to the shoulder is biceps brachii. Biceps has two parts, a "long head" and a "short head". The short head originates on the coracoid process; the long head, on the upper margin of the glenoid fossa. The tendon of the long head passes through the capsule of the glenohumeral joint, and emerges in the bicipital groove between the greater and lesser tuberosities of the humerus. Encased in a synovial sheath, the tendon glides smoothly in the bicipital groove during movements of the humerus; it is kept from slipping out of the groove by the transverse humeral ligament. The two heads of biceps come together distally and insert on the radius, just below the elbow. Although its tendon passes through the shoulder, biceps is not primarily a mover of the shoulder. Its main actions are supination of the forearm (rotation of the forearm palm upward) and flexion of the elbow.

Shoulder anatomy... The two main bones of the shoulder are the humerus and the scapula (shoulder blade). The scapula extends up and around the shoulder joint at the rear to form a roof called the acromion, and around the shoulder joint at the front to form the coracoid process. The scapula is connected to the body by the collar bone (Clavicle) through the Acromio-Clavicular Joint. The end of the scapula, called the glenoid, meets the head of the humerus to form a glenohumeral cavity that acts as a flexible ball-and-socket joint. The joint cavity is cushioned by articular cartilage covering the head of the humerus and face of the glenoid. The joint is stabilized by a ring of fibrous cartilage surrounding the glenoid called the labrum.

Ligaments connect the bones of the shoulder, and tendons join the bones to surrounding muscles. The biceps tendon attaches the biceps muscle to the shoulder and helps to stabilize the joint. Four short muscles originate on the scapula and pass around the shoulder where their tendons fuse together to form the rotator cuff. (Get the FAQs on rotator cuff tears). All of these components of your shoulder, along with the muscles of your upper body, work together to manage the stress your shoulder receives as you extend, flex, lift and throw.

The clavicle (collar bone) articulates laterally with the scapula at its acromion (acromioclavicular joint) and medially with the sternum (sternoclavicular joint). As the clavicle is part of the upper limb, the sternoclavicular joint is the junction of the upper limb and trunk. The shoulder joint between humerus and scapula, because of the shape of the joint surfaces, allows mobility at the expense of stability and is thus liable to dislocation and subsequent nerve damage. The elbow joint although more stable, can still sustain fracture and dislocation resulting in damage to surrounding nerves and vessels. The wrist (radius and carpal bones) is frequently fractured in elderly people (Colles fracture of lower end of radius). The tendons to the fingers at the wrist are held by thick inelastic bands of fibrous tissue (retinacula).

Muscles and Movements The stability of the shoulder joint depends on the muscles arising from the scapula and inserting into the upper end of the humerus forming the rotator cuff. The upper arm and forearm are divided into anterior and posterior muscle compartments by fascia. In the upper arm the muscles of the anterior compartment produce flexion of the elbow and are supplied by the musculocutaneous nerve. The muscles in the posterior compartment produce extension at the elbow and are supplied by the radial nerve. The muscles of the anterior compartment of the forearm gain their nerve supply from the ulnar and median nerves. These muscles produce flexion at the wrist and the fingers. Those muscles of the posterior compartment of the forearm extend the wrist and fingers. They are supplied by the radial nerve or its branches. The forearm is able to rotate along its axis to give pronation and supination. The dexterity of the human hand is, in part, due to the mobility of the thumb at its base and the presence of many small muscles in the hand. Knowledge of their action and nerve supply helps in the diagnosis of nerve lesions. In both limbs the deep fascia forms thicker bands called retinacula at the wrist and ankle to prevent bowstringing of the long tendons acting over the joints. In the leg the deep fascia is thicker than in the arm, particularly on the lateral aspect of the thigh where it forms the iliotibial tract. The deep fascia of the leg aids venous return.

Vessels and Nerves The body is developed segmentally, each segment having its own nerve, artery and vein. This arrangement can be seen in the thorax and abdomen. The limbs are pushed out with development and carry nerves, arteries and veins with them. The five main nerves of the upper limb arise from the brachial plexus in the axilla (armpit). The nerve supply to the skin of the arm is also arranged segmentally along the length of the arm. The subclavian artery, as the name implies, begins behind the clavicle. It becomes the axillary artery at the outer border of the first rib and then becomes the brachial artery in the anterior compartment of the upper arm. In front of the elbow it divides into the radial and ulnar arteries. The former passes down the forearm in the anterior compartment and is readily palpable on the lower end of the radius as the radial pulse. The ulnar artery also passes down the forearm in the anterior compartment but gives a branch to the posterior compartment. Radial and ulnar arteries enter into the hand to give an anastomosis (a joining of vessels).

The veins draining the limbs form two groups, superficial and deep. The deep veins accompany the arteries and the flow of blood is controlled by valves. In the arm there are two main superficial veins. The cephalic lies on the lateral aspect of the arm and the basilic lies on the medial aspect. There is a connecting vein between the two in front of the elbow. Such veins are used for taking blood and giving intravenous injections or transfusions. The lymphatic drainage of the arm follows the course of the arteries for the deep structures and the superficial veins for the skin. Lymph nodes are found in the axilla. They filter lymph from the arm, upper chest wall, upper abdominal wall and the breast.

P. Axilla (1) DESCRIBE and DEMONSTRATE on a living subject, the boundaries of the axilla. (2) DESCRIBE the route of the axillary artery and NAME its main branches. (3) DRAW the brachial plexus, showing the derivation of the following nerves from the spinal nerves: Axillary Radial Subscapular Thoracodorsal Long thoracic Musculocutaneous Median Ulnar Median brachial and antebrachial cutaneous (4) DESCRIBE and DEMONSTRATE the relations of the axillary parts of the brachial plexus and its branches to the axillary artery and axillary walls. (5) DESCRIBE the arrangement of the axillary lymph nodes and NAME the main areas that each group drains. Index Q. Shoulder region (1) DEMONSTRATE the following features of the scapula: Superior border Medial border Lateral border Inferior angle Supraspinous fossa Supraglenoid tubercle Suprascapular notch Spine Acromion process Coracoid process Glenoid fossa Infraspinous fossa Infraglenoid tubercle (2) DEMONSTRATE the following features of the humerus: Head Bicipital groove and lips Anatomical neck Surgical neck Greater tuberosity Lesser tuberosity Deltoid tuberosity Spiral groove Capitulum Trochlea Medial epicondyle Lateral epicondyle (3) DEMONSTRATE the following movements of the shoulder region: Extension Flexion Adduction Abduction Scapular rotation Medial and lateral shoulder rotation 4) LIST the muscles mainly involved in the above movements, and STATE the attachments and nerve supply of each. (5) Using a living subject and a skeleton, DEMONSTRATE the functions of the following muscles in the movements indicated: Abduction - deltoid Scapular rotation - serratus anterior, trapezius Adduction - pectoralis major, latissimus dorsi, teres major (6) DEFINE the "rotator cuff", LIST the attachments and nerve supplies of the muscles forming it, and SUMMARIZE the factors contributing to stabilization of the shoulder joint. (7) DESCRIBE the attachments and functions of the following ligaments: Coracoclavicular Transverse humeral Coracoacromial Glenohumeral (8) DESCRIBE the courses by which the radial and axillary nerves leave the axilla, and STATE the relevance of shoulder dislocation to this. 9) DESCRIBE the main features of the scapular anastomosis and EXPLAIN its function. 10) DESCRIBE the position, connections and functions of the subacromial and subscapular bursae. Index R. Upper Arm, Elbow, Cubital Fossa (1) DEMONSTRATE flexion and extension of the elbow and pronation and supination of the forearm. (2) LIST the main muscles producing the above movement; DESCRIBE their attachments and nerve supplies. (3) DEMONSTRATE and NAME the following features of the radius: Head Neck Interosseous border Bicipital tuberosity Ulnar notch Styloid process Dorsal tubercle and of the ulna: Olecranon process Coronoid process Trochlear notch Radial notch Interosseous border Subcutaneous border Styloid process (4) DEMONSTRATE the following features of the elbow and proximal radio-ulnar joints: Capsule Annular ligament Lateral ligament Quadrate ligament Medial ligament (5) DEFINE the boundaries of the cubital fossa, and SKETCH the positions in relation to these boundaries of the following structures: Brachial artery Median nerve Radial artery Anterior interosseous nerve Ulnar artery Biceps tendon Common interosseous artery Bicipital aponeurosis Radial nerve Lymph nodes (6) DESCRIBE the course and branches of the brachial artery, and EXPLAIN the role of its branches and those of the radial and ulnar arteries in the anastomosis round the elbow joint. (7) DESCRIBE the course of the ulnar nerve in the upper arm and elbow regions. Index S. Forearm and Wrist (excluding digital muscles) (1) SKETCH the relationship between the distal ends of the radius and ulna and the carpal bones. LABEL all the carpals and the main features of the long bones. (2) DEMONSTRATE flexion, extension, radial deviation and ulnar deviation of the wrist. (3) NAME the most important muscles producing the above movements; LIST their attachments and nerve supplies. (4) DEMONSTRATE the attachments of the supinator and the relationship of the radial nerve to it. (5) DEMONSTRATE the origins of pronator teres and the relationship of the median nerve to it. (6) DEMONSTRATE the origins of flexor carpi ulnaris and the relationship of the ulnar nerve to it. (7) DESCRIBE the attachments and nerve supply of brachioradialis; DISTINGUISH between its actions and those of biceps and brachialis. (8) DESCRIBE the interosseous membrane and LIST its main functions. (9) DEMONSTRATE the course of the radial artery from the cubital fossa to the first metacarpal space. (10) DESCRIBE the attachments of the flexor retinaculum, LIST the structures passing deep to it and superficial to it, and EXPLAIN its function. Index T. Hand and Digital Muscles (1) NAME the digits; DEMONSTRATE flexion, extension, adduction and abduction of all digits and opposition of the thumb. (2) DESCRIBE the origins, courses, insertions and nerve supplies of both digital flexors and flexor pollicis longus. (3) DEFINE the thenar, hypothenar, lateral palmar and medial palmar spaces; DESCRIBE the likely consequences of infection of the palmar spaces. (4) SUMMARIZE the attachments of the lumbrical and interosseous muscles, the thenar and hypothenar muscles and adductor pollicis; DESCRIBE their nerve supplies and DEMONSTRATE their actions. (5) DESCRIBE the mechanisms preventing separation of the distal ends of the metacarpals. (6) COMPARE the first carpo-metacarpal joint with the other four. (7) LIST the main sensory and motor effects of the following nerve injuries: (a) Radial nerve in the spiral groove of the humerus. (b) Ulnar nerve at the elbow. (c) Median nerve in the carpal tunnel. (d) Radial nerve at the wrist. (8) SUMMARIZE how you would test the sensory and motor functions of the axillary, musculocutaneous, radial, median and ulnar nerves. (9) SUMMARIZE the effects of: (a) Tearing of nerve roots C8 and T1 by an upward jerk on the elevated arm. (b) Tearing of nerve roots C5 and C6 by violent downward displacement of the point of the shoulder. (10) DESCRIBE the limits to the spread of synovial flexor tendon sheath infections starting in: (a) The thumb (b) The index finger (c) The little finger (11) DESCRIBE the origins and pattern of the arterial supply to the hand and digits. (12) OUTLINE the pattern of venous and lymphatic drainage of the hand. (13) In the living subject, DEMONSTRATE: (a) The tendons of flexor carpi radialis ... palmaris longus ... flexor digitorum superficialis ... flexor carpi ulnaris (b) The tendons of extensor pollicis longus and brevis ... abductor pollicis longus ... the digital extensors (c) The styloid processes of radius and ulna. The positions of the scaphoid, trapezium and hamate. (d) The course of the radial and ulnar arteries and the median and ulnar nerves in the wrist region. (14) Using suitable radiographs, DEMONSTRATE the osteological landmarks of the limb already mentioned. (15) Using suitable radiographs, ESTIMATE the age of children's limbs on the basis of carpal ossification and epiphysis formation and closure. DESCRIBE the normal ossification sequence of the bones of the wrist and hand. Index Mammalian embryogenesis is the process of cell division and cellular differentiation which leads to the development of a mammalian embryo.

Contents [hide] 1 From one cell to blastocyst 2 Blastocyst grows and invades 3 Inner cell mass differentiation 4 Cavity formation 5 See also 6 External links

[edit] From one cell to blastocyst A mammal develops from a single cell called a zygote, which results from an oocyte (egg) being fertilized by a single sperm. The zygote is surrounded by a strong membrane of glycoproteins called the zona pellucida which the successful sperm has managed to penetrate.

The zygote undergoes cleavage, increasing the number of cells within the zona pellucida. After the 8-cell stage, mammalian embryos undergo what is called compactation, where the cells bind tightly to each other, forming a compact sphere. After compactation, the embryo is in the morula stage (16 cells). Cavitation ocurrs next, where the outtermost layer of cells - the trophoblast - secrete water into the morula. As a consequence of this when the number of cells reaches 40 to 150, a central, fluid-filled cavity (blastocoel) has been formed. The zona pellucida begins to degenerate, allowing the embryo to increase its volume. This stage in the developing embryo, reached after four to six days, is the blastocyst (akin to the blastula stage), and lasts approximately until the implantation in the uterus.

[edit] Blastocyst grows and invades Blastocyst with an inner cell mass and trophoblast.The blastocyst is characterized by a group of cells, called the inner cell mass (also called embryoblast) and the mentioned trophoblast (the outer cells). The inner cell mass gives rise to the embryo proper, the amnion, yolk sac and allantois, while the trophoblast will eventually form the placenta. Recently the inner cell mass has become a source for embryonic stem cells. The blastocyst can be thought of as a ball of a (mostly single) layer of trophoblast cells,with the inner cell mass attached to this ball's inner wall. The embryo plus its membranes is called the conceptus. By this stage the conceptus is in the uterus. The zona pellucida ultimately disappears completely, allowing the blastocyst to invade the endometrium.

The trophoblast then differentiates into two distinct layers: the inner is the cytotrophoblast consisting of cuboidal cells that are the source of dividing cells, and the outer is the syncytiotrophoblast.

The cytotrophoblast implants the blastocyst in the endometrium (innermost epithelial lining) of the uterus by forming finger-like projections called villi that make their way into the uterus, and spaces called lacunae that fill up with the mother's blood. This is assisted by hydrolytic enzymes that erode the epithelium. The syncytiotrophoblast also produces human chorionic gonadotropin (hCG), a hormone that "notifies" the mother's body that she is pregnant, preventing menstruation by sustaining the function of the corpus luteum. The villi begin to branch, and contain blood vessels of the fetus that allow gas exchange between mother and child.

[edit] Inner cell mass differentiation A human blastocystWhile the syncytiotrophoblast starts to penetrate into the wall of the uterus, the inner cell mass (embryoblast) also develops.

The embryoblast forms a bilaminar (two layered) embryo, composed of the epiblast and the hypoblast. The epiblast is adjacent to the trophoblast and made of columnar cells; the hypoblast is closest to the blastocyst cavity, and made of cuboidal cells. The epiblast, now called primitive ectoderm will give rise to all three germ layers of the embryo: ectoderm, mesoderm, and endoderm. The hypoblast, or primitive endoderm, will give rise to extraembryonic structures only, such as the lining of the yolk sac.

[edit] Cavity formation By separating from the trophoblast, the epiblast forms a new cavity, the amniotic cavity. This is lined by the amnionic membrane, with cells that come from the epiblast (called amnioblasts). Some hypoblast cells migrate along the inner cytotrophoblast lining of the blastocoel, secreting an extracellular matrix along the way. These hypoblast cells and extracellular matrix are called Heuser's membrane (or exocoelomic membrane), and the blastocoel is now called the primary yolk sac (or exocoelomic cavity).

Cytotrophoblast cells and cells of Heuser's membrane continue secreting extracellular matrix between them. This matrix is called the extraembryonic reticulum. Cells of the epiblast migrate along the outer edges of this reticulum and form the extraembryonic mesoderm, which makes it difficult to maintain the extraembryonic reticulum. Soon pockets form in the reticulum, which ultimately coalesce to form the chorionic cavity or extraembryonic coelom.

Another layer of cells leaves the hypoblast and migrates along the inside of the primary yolk sac. The primary yolk sac is pushed to the opposite side of the embryo (the abembryonic pole), while a new cavity forms, the secondary or definitive yolk sac. The remnants of the primary yolk sac are called exocoelomic vesicles.

Molecular Biochemistry ICarbohydrates - Sugars and Polysaccharides Carbohydrates (also referred to as glycans) have the basic composition:

•	Monosaccharides - simple sugars, with multiple hydroxyl groups. Based on the number of carbons (e.g., 3, 4, 5, or 6) a monosaccharide is a triose, tetrose, pentose, or hexose, etc. •	Disaccharides - two monosaccharides covalently linked •	Oligosaccharides - a few monosaccharides covalently linked. •	Polysaccharides - polymers consisting of chains of monosaccharide or disaccharide units. Monosaccharides: Aldoses (e.g., glucose) have an aldehyde at one end. Ketoses (e.g., fructose) have a keto group, usually at C #2.

Nomenclature for stereoisomers: D and L designations are based on the configuration about the single asymmetric carbon in glyceraldehyde. (See also Voet & Voet, 3rd Ed, p. 73). The lower representations are Fischer Projections.

For sugars with more than one chiral center, the D or L designation refers to the asymmetric carbon farthest from the aldehyde or keto group. Most naturally occurring sugars are D isomers. D & L sugars are mirror images of one another. They have the same name. For example, D-glucose and L-glucose are shown at right.

Other stereoisomers have unique names, e.g., glucose, mannose, galactose, etc. The number of stereoisomers is 2 n, where n is the number of asymmetric centers. The six-carbon aldoses have 4 asymmetric centers, and thus 16 stereoisomers (8 D-sugars and 8 L-sugars). See diagrams of D-aldoses in Voet & Voet on p. 357, and D-ketoses on p. 358. An aldehyde can react with an alcohol to form a hemiacetal. Similarly a ketone can react with an alcohol to form a hemiketal.

Pentoses and hexoses can cyclize, as the aldehyde or keto group reacts with a hydroxyl on one of the distal carbons. E.g., glucose forms an intra-molecular hemiacetal by reaction of the aldehyde on C1 with the hydroxyl on C5, forming a six-member pyranose ring, named after the compound pyran. See also diagrams p. 359. The representations of the cyclic sugars at right are called Haworth projections.

Fructose can form either: •	a six-member pyranose ring, by reaction of the C2 keto group with the hydroxyl on C6 •	a 5-member furanose ring, by reaction of the C2 keto group with the hydroxyl on C5.

Cyclization of glucose produces a new asymmetric center at C1, with the two stereoisomers called anomers, a & b. Haworth projections represent the cyclic sugars as having essentially planar rings, with the OH at the anomeric C1 extending either: •	below the ring (a) •	above the ring (b).

Because of the tetrahedral nature of carbon bonds, the cyclic form of pyranose sugars actually assume a "chair" or "boat" configuration, depending on the sugar (diagrams p. 360). The representation at right reflects the chair configuration of the glucopyranose ring more accurately than the Haworth projection. The displays below use the Chime plug-in. (These structure files were produced using the program Insight II from Molecular Simulations. )

Sugar derivatives. Various derivatives of sugars exist (diagrams p. 361-363), including: Sugar alcohol - lacks an aldehyde or ketone. An example is ribitol.

Sugar acid - the aldehyde at C1, or the hydroxyl on the terminal carbon, is oxidized to a carboxylic acid. Examples are gluconic acid and glucuronic acid. Amino sugar - an amino group substitutes for one of the hydroxyls. An example is glucosamine. The amino group may be acetylated. At right, the acetic acid moiety is shown in red. N-acetylneuraminate, (N-acetylneuraminic acid, also called sialic acid) is often found as a terminal residue of oligosaccharide chains of glycoproteins. (See also p. 363.) Sialic acid imparts negative charge to glycoproteins, because its carboxyl group tends to dissociate a proton at physiological pH, as shown here.

Glycosidic bonds: The anomeric hydroxyl group and a hydroxyl group of another sugar or some other compound can join together, splitting out water to form a glycosidic bond. R-OH + HO-R'  --> R-O-R' + H2O For example, methanol reacts with the anomeric hydroxyl on glucose to form methyl glucoside (methyl-glucopyranose).

Disaccharides: Maltose, a cleavage product of starch (e.g., amylose, see below), is a disaccharide with an a(1®4) glycosidic linkage between the C1 hydroxyl of one glucose and the C4 hydroxyl of a second glucose. Maltose is the a anomer, because the O at C1 points down from the ring.

Cellobiose, a product of cellulose breakdown, is the otherwise equivalent b anomer. The configuration at the anomeric C1 is b (O points up from the ring). The b(1®4) glycosidic linkage is represented as a "zig-zag" line, but one glucose residue is actually flipped over relative to the other. (See Chime view of cellulose below.)

Other disaccharides include (diagrams p. 364): •	Sucrose, common table sugar, has a glycosidic bond linking the anomeric hydroxyls of glucose and fructose. Because the configuration at the anomeric carbon of glucose is a (O points down from the ring), the linkage is designated a(1®2). The full name is a-D-glucopyranosyl-(1®2)b-D- fructopyranose. •	Lactose, milk sugar, is composed of glucose and galactose with b(1®4) linkage from the anomeric hydroxyl of galactose. Its full name is b-D-galactopyranosyl-(1®4)-a-D-glucopyranose. Polysaccharides: Plants store glucose as amylose or amylopectin, glucose polymers collectively called starch. Glucose storage in polymeric form minimizes osmotic effects. Amylose is a glucose polymer with a(1®4) glycosidic linkages, as represented above (see also diagram p. 366). The end of the polysaccharide with an anomeric carbon (C1) that is not involved in a glycosidic bond is called the reducing end.

Amylopectin is a glucose polymer with mainly a(1®4) linkages, but it also has branches formed by a(1®6) linkages. The branches are generally longer than shown above. The branches produce a compact structure, and provide multiple chain ends at which enzymatic cleavage of the polymer can occur. Glycogen, the glucose storage polymer in animals, is similar in structure to amylopectin. But glycogen has more a(1®6) branches. See the structure of amylopectin above and diagrams on p. 367. The highly branched structure permits rapid release of glucose from glycogen stores, e.g., in muscle cells during exercise. The ability to rapidly mobilize glucose is more essential to animals than to plants. Cellulose, a major constituent of plant cell walls, consists of long linear chains of glucose, with b(1®4) linkages. Every other glucose in cellulose is flipped over, due to the b linkages. This promotes intrachain and interchain hydrogen bonds, as well as van der Waals interactions, that cause cellulose chains to be straight and rigid, and pack with a crystalline arrangement in thick bundles called microfibrils. The regular packing of cellulose strands within a microfibril, stabilized by lateral and above/below strand interactions, is schematically represented at right. Multisubunit Cellulose Synthase complexes in the plasma membrane spin out from the cell surface microfibrils consisting of 36 parallel, interacting cellulose chains. These microfibrils are very strong. The role of cellulose is to impart strength and rigidity to plant cell walls, which can withstand high hydrostatic pressure gradients. Osmotic swelling is prevented. A short glucose polymer, equivalent to a single cellulose strand with b(1®4) linkages, may be viewed by Chime below right. In cellulose the strand would straighter, due to interactions between adjacent strands in the cellulose fiber bundle. Glycosaminoglycans (mucopolysaccharides) are polymers of repeating disaccharides (diagrams p. 368-369). The constituent monosaccharides tend to be modified, with acidic groups, amino groups, sulfated hydroxyl and amino groups, etc. Glycosaminoglycans tend to be negatively charged, because of the prevalence of acidic groups. Hyaluronate (hyaluronan) is a glycosaminoglycan with a repeating disaccharide consisting of two glucose derivatives, glucuronate (glucuronic acid) and N-acetylglucosamine. The glycosidic linkages are b(1®3) and b(1®4). Proteoglycans are glycosaminoglycans that are covalently linked to serine residues of specific core proteins. The glycosaminoglycan chain is synthesized by sequential addition of sugar residues to the core protein. Some proteoglycans of the extracellular matrix bind non-covalently to hyaluronate via protein domains called link modules. For example: Heparan sulfate is initially synthesized on a membrane-embedded core protein as a polymer of alternating glucuronate and N-acetylglucosamine residues. Later, in segments of the polymer, glucuronate residues may be converted to the sulfated sugar iduronic acid, while N-acetylglucosamine residues may be deacetylated and/or sulfated. Heparin, a soluble glycosaminoglycan found in granules of mast cells, has a structure similar to that of heparan sulfates, but is relatively highly sulfated. When released into the blood, it inhibits clot formation by interacting with the protein antithrombin. Heparin has an extended helical conformation. Charge repulsion by the many negatively charged groups may contribute to this conformation. The heparin molecule depicted at right includes 10 residues, alternating IDS (iduronate-2-sulfate) and SGN (N-sulfo-glucosamine-6-sulfate). Some cell surface heparan sulfate glycosaminoglycans remain covalently linked to core proteins embedded in the plasma membrane. Proteins involved in signaling and adhesion at the cell surface recognize and bind segments of heparan sulfate chains having particular patterns of sulfation. Oligosaccharides of glycoproteins and glycolipids: Oligosaccharides that are covalently attached to proteins or to membrane lipids may be linear or branched chains. They often include modified sugars, e.g., acetylglucosamine, etc. O-linked oligosaccharide chains of glycoproteins vary in complexity. They link to a protein via a glycosidic bond between a sugar residue and a serine or threonine hydroxyl (diagram p. 376). O-linked oligosaccharides have roles in recognition, interaction. (See discussion of lectins below.) N-acetylglucosamine (abbreviated GlcNAc) is a common O-linked glycosylation of protein serine or threonine residues. Many cellular proteins, including enzymes and transcription factors, are regulated by reversible attachment of GlcNAc. Often attachment of GlcNAc to a protein hydroxyl group alternates with phosphorylation, with these two modifications having opposite regulatory effects (stimulation or inhibition). N-linked oligosaccharides of glycoproteins tend to be complex and branched. Initally N-acetylglucosamine is linked to a protein via the side-chain N of an asparagine residue in a particular 3-amino acid sequence.

Additional monosaccharides are added, and the N-linked oligosaccharide chain is modified by removal and addition of residues, to yield a characteristic branched structure, as at right. (See also p. 376). Many proteins secreted by cells have attached N-linked oligosaccharide chains. Genetic diseases have been attributed to deficiency of particular enzymes involved in synthesizing or modifying oligosaccharide chains of these glycoproteins. Such diseases, and gene knockout studies in mice, have been used to define pathways of modification of oligosaccharide chains of glycoproteins and glycolipids.

Carbohydrate chains of plasma membrane glycoproteins and glycolipids usually face the outside of the cell. They have roles in cell-cell interaction and signaling, and in forming a protective layer on the surface of some cells. Lectins are glycoproteins that recognize and bind to specific oligosaccharides. Concanavalin A and wheat germ agglutinin are plant lectins that have been useful research tools (discussed p. 363). The C-type lectin-like domain is a Ca++-binding carbohydrate recognition domain present in many animal lectins. Recognition and binding of carbohydrate moieties of glycoproteins, glycolipids, and proteoglycans by animal lectins is a factor in cell-cell recognition, adhesion of cells to the extracellular matrix, interaction of cells with chemokines and growth factors, recognition of disease-causing microorganisms, and initiation and control of inflammation. For example: •	Mannan-binding lectin (MBL) is a glycoprotein found in blood plasma. It binds cell surface carbohydrates of disease-causing microorganisms and promotes phagocytosis of these organisms as part of the immune response. •	Selectins are integral proteins of mammalian cell plasma membranes with roles in cell-cell recognition and binding. The C-type lectin-like domain is at the end of a multi-domain extracellular segment extending outward from the cell surface. A cleavage site just outside the transmembrane a-helix provides a mechanism for regulated release of some lectins from the cell surface. A cytosolic domain participates in regulated interaction with the actin cytoskeleton.