Musculoskeletal pain is pain that affects the muscles, ligaments and tendons, along with the bones.The causes of musculoskeletal pain are varied. Muscle tissue can be damaged with the wear and tear of daily activities. Trauma to an area (jerking movements, auto accidents, falls, fractures, sprains, dislocations, and direct blows to the muscle) also can cause musculoskeletal pain. Other causes of pain include postural strain, repetitive movements, overuse, and prolonged immobilization. Changes in posture or poor body mechanics may bring about spinal alignment problems and muscle shortening, therefore causing other muscles to be misused and become painful.
Musculoskeletal pain affects the bones, muscles, ligaments, tendons, and nerves. It can be acute (having a rapid onset with severe symptoms) or chronic (long-lasting). Musculoskeletal pain can be localized in one area, or widespread.
Lower back pain is the most common type of musculoskeletal pain. Other common types include tendonitis, myalgia (muscle pain), and stress fractures.
Nociceptive pain is caused by stimulation of peripheral nerve fibers that respond only to stimuli approaching or exceeding harmful intensity (nociceptors), and may be classified according to the mode of noxious stimulation; the most common categories being "thermal" (heat or cold), "mechanical" (crushing, tearing, etc.) and "chemical" (iodine in a cut, chili powder in the eyes).
Nociceptive pain may also be divided into "visceral," "deep somatic" and "superficial somatic" pain. Visceral structures are highly sensitive to stretch, ischemia and inflammation, but relatively insensitive to other stimuli that normally evoke pain in other structures, such as burning and cutting. Visceral pain is diffuse, difficult to locate and often referred to a distant, usually superficial, structure. It may be accompanied by nausea and vomiting and may be described as sickening, deep, squeezing, and dull.[15] Deep somatic pain is initiated by stimulation of nociceptors in ligaments, tendons, bones, blood vessels, fasciae and muscles, and is dull, aching, poorly-localized pain. Examples include sprains and broken bones. Superficial pain is initiated by activation of nociceptors in the skin or other superficial tissue, and is sharp, well-defined and clearly located. Examples of injuries that produce superficial somatic pain include minor wounds and minor (first degree) burns.
Complex life cycle of Plasmodium parasite. Life Cycle of the Malaria Parasite A female Anopheles mosquito carrying malaria-causing parasites feeds on a human and injects the parasites in the form of sporozoites into the bloodstream. The sporozoites travel to the liver and invade liver cells. Over 5-16 days*, the sporozoites grow, divide, and produce tens of thousands of haploid forms, called merozoites, per liver cell. Some malaria parasite species remain dormant for extended periods in the liver, causing relapses weeks or months later.
The merozoites exit the liver cells and re-enter the bloodstream, beginning a cycle of invasion of red blood cells, asexual replication, and release of newly formed merozoites from the red blood cells repeatedly over 1-3 days*. This multiplication can result in thousands of parasite-infected cells in the host bloodstream, leading to illness and complications of malaria that can last for months if not treated. Some of the merozoite-infected blood cells leave the cycle of asexual multiplication. Instead of replicating, the merozoites in these cells develop into sexual forms of the parasite, called male and female gametocytes, that circulate in the bloodstream. When a mosquito bites an infected human, it ingests the gametocytes. In the mosquito gut, the infected human blood cells burst, releasing the gametocytes, which develop further into mature sex cells called gametes. Male and female gametes fuse to form diploid zygotes, which develop into actively moving ookinetes that burrow into the mosquito midgut wall and form oocysts. Growth and division of each oocyst produces thousands of active haploid forms called sporozoites. After 8-15 days*, the oocyst bursts, releasing sporozoites into the body cavity of the mosquito, from which they travel to and invade the mosquito salivary glands. The cycle of human infection re-starts when the mosquito takes a blood meal, injecting the sporozoites from its salivary glands into the human bloodstream .
Watch the F1 component of the ATP Synthase molecule make ATP. The rotational force produce by the F0 component (not seen here) allows the rotation of the gamma component to move similar to a cam-shaft on an auto. This rotation allows the F1 component to open and close. The action of the opening and closing allows the ADP and Pi to enter, be brought into proximity and joined to make ATP. Watch the sequence.
The Gibbs–Donnan effect (also known as the Donnan effect, Donnan law, Donnan equilibrium, or Gibbs–Donnan equilibrium) is a name for the behavior of charged particles near a semi-permeable membrane to sometimes fail to distribute evenly across the two sides of the membrane. The usual cause is the presence of a different charged substance that is unable to pass through the membrane and thus creates an uneven electrical charge. For example, the large anionic proteins in blood plasma are not permeable to capillary walls. Because small cations are attracted, but are not bound to the proteins, small anions will cross capillary walls away from the anionic proteins more readily than small cations.
Agglutination assays are based upon the premise that antibody or antigen coated particles are agglutinated in the presence of the complementary soluble antigen or antibody. The tests are usually performed in microwells and the results are read, usually by eye or sometimes by automated pattern reading, simply by looking for agglutination in the bottom of the microwe
Immunofluorescence is a technique used for light microscopy with a fluorescence microscope and is used primarily on biological samples. This technique uses the specificity of antibodies to their antigen to target fluorescent dyes to specific biomolecule targets within a cell, and therefore allows visualisation of the distribution of the target molecule through the sample. Immunofluorescence is a widely used example of immunostaining and is a specific example of immunohistochemistry that makes use of fluorophores to visualise the location of the antibodies.
A muscle contraction (also known as a muscle twitch or simply twitch) occurs when a muscle fiber generates tension through the action of actin and myosin cross-bridge cycling. While under tension, the muscle may lengthen, shorten or remain the same. Though the term 'contraction' implies a shortening or reduction, when used as a scientific term referring to the muscular system contraction refers to the generation of tension by muscle fibers with the help of motor neurons. Locomotion in most higher animals is possible only through the repeated contraction of many muscles at the correct times. Contraction is controlled by the central nervous system (CNS), which comprises the brain and spinal cord. Voluntary muscle contractions are initiated in the brain, while the spinal cord initiates involuntary reflexes.
An action potential originating in the CNS reaches an alpha motor neuron, which then transmits an action potential down its own axon.
The action potential activates voltage-dependent calcium channels on the axon, and calcium rushes in.
Calcium causes vesicles containing the neurotransmitter acetylcholine to fuse with the plasma membrane, releasing acetylcholine into the synaptic cleft between the motor neuron terminal and the motor end plate of the skeletal muscle fiber.
The acetylcholine diffuses across the synapse and binds to and activates nicotinic acetylcholine receptor on the motor end plate. Activation of the nicotinic receptor opens its intrinsic sodium/potassium channel, causing sodium to rush in and potassium to trickle out. Because the channel is more permeable to sodium, the muscle fiber membrane becomes more positively charged, triggering an action potential.
The action potential spreads through the muscle fiber's network of T-tubules, depolarizing the inner portion of the muscle fiber.
The depolarization activates L-type voltage-dependent calcium channels (dihydropyridine receptors) in the T tubule membrane, which are in close proximity to calcium-release channels (ryanodine receptors) in the adjacent sarcoplasmic reticulum.
Activated voltage-gated calcium channels physically interact with calcium-release channels to activate them, causing the sarcoplasmic reticulum to release calcium.
The calcium binds to the troponin C present on the actin-containing thin filaments of the myofibrils. The troponin then allosterically modulates the tropomyosin. Normally the tropomyosin sterically obstructs binding sites for myosin on the thin filament; once calcium binds to the troponin C and causes an allosteric change in the troponin protein, troponin T allows tropomyosin to move, unblocking the binding sites.
Myosin (which has ADP and inorganic phosphate bound to its nucleotide binding pocket and is in a ready state) binds to the newly uncovered binding sites on the thin filament (binding to the thin filament is very tightly coupled to the release of inorganic phosphate). Myosin is now bound to actin in the strong binding state. The release of ADP and inorganic phosphate are tightly coupled to the power stroke (actin acts as a cofactor in the release of inorganic phosphate, expediting the release). This will pull the Z-bands towards each other, thus shortening the sarcomere and the I-band.
ATP binds myosin, allowing it to release actin and be in the weak binding state (a lack of ATP makes this step impossible, resulting in the rigor state characteristic of rigor mortis). The myosin then hydrolyzes the ATP and uses the energy to move into the "cocked back" conformation. In general, evidence (predicted and in vivo) indicates that each skeletal muscle myosin head moves 10-12 nm each power stroke, however there is also evidence (in vitro) of variations (smaller and larger) that appear specific to the myosin isoform.
Steps 9 and 10 repeat as long as ATP is available and calcium is present on thin filament.
While the above steps are occurring, calcium is actively pumped back into the sarcoplasmic reticulum. When calcium is no longer present on the thin filament, the tropomyosin changes conformation back to its previous state so as to block the binding sites again. The myosin ceases binding to the thin filament, and the contractions cease.
The calcium ions leave the troponin molecule in order to maintain the calcium ion concentration in the sarcoplasm. The active pumping of calcium ions into the sarcoplasmic reticulum creates a deficiency in the fluid around the myofibrils. This causes the removal of calcium ions from the troponin. Thus the tropomyosin-troponin complex again covers the binding sites on the actin filaments and contraction ceases.
Acne vulgaris (commonly called Acne) is a skin disease, caused by changes in the pilosebaceous units (skin structures consisting of a hair follicle and its associated sebaceous gland). Severe acne is inflammatory, but acne can also manifest in noninflammatory forms. Acne lesions are commonly referred to as pimples, spots, or zits. Acne is most common during adolescence, affecting more than 85% of teenagers, and frequently continues into adulthood. For most people, acne diminishes over time and tends to disappear, or at least decrease, after one reaches his or her early twenties. There is, however, no way to predict how long it will take for it to disappear entirely, and some individuals will continue to suffer from acne decades later, into their thirties and forties and even beyond. The term acne comes from a corruption of the Greek άκμή (acme in the sense of a skin eruption) in the writings of Aëtius Amidenus. The vernacular term bacne or backne is often used to indicate acne found specifically on one's back.
Symptoms
The most common form of acne is known as "acne vulgaris", meaning "common acne". Many teenagers get this type of acne. The face and upper neck are the most commonly affected, but the chest, back and shoulders may have acne as well. The upper arms can also have acne, but lesions found there are often keratosis pilaris, not acne. The typical acne lesions are comedones and inflammatory papules, pustules, and nodules. Some of the large nodules were previously called "cysts" and the term nodulocystic has been used to describe severe cases of inflammatory acne.
Aside from scarring, its main effects are psychological, such as reduced self-esteem and, according to at least one study, depression or suicide. Acne usually appears during adolescence, when people already tend to be most socially insecure. Early and aggressive treatment is therefore advocated by some to lessen the overall impact to individuals.
Causes of acne
Acne develops as a result of blockages in follicles. Hyperkeratinization and formation of a plug of keratin and sebum (a microcomedo) is the earliest change. Enlargement of sebaceous glands and an increase in sebum production occur with increased androgen (DHEA-S) production at adrenarche. The microcomedo may enlarge to form an open comedo (blackhead) or closed comedo (whitehead). In these conditions the naturally occurring largely commensual bacteria Propionibacterium acnes can cause inflammation, leading to inflammatory lesions (papules, infected pustules, or nodules) in the dermis around the microcomedo or comedo, which results in redness and and may result in scarring or hyperpigmentation. Primary causes
Exactly why some people get acne and some do not is not fully known. It is known to be partly hereditary. Several factors are known to be linked to acne: * Family/Genetic history. The tendency to develop acne runs in families. For example, school-age boys with acne have other members of their family with acne. A family history of acne is associated with an earlier occurrence of acne and an increased number of retentional acne lesions. * Hormonal activity, such as menstrual cycles and puberty. During puberty, an increase in male sex hormones called androgens cause the glands to get larger and make more sebum. * Stress, through increased output of hormones from the adrenal (stress) glands. * Hyperactive sebaceous glands, secondary to the three hormone sources above. * Accumulation of dead skin cells. * Bacteria in the pores. Propionibacterium acnes (P. acnes) is the anaerobic bacterium that causes acne. In-vitro resistance of P. acnes to commonly used antibiotics has been increasing. * Skin irritation or scratching of any sort will activate inflammation. * Use of anabolic steroids. * Any medication containing halogens (iodides, chlorides, bromides), lithium, barbiturates, or androgens. * Exposure to certain chemical compounds. Chloracne is particularly linked to toxic exposure to dioxins, namely Chlorinated dioxins. Several hormones have been linked to acne: the androgens testosterone, dihydrotestosterone (DHT) and dehydroepiandrosterone sulfate (DHEAS), as well as insulin-like growth factor 1 (IGF-I). In addition, acne-prone skin has been shown to be insulin resistant. Development of acne vulgaris in later years is uncommon, although this is the age group for Rosacea which may have similar appearances. True acne vulgaris in adults may be a feature of an underlying condition such as pregnancy and disorders such as polycystic ovary syndrome or the rare Cushing's syndrome. Menopause-associated acne occurs as production of the natural anti-acne ovarian hormone estradiol fails at menopause. The lack of estradiol also causes thinning hair, hot flashes, thin skin, wrinkles, vaginal dryness, and predisposes to osteopenia and osteoporosis as well as triggering acne (known as acne climacterica in this situation).
Sarcoplasmic Reticulum(SR) is a special type of smooth ER found in smooth and striated muscle. The only structural difference between this organelle and the smooth endoplasmic reticulum is the medley of protein they have, both bound to their membranes and drifting within the confines of their lumens. This fundamental difference is indicative of their functions: the smooth ER synthesizes molecules and the sarcoplasmic reticulum stores and pumps calcium ions. The sarcoplasmic reticulum contains large stores of calcium, which it sequesters and then releases when the cell is depolarized. This has the effect of triggering muscle contraction.
Sarcoplasmic Reticulum is physically separate from the sarcolemma and surrounds each myofibril. Sarcoplasmic reticulum membrane contains high levels of calcium ATPase. The sarcoplasmic reticulum functions to uptake calcium from the sarcoplasm and to release calcium into the sarcoplasm to initiate contraction and sequester it during relaxation.
it has been implicated as a major contributor to the depressed function in heart failure. The SR acts as a calcium source during contraction and a calcium sink during relaxation. Relaxation is mediated by the transport of calcium into the sarcoplasmic reticulum lumen by a Ca-ATPase, which is under reversible regulation by phospholamban, a low molecular weight phosphoprotein. Calcium then binds to calsequestrin in the lumen of the SR. For the initiation of contraction, calcium is released through the calcium channels or ryanodine receptors, which are under regulation by junctin, triadin and partially by a novel protein, the histidine rich calcium-binding protein. Thus, the SR is the major regulator of Ca2+-handling and contractility in muscle
Electron transport chain associates electron carriers (such as NADH and FADH2) and mediating biochemical reactions that produce adenosine triphosphate (ATP), which is a major energy intermediate in living organisms. Only two sources of energy are available to biosynthesize organic molecules and maintain biochemical and kinetic processes in living organisms: oxidation-reduction (redox) reactions and some forms of radiation, such as sunlight (used for photosynthesis). Organisms that use redox reactions to produce ATP are called chemotrophs. Organisms that use sunlight are called phototrophs. Both chemotrophs and phototrophs use electron transport chains to convert energy into ATP. This is achieved through a three-step process:
Gradually sap energy from high-energy electrons in a series of individual steps.
Use that energy to forcibly unbalance the proton concentration across the membrane, creating an electrochemical gradient.
Use the energy released by the drive to re-balance the proton distribution as a means of producing ATP.
The Electron Transport Chain is also called the ETC. ATP is made by an enzyme called ATP Synthase. The structure of this enzyme and its underlying genetic code is remarkably conserved in all known forms of life.
ATP synthase is powered by a transmembrane electrochemical potential gradient, usually in the form of a proton gradient. The function of the electron transport chain is to produce this gradient. In all living organisms, a series of redox reactions is used to produce a transmembrane electrochemical potential gradient.
Redox reactions are chemical reactions in which electrons are transferred from a donor molecule to an acceptor molecule. The underlying force driving these reactions is the Gibbs free energy of the reactants and products. The Gibbs free energy is the energy available ("free") to do work. Any reaction that decreases the overall Gibbs free energy of a system will proceed spontaneously.
The transfer of electrons from a high-energy molecule (the donor) to a lower-energy molecule (the acceptor) can be spatially separated into a series of intermediate redox reactions. This is an electron transport chain.
The fact that a reaction is thermodynamically possible does not mean that it will actually occur; for example, a mixture of hydrogen gas and oxygen gas does not spontaneously ignite. It is necessary either to supply an activation energy or to lower the intrinsic activation energy of the system, in order to make most biochemical reactions proceed at a useful rate. Living systems use complex macromolecular structures (enzymes) to lower the activation energies of biochemical reactions.
It is possible to couple a thermodynamically favorable reaction (a transition from a high-energy state to a lower-energy state) to a thermodynamically unfavorable reaction (such as a separation of charges, or the creation of an osmotic gradient), in such a way that the overall free energy of the system decreases (making it thermodynamically possible), while useful work is done at the same time. Biological macromolecules that catalyze a thermodynamically unfavorable reaction if and only if a thermodynamically favorable reaction occurs simultaneously underlie all known forms of life.
Electron transport chains capture energy in the form of a transmembrane electrochemical potential gradient. This energy can then be harnessed to do useful work. The gradient can be used to transport molecules across membranes. It can be used to do mechanical work, such as rotating bacterial flagella. It can be used to produce ATP high-energy molecules that are necessary for growth.
A small amount of ATP is available from substrate-level phosphorylation (for example, in glycolysis). Some organisms can obtain ATP exclusively by fermentation. In most organisms, however, the majority of ATP is generated by electron transport chains.
Cell biology (also called cellular biology or formerly cytology, from the Greek kytos, "container") is an academic discipline that studies cells – their physiological properties, their structure, the organelles they contain, interactions with their environment, their life cycle, division and death. This is done both on a microscopic and molecular level. Cell biology research extends to both the great diversity of single-celled organisms like bacteria and the many specialized cells in multicellular organisms like humans.
Knowing the composition of cells and how cells work is fundamental to all of the biological sciences. Appreciating the similarities and also differences between cell types is particularly important to the fields of cell and molecular biology. These fundamental similarities and differences provide a unifying theme, allowing the principles learned from studying one cell type to be extrapolated and generalized to other cell types. Research in cell biology is closely related to genetics, biochemistry, molecular biology and developmental biology.
Processes
Movement of proteins
Each type of protein is usually sent to a particular part of the cell. An important part of cell biology is the investigation of molecular mechanisms by which proteins are moved to different places inside cells or secreted from cells.
Most proteins are synthesized by ribosomes in the cytoplasm. This process is also known as protein biosynthesis or simply protein translation. Some proteins, such as those to be incorporated in membranes membrane proteins, are transported into the ER or endoplasmic reticulum during synthesis and further processed in the Golgi apparatus. From the Golgi, membrane proteins can move to the plasma membrane, to other subcellular compartments or they can be secreted from the cell. The ER and Golgi can be thought of as the "membrane protein synthesis compartment" and the "membrane protein processing compartment", respectively. There is a semi-constant flux of proteins through these compartments. ER and Golgi-resident proteins associate with other proteins but remain in their respective compartments. Other proteins "flow" through the ER and Golgi to the plasma membrane. Motor proteins transport membrane protein-containing vesicles along cytoskeletal tracks to distant parts of cells such as axon terminals.
Some proteins that are made in the cytoplasm contain structural features that target them for transport into mitochondria or the nucleus. Some mitochondrial proteins are made inside mitochondria and are coded for by mitochondrial DNA. In plants, chloroplasts also make some cell proteins.
Extracellular and cell surface proteins destined to be degraded can move back into intracellular compartments upon being incorporated into endocytosed vesicles. Some of these vesicles fuse with lysosomes where the proteins are broken down to their individual amino acids. The degradation of some membrane proteins begins while still at the cell surface when they are cleaved by secretases. Proteins that function in the cytoplasm are often degraded by proteasomes.
The lung is the essential respiration organ in air-breathing animals, including most tetrapods, a few fish and a few snails. The most primitive animals with a lung are the lungfish (vertebrate) and the pulmonate snails (invertebrate). In mammals and the more complex life forms, the two lungs are located in the chest on either side of the heart. Their principal function is to transport oxygen from the atmosphere into the bloodstream, and to release carbon dioxide from the bloodstream into the atmosphere. This exchange of gases is accomplished in the mosaic of specialized cells that form millions of tiny, exceptionally thin-walled air sacs called alveoli.
Medical terms related to the lung often begin with pulmo-, from the Latin pulmonarius ("of the lungs"), or with pneumo- (from Greek πνεύμω "breath")
The lungs are very important. Energy production to aerobic respiration requires oxygen and glucose and produces carbon dioxide as a gaseous waste product, creating a need for an efficient means of oxygen delivery to cells and excretion of carbon dioxide from cells. In small organisms, such as single-celled bacteria, this process of gas exchange can take place entirely by simple diffusion. In larger organisms, this is not possible; only a small proportion of cells are close enough to the surface for oxygen from the atmosphere to enter them through diffusion. Two major adaptations made it possible for organisms to attain great multicellularity: an efficient circulatory system that conveyed gases to and from the deepest tissues in the body, and a large, internalized respiratory system that centralized the task of obtaining oxygen from the atmosphere and bringing it into the body, whence it could rapidly be distributed to all the circulatory system. The lungs also protect the heart from damage to a certain degree.
In air-breathing vertebrates, respiration occurs in a series of steps. Air is brought into the animal via the airways — in reptiles, birds and mammals this often consists of the nose; the pharynx; the larynx; the trachea (also called the windpipe); the bronchi and bronchioles; and the terminal branches of the respiratory tree. The lungs of mammals are a rich lattice of alveoli, which provide an enormous surface area for gas exchange. A network of fine capillaries allows transport of blood over the surface of alveoli. Oxygen from the air inside the alveoli diffuses into the bloodstream, and carbon dioxide diffuses from the blood to the alveoli, both across thin alveolar membranes.
The drawing and expulsion of air is driven by muscular action; in early tetrapods, air was driven into the lungs by the pharyngeal muscles, whereas in reptiles, birds and mammals a more complicated musculoskeletal system is used. In the mammal, a large muscle, the diaphragm (in addition to the internal intercostal muscles) drives ventilation by periodically altering the intra-thoracic volume and pressure; by increasing volume and thus decreasing pressure, air flows into the airways down a pressure gradient, and by reducing volume and increasing pressure, the reverse occurs. During normal breathing, expiration is passive and no muscles are contracted (the diaphragm relaxes).
Another name for this inspiration and expulsion of air is ventilation. Vital capacity is the maximum volume of air that a person can exhale after maximum inhalation. A person's vital capacity can be measured by a spirometer (spirometry). In combination with other physiological measurements, the vital capacity can help make a diagnosis of underlying lung disease.
Coagulation is a complex process by which blood forms solid clots. It is an important part of hemostasis (the cessation of blood loss from a damaged vessel) whereby a damaged blood vessel wall is covered by a platelet- and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel. Disorders of coagulation can lead to an increased risk of bleeding and/or clotting and embolism.
Coagulation is highly conserved throughout biology; in all mammals, coagulation involves both a cellular (platelet) and a protein (coagulation factor) component. The system in humans has been the most extensively researched and therefore is the best understood.
Coagulation is initiated almost instantly after an injury to the blood vessel damages the endothelium (lining of the vessel). Platelets immediately form a hemostatic plug at the site of injury; this is called primary hemostasis. Secondary hemostasis occurs simultaneously—proteins in the blood plasma, called coagulation factors, respond in a complex cascade to form fibrin strands which strengthen the platelet plug.
Physiology
Damage to blood vessel walls exposes collagen normally present under the endothelium. Circulating platelets bind to the collagen with the surface collagen-specific glycoprotein Ia/IIa receptor. This adhesion is strengthened further by the large multimeric circulating protein von Willebrand factor (vWF), which forms links between the platelet glycoprotein Ib/IX/V and collagen fibrils.
The platelets are then activated and release the contents of their granules into the plasma, in turn activating other platelets. The platelets undergo a change in their shape which exposes a phospholipid surface for those coagulation factors that require it. Fibrinogen links adjacent platelets by forming links via the glycoprotein IIb/IIIa. In addition, thrombin activates platelets.
The coagulation cascade
The coagulation cascade of secondary hemostasis has two pathways, the Contact Activation pathway (formerly known as the Intrinsic Pathway) and the Tissue Factor pathway (formerly known as the Extrinsic pathway) that lead to fibrin formation. It was previously thought that the coagulation cascade consisted of two pathways of equal importance joined to a common pathway. It is now known that the primary pathway for the initiation of blood coagulation is the Tissue Factor pathway. The pathways are a series of reactions, in which a zymogen (inactive enzyme precursor) of a serine protease and its glycoprotein co-factor are activated to become active components that then catalyze the next reaction in the cascade, ultimately resulting in cross-linked fibrin. Coagulation factors are generally indicated by Roman numerals, with a lowercase a appended to indicate an active form.
The coagulation factors are generally serine proteases (enzymes). There are some exceptions. For example, FVIII and FV are glycoproteins and Factor XIII is a transglutaminase. Serine proteases act by cleaving other proteins at specific sites. The coagulation factors circulate as inactive zymogens.
The coagulation cascade is classically divided into three pathways. The tissue factor and contact activation pathways both activate the "final common pathway" of factor X, thrombin and fibrin.
Tissue factor pathway
The main role of the tissue factor pathway is to generate a "thrombin burst," a process by which thrombin, the single most important constituent of the coagulation cascade in terms of its feedback activation roles, is released instantaneously. FVIIa circulates in a higher amount than any other activated coagulation factor.
Following damage to the blood vessel, endothelium Tissue Factor (TF) is released, forming a complex with FVII and in so doing, activating it (TF-FVIIa).
TF-FVIIa activates FIX and FX.
FVII is itself activated by thrombin, FXIa, plasmin, FXII and FXa.
The activation of FXa by TF-FVIIa is almost immediately inhibited by tissue factor pathway inhibitor (TFPI).
FXa and its co-factor FVa form the prothrombinase complex which activates prothrombin to thrombin.
Thrombin then activates other components of the coagulation cascade, including FV and FVII (which activates FXI, which in turn activates FIX), and activates and releases FVIII from being bound to vWF.
FVIIIa is the co-factor of FIXa and together they form the "tenase" complex which activates FX and so the cycle continues. ("Tenase" is a contraction of "ten" and the suffix "-ase" used for enzymes.)
Contact activation pathway
The contact activation pathway begins with formation of the primary complex on collagen by high-molecular weight kininogen (HMWK), prekallikrein, and FXII (Hageman factor). Prekallikrein is converted to kallikrein and FXII becomes FXIIa. FXIIa converts FXI into FXIa. Factor XIa activates FIX, which with its co-factor FVIIIa form the tenase complex, which activates FX to FXa. The minor role that the contact activation pathway has in initiating clot formation can be illustrated by the fact that patients with severe deficiencies of FXII, HMWK, and prekallikrein do not have a bleeding disorder.
Final common pathway
Thrombin has a large array of functions. Its primary role is the conversion of fibrinogen to fibrin, the building block of a hemostatic plug. In addition, it activates Factors VIII and V and their inhibitor protein C (in the presence of thrombomodulin), and it activates Factor XIII, which forms covalent bonds that crosslink the fibrin polymers that form from activated monomers.
Following activation by the contact factor or tissue factor pathways the coagulation cascade is maintained in a prothrombotic state by the continued activation of FVIII and FIX to form the tenase complex, until it is down-regulated by the anticoagulant pathways.
Cofactors
Various substances are required for the proper functioning of the coagulation cascade:
Calcium and phospholipid (a platelet membrane constituent) are required for the tenase and prothrombinase complexes to function. Calcium mediates the binding of the complexes via the terminal gamma-carboxy residues on FXa and FIXa to the phospholipid surfaces expressed by platelets as well as procoagulant microparticles or microvesicles shedded from them. Calcium is also required at other points in the coagulation cascade.
Vitamin K is an essential factor to a hepatic gamma-glutamyl carboxylase that adds a carboxyl group to glutamic acid residues on factors II, VII, IX and X, as well as Protein S, Protein C and Protein Z. Deficiency of vitamin K (e.g. in malabsorption), use of inhibiting anticoagulants (warfarin, acenocoumarol and phenprocoumon) or disease (hepatocellular carcinoma) impairs the function of the enzyme and leads to the formation of PIVKAs (proteins formed in vitamin K absence) this causes partial or non gamma carboxylation and affects the coagulation factors ability to bind to expressed phospholipid.
Inhibitors
Three mechanisms keep the coagulation cascade in check. Abnormalities can lead to an increased tendency toward thrombosis:
Protein C is a major physiological anticoagulant. It is a vitamin K-dependent serine protease enzyme (EC 3.4.21.69) that is activated by thrombin into activated protein C (APC). The activated form (with protein S and phospholipid as a cofactor) degrades Factor Va and Factor VIIIa. Quantitative or qualitative deficiency of either may lead to thrombophilia (a tendency to develop thrombosis). Impaired action of Protein C (activated Protein C resistance), for example by having the "Leiden" variant of Factor V or high levels of FVIII also may lead to a thrombotic tendency.
Antithrombin is a serine protease inhibitor (serpin) that degrades the serine proteases; thrombin and FXa, as well as FXIIa, and FIXa. It is constantly active, but its adhesion to these factors is increased by the presence of heparan sulfate (a glycosaminoglycan) or the administration of heparins (different heparinoids increase affinity to F Xa, thrombin, or both). Quantitative or qualitative deficiency of antithrombin (inborn or acquired, e.g. in proteinuria) leads to thrombophilia.
Tissue factor pathway inhibitor (TFPI) inhibits F VIIa-related activation of F IX and F X after its original initiation.
Fibrinolysis
Eventually, all blood clots are reorganised and resorbed by a process termed fibrinolysis. The main enzyme responsible for this process (plasmin) is regulated by various activators and inhibitors.
Binding gold nanoparticles to a specific antibody for cancer cells could make cancer detection much easier, suggests research at the Georgia Institute of Technology and the University of California at San Francisco (UCSF). The report is published in the May 11, 2005 edition of the journal Nano Letters.
“Gold nanoparticles are very good at scattering and absorbing light,” said Mostafa El-Sayed, director of the Laser Dyanamics Laboratory and chemistry professor at Georgia Tech. “We wanted to see if we could harness that scattering property in a living cell to make cancer detection easier. So far, the results are extremely promising.”
Many cancer cells have a protein, known as Epidermal Growth Factor Receptor (EFGR), all over their surface, while healthy cells typically do not express the protein as strongly. By conjugating, or binding, the gold nanoparticles to an antibody for EFGR, suitably named anti-EFGR, researchers were able to get the nanoparticles to attach themselves to the cancer cells.
“If you add this conjugated nanoparticle solution to healthy cells and cancerous cells and you look at the image, you can tell with a simple microscope that the whole cancer cell is shining,” said El-Sayed. “The healthy cell doesn’t bind to the nanoparticles specifically, so you don’t see where the cells are. With this technique, if you see a well defined cell glowing, that’s cancer.”
In the study, researchers found that the gold nanoparticles have 600 percent greater affinity for cancer cells than for noncancerous cells. The particles that worked the best were 35 nanometers in size. Researchers tested their technique using cell cultures of two different types of oral cancer and one nonmalignant cell line. The shape of the strong absorption spectrum of the gold nanoparticles are also found to distinguish between cancer cells and noncancerous cells.
What makes this technique so promising, said El-Sayed, is that it doesn’t require expensive high-powered microscopes or lasers to view the results, as other techniques require. All it takes is a simple, inexpensive microscope and white light.
Another benefit is that the results are instantaneous. “If you take cells from a cancer stricken tissue and spray them with these gold nanoparticles that have this antibody you can see the results immediately. The scattering is so strong that you can detect a single particle,” said El-Sayed.
Finally, the technique isn’t toxic to human cells. A similar technique using artificial atoms known as Quantum Dots uses semiconductor crystals to mark cancer cells, but the semiconductor material is potentially toxic to the cells and humans.
Alpha-amino acids are the building blocks of proteins. A protein forms via the condensation of amino acids to form a chain of amino acid "residues" linked by peptide bonds. Proteins are defined by their unique sequence of amino acid residues; this sequence is the primary structure of the protein. Just as the letters of the alphabet can be combined to form an almost endless variety of words, amino acids can be linked in varying sequences to form a huge variety of proteins.
Twenty standard amino acids are used by cells in protein biosynthesis, and these are specified by the general genetic code. These 20 amino acids are biosynthesized from other molecules, but organisms differ in which ones they can synthesize and which ones must be provided in their diet. The ones that cannot be synthesized by an organism are called essential amino acids.
Functions in proteins
Amino acids are the basic structural building units of proteins. They form short polymer chains called peptides or longer chains called either polypeptides or proteins. The process of such formation from an mRNA template is known as translation, which is part of protein biosynthesis. Twenty amino acids are encoded by the standard genetic code and are called proteinogenic or standard amino acids. Other amino acids contained in proteins are usually formed by post-translational modification, which is modification after translation in protein synthesis. These modifications are often essential for the function or regulation of a protein; for example, the carboxylation of glutamate allows for better binding of calcium cations, and the hydroxylation of proline is critical for maintaining connective tissues and responding to oxygen starvation. Such modifications can also determine the localization of the protein, e.g., the addition of long hydrophobic groups can cause a protein to bind to a phospholipid membrane.
Non-protein functions
The 20 standard amino acids are either used to synthesize proteins and other biomolecules or oxidized to urea and carbon dioxide as a source of energy. The oxidation pathway starts with the removal of the amino group by a transaminase, the amino group is then fed into the urea cycle. The other product of transamidation is a keto acid that enters the citric acid cycle.Glucogenic amino acids can also be converted into glucose, through gluconeogenesis.
Hundreds of types of non-protein amino acids have been found in nature and they have multiple functions in living organisms. Microorganisms and plants can produce uncommon amino acids. In microbes, examples include 2-aminoisobutyric acid and lanthionine, which is a sulfide-bridged alanine dimer. Both these amino acids are both found in peptidic lantibiotics such as alamethicin.While in plants, 1-aminocyclopropane-1-carboxylic acid is a small disubstituted cyclic amino acid that is a key intermediate in the production of the plant hormone ethylene.
In humans, non-protein amino acids also have important roles. Glycine, gamma-aminobutyric acid, and glutamate are neurotransmitters. Many amino acids are used to synthesize other molecules, for example:
Tryptophan is a precursor of the neurotransmitter serotonin.
Glycine is a precursor of porphyrins such as heme.
Arginine is a precursor of nitric oxide.
Carnitine is used in lipid transport within the cell.
Ornithine and S-adenosylmethionine are precursors of polyamines.
Homocysteine is an intermediate in S-adenosylmethionine recycling.
Hydroxyproline, hydroxylysine, and sarcosine are also non-protein amino acids. The thyroid hormones are also alpha-amino acids.
Some amino acids have even been detected in meteorites, especially in a type known as carbonaceous chondrites. This observation has prompted the suggestion that life may have arrived on earth from an extraterrestrial source.
General structure
In the structure shown at the right, R represents a side chain specific to each amino acid. The central carbon atom, called Cα, is a chiral central carbon atom (with the exception of glycine) to which the two termini and the R-group are attached. Amino acids are usually classified by the properties of the side chain into four groups. The side chain can make them behave like a weak acid, a weak base, a hydrophile if they are polar, and hydrophobe if they are nonpolar. The chemical structures of the 20 standard amino acids, along with their chemical properties, are catalogued in the list of standard amino acids.
The phrase "branched-chain amino acids" or BCAA is sometimes used to refer to the amino acids having aliphatic side chains that are non-linear; these are leucine, isoleucine, and valine. Proline is the only proteinogenic amino acid whose side group links to the α-amino group and, thus, is also the only proteinogenic amino acid containing a secondary amine at this position. Proline has sometimes been termed an imino acid, but this is not correct in the current nomenclature.
Isomerism
Most amino acids can exist in either of two optical isomers, called D and L. The L-amino acids represent the vast majority of amino acids found in proteins. D-amino acids are found in some proteins produced by exotic sea-dwelling organisms, such as cone snails. They are also abundant components of the peptidoglycan cell walls of bacteria.
The L and D conventions for amino acid configuration do not refer to the optical activity of the amino acid itself, but rather to the optical activity of the isomer of glyceraldehyde having the same stereochemistry as the amino acid. S-glyceraldehyde is levorotary, and R-glyceraldehyde is dexterorotary, and so S-amino acids are called L-amino acids even if they are not levorotary, and R-amino acids are likewise called D-amino acids even if they are not dexterorotary.
There are two exceptions to these general rules of amino acid isomerism. Firstly, glycine, where R = H, no isomerism is possible because the alpha-carbon bears two identical groups (hydrogen). Secondly, in cysteine, the L = S and D = R assignment is reversed to L = R and D = S. Cysteine is structured similarly (with respect to glyceraldehyde) to the other amino acids but the sulfur atom alters the interpretation of the Cahn-Ingold-Prelog priority rule.
Reactions
As amino acids have both a primary amine group and a primary carboxyl group, these chemicals can undergo most of the reactions associated with these functional groups. These include nucleophilic addition, amide bond formation and imine formation for the amine group and esterification, amide bond formation and decarboxylation for the carboxylic acid group. The multiple side chains of amino acids can also undergo chemical reactions. The types of these reactions are determined by the groups on these side chains and are discussed in the articles dealing with each specific type of amino acid.
Peptide bond formation
As both the amine and carboxylic acid groups of amino acids can react to form amide bonds, one amino acid molecule can react with another and become joined through an amide linkage. This polymerization of amino acids is what creates proteins. This condensation reaction yields the newly formed peptide bond and a molecule of water. In cells, this reaction does not occur directly, instead the amino acid is activated by attachment to a transfer RNA molecule through an ester bond. This aminoacyl-tRNA is produced in an ATP-dependent reaction carried out by an aminoacyl tRNA synthetase. This aminoacyl-tRNA is then a substrate for the ribosome, which catalyzes the attack of the amino group of the elongating protein chain on the ester bond. As a result of this mechanism, all proteins are synthesized starting at their N-terminus and moving towards their C-terminus.
However, not all peptide bonds are formed in this way. In a few cases peptides are synthesized by specific enzymes. For example, the tripeptide glutathione is an essential part of the defenses of cells against oxidative stress. This peptide is synthesized in two steps from free amino acids. In the first step gamma-glutamylcysteine synthetase condenses cysteine and glutamic acid through a peptide bond formed between the side-chain carboxyl of the glutamate (the gamma carbon of this side chain) and the amino group of the cysteine. This dipeptide is then condensed with glycine by glutathione synthetase to form glutathione.
In chemistry, peptides are synthesized by a variety of reactions. One of the most used in solid-phase peptide synthesis, which uses the aromatic oxime derivatives of amino acids as activated units. These are added in sequence onto the growing peptide chain, which is attached to a solid resin support.
Zwitterions
As amino acids have both the active groups of an amine and a carboxylic acid they can be considered both acid and base (though their natural pH is usually influenced by the R group). At a certain pH known as the isoelectric point, the amine group gains a positive charge (is protonated) and the acid group a negative charge (is deprotonated). The exact value is specific to each different amino acid. This ion is known as a zwitterion, which comes from the German word Zwitter meaning "hybrid". A zwitterion can be extracted from the solution as a white crystalline structure with a very high melting point, due to its dipolar nature. Near-neutral physiological pH allows most free amino acids to exist as zwitterions.
Hydrophilic and hydrophobic amino acids
Depending on the polarity of the side chain, amino acids vary in their hydrophilic or hydrophobic character. These properties are important in protein structure and protein-protein interactions. The importance of the physical properties of the side chains comes from the influence this has on the amino acid residues' interactions with other structures, both within a single protein and between proteins. The distribution of hydrophilic and hydrophobic amino acids determines the tertiary structure of the protein, and their physical location on the outside structure of the proteins influences their quaternary structure. For example, soluble proteins have surfaces rich with polar amino acids like serine and threonine, while integral membrane proteins tend to have outer ring of hydrophobic amino acids that anchors them into the lipid bilayer, and proteins anchored to the membrane have a hydrophobic end that locks into the membrane. Similarly, proteins that have to bind to positively-charged molecules have surfaces rich with negatively charged amino acids like glutamate and aspartate, while proteins binding to negatively-charged molecules have surfaces rich with positively charged chains like lysine and arginine. Recently a new scale of hydrophobicity based on the free energy of hydrophobic association has been proposed.
Hydrophilic and hydrophobic interactions of the proteins do not have to rely only on the sidechains of amino acids themselves. By various posttranslational modifications other chains can be attached to the proteins, forming hydrophobic lipoproteins or hydrophilic glycoproteins.
Nonstandard amino acids
Aside from the twenty standard amino acids, there are a vast number of "non-standard" amino acids. Two of these can be specified by the genetic code, but are rather rare in proteins. Selenocysteine is incorporated into some proteins at a UGA codon, which is normally a stop codon.Pyrrolysine is used by some methanogenic archaea in enzymes that they use to produce methane. It is coded for with the codon UAG.
Examples of nonstandard amino acids that are not found in proteins include lanthionine, 2-aminoisobutyric acid, dehydroalanine and the neurotransmitter gamma-aminobutyric acid. Nonstandard amino acids often occur as intermediates in the metabolic pathways for standard amino acids — for example ornithine and citrulline occur in the urea cycle, part of amino acid catabolism.
Nonstandard amino acids are usually formed through modifications to standard amino acids. For example, homocysteine is formed through the transsulfuration pathway or by the demethylation of methionine via the intermediate metabolite S-adenosyl methionine, while dopamine is synthesized from l-DOPA, and hydroxyproline is made by a posttranslational modification of proline
Nutritional importance
Of the 20 standard proteinogenic amino acids, 8 are called essential amino acids because the human body cannot synthesize them from other compounds at the level needed for normal growth, so they must be obtained from food. However, the situation is a little more complicated since cysteine, tyrosine, histidine and arginine are semiessential amino acids in children, because the metabolic pathways that synthesize these amino acids are not fully developed.The amounts required also depend on the age and health of the individual, so it is hard to make general statements about the dietary requirement for some amino acids.
A ribozyme (from ribonucleic acid enzyme, also called RNA enzyme or catalytic RNA) is an RNA molecule that catalyzes a chemical reaction. Many natural ribozymes catalyze either the hydrolysis of one of their own phosphodiester bonds, or the hydrolysis of bonds in other RNAs, but they have also been found to catalyze the aminotransferase activity of the ribosome.
Investigators studying the origin of life have produced ribozymes in the laboratory that are capable of catalyzing their own synthesis under very specific conditions, such as an RNA polymerase ribozyme. Mutagenesis and selection has been performed resulting in isolation of improved variants of the "Round-18" polymerase ribozyme from 2001. "B6.61" is able to add up to 20 nucleotides to a primer template in 24 hours, until it decomposes by hydrolysis of its phosphodiester bonds.
Some ribozymes may play an important role as therapeutic agents, as enzymes which tailor defined RNA sequences, as biosensors, and for applications in functional genomics and gene discovery.
most ribozymes are quite rare in the cell, their roles are sometimes essential to life. For example, the functional part of the ribosome, the molecular machine that translates RNA into proteins, is fundamentally a ribozyme. Ribozymes often have divalent metal ions such as Mg2+ as cofactors.
RNA can also act as a hereditary molecule, which encouraged Walter Gilbert to propose that in the past, the cell used RNA as both the genetic material and the structural and catalytic molecule, rather than dividing these functions between DNA and protein as they are today. This hypothesis became known as the "RNA world hypothesis" of the origin of life.
If ribozymes were the first molecular machines used by early life, then today's remaining ribozymes -- such as the ribosome machinery -- could be considered living fossils of a life based primarily on nucleic acids.
A recent test-tube study of prion folding suggests that an RNA may catalyze the pathological protein conformation in the manner of a chaperone enzyme
The Humoral Immune Response (HIR) is the aspect of immunity that is mediated by secreted antibodies, produced in the cells of the B lymphocyte lineage (B cell). Secreted antibodies bind to antigens on the surfaces of invading microbes (such as viruses or bacteria), which flags them for destruction. Humoral immunity is called as such, because it involves substances found in the humours, or body fluids.
The Humoral Immune Response (HIR) is the aspect of immunity that is mediated by secreted antibodies, produced in the cells of the B lymphocyte lineage (B cell). Secreted antibodies bind to antigens on the surfaces of invading microbes (such as viruses or bacteria), which flags them for destruction. Humoral immunity is called as such, because it involves substances found in the humours, or body fluids.
The study of the molecular and cellular components that comprise the immune system, including their function and interaction, is the central science of immunology. The immune system is divided into a more primitive innate immune system, and acquired or adaptive immune system of vertebrates, the latter of which is further divided into humoral and cellular components.
Humoral immunity refers to antibody production, and the accessory processes that accompany it, including: Th2 activation and cytokine production, germinal center formation and isotype switching, affinity maturation and memory cell generation. It also refers to the effector functions of antibody, which include pathogen and toxin neutralization, classical complement activation, and opsonin promotion of phagocytosis and pathogen elimination
History
The concept of humoral immunity developed based on analysis of antibacterial activity of the components of serum. Hans Buchner is credited with the development of the humoral theory. In 1890 he described alexins, or “protective substances”, which exist in the serum and other bodily fluids and are capable of killing microorganisms. Alexins, later redefined "complement" by Paul Ehrlich, were shown to be the soluble components of the innate response that lead to a combination of cellular and humoral immunity, and bridged the features of innate and acquired immunity.
Following the 1888 discovery of diphtheria and tetanus, Emil von Behring and Shibasaburo Kitasato showed that disease need not be caused by microorganisms themselves. They discovered that cell-free filtrates were sufficient to cause disease. In 1890, filtrates of diphtheria (later named diphtheria toxins) were used immunize animals in an attempt to demonstrate that immunized serum contained an antitoxin that could neutralize the activity of the toxin and could transfer immunity to non immune animals. In 1897, Paul Ehrlich showed that antibodies form against the plant toxins ricin and abrin, and proposed that these antibodies are responsible for immunity. Ehrlich, with his friend Emil von Behring, went on to develop the diphtheria antitoxin, which became the first major success of modern immunotherapy. The presence and specificity of antibodies became the major tool for standardizing the state of immunity and identifying the presence of previous infections.
Complement system
The complement system is a biochemical cascade of the immune system that helps clear pathogens from an organism. It is derived from many small plasma proteins that work together to disrupt the target cell's plasma membrane leading to cytolysis of the cell. The complement system consists of more than 35 soluble and cell-bound proteins, 12 of which are directly involved in the complement pathways. The complement system is involved in the activities of both innate immunity and acquired immunity.
Activation of this system leads to cytolysis, chemotaxis, opsonization, immune clearance, and inflammation, as well as the marking of pathogens for phagocytosis. The proteins account for 5% of the serum globulin fraction. Most of these proteins circulate as zymogens, which are inactive until proteolytic cleavage.
Three biochemical pathways activate the complement system: the classical complement pathway, the alternate complement pathway, and the mannose-binding lectin pathway. The classical complement pathway typically requires antibodies for activation and is a specific immune response, while the alternate pathway can be activated without the presence of antibodies and is considered a non-specific immune response. Antibodies, in particular the IgG1 class, can also "fix" complement.
Antibodies
Immunoglobulins are glycoproteins in the immunoglobulin superfamily that function as antibodies. The terms antibody and immunoglobulin are often used interchangeably. They are found in the blood and tissue fluids, as well as many secretions. In structure, they are large Y-shaped globular proteins. In mammals there are five types of antibody: IgA, IgD, IgE, IgG, and IgM. Each immunoglobulin class differs in its biological properties and has evolved to deal with different antigens. Antibodies are synthesized and secreted by plasma cells that are derived from the B cells of the immune system.
An antibody is used by the immune system to identify and neutralize foreign objects like bacteria and viruses. Each antibody recognizes a specific antigen unique to its target. By binding their specific antigens, antibodies can cause agglutination and precipitation of antibody-antigen products, prime for phagocytosis by macrophages and other cells, block viral receptors, and stimulate other immune responses, such as the complement pathway.
An incompatible blood transfusion, causes a transfusion reaction, which is mediated by the humoral immune response. This type of reaction, called an acute hemolytic reaction, results in the rapid destruction (hemolysis) of the donor red blood cells by host antibodies. The cause is usually a clerical error (i.e. the wrong unit of blood being given to the wrong patient). The symptoms are fever and chills, sometimes with back pain and pink or red urine (hemoglobinuria). The major complication is that hemoglobin released by the destruction of red blood cells can cause acute renal failure.
B cells
The principal function of B cells is to make antibodies against soluble antigens. B cell recognition of antigen is not the only element necessary for B cell activation (a combination of clonal proliferation and terminal differentiation into plasma cells).
Naive B cells can be activated in a T-cell dependent or independent manner, but two signals are always required to initiate activation.
B-cell activation depends on one of three mechanisms: Type 1 T cell-independent (polyclonal) activation, type 2 T cell-dependent activation (in which macrophages present several of the same antigen in a way that causes cross-linking of antibodies on the surface of B cells), and, T cell-dependent activation. During T cell-dependent activation, an antigen presenting cell (APC) presents a processed antigen to a helper T (Th) cell, priming it. When a B cell processes and presents the same antigen to the primed Th cell, the T cell releases cytokines that activate the B cell.
Allergy is a disorder of the immune system that is often called atopy. Allergic reactions occur to environmental substances known as allergens; these reactions are acquired, predictable and rapid. Strictly, allergy is one of four forms of hypersensitivity and is called type I (or immediate) hypersensitivity. It is characterized by excessive activation of certain white blood cells called mast cells and basophils by a type of antibody, known as IgE, resulting in an extreme inflammatory response. Common allergic reactions include eczema, hives, hay fever, asthma, food allergies, and reactions to the venom of stinging insects such as wasps and bees.
Mild allergies like hay fever, are highly prevalent in the human population and cause symptoms such as allergic conjunctivitis and runny nose. Similarly, conditions such as asthma are common, in which allergy plays a major role. In some people, severe allergies to environmental or dietary allergens, or to medication, occur that may result in life-threatening anaphylactic reactions and potentially death.
A variety of tests now exist to diagnose allergic conditions; these include testing the skin for responses to known allergens or analyzing the blood for the presence and levels of allergen-specific IgE. Treatments for allergies include allergen avoidance, use of antihistamines, steroids or other oral medications, immunotherapy to desensitize the response to allergen, and targeted therapy.
Classification and history
The concept "allergy" was originally introduced in 1906 by the Viennese pediatrician Clemens von Pirquet, after noting that some of his patients were hypersensitive to normally innocuous entities such as dust, pollen, or certain foods. Pirquet called this phenomenon "allergy" from the Greek words allos meaning "other" and ergon meaning "work".Historically, all forms of hypersensitivity were classified as allergies, and all were thought to be caused by an improper activation of the immune system. Later, it became clear that several different disease mechanisms were implicated, with the common link to a disordered activation of the immune system. In 1963, a new classification scheme was designed by Philip Gell and Robin Coombs that described four types of hypersensitivity reactions, known as Type I to Type IV hypersensitivity. With this new classification, the word "allergy" was restricted to only type I hypersensitivities (also called immediate hypersensitivity), which are characterized as rapidly developing reactions.
A major breakthrough in understanding the mechanisms of allergy was the discovery of the antibody class labeled immunoglobulin E (IgE) - Kimishige Ishizaka and co-workers were the first to isolate and describe IgE in the 1960s.
Signs and symptoms
Many allergens are airborne particles, such as dust or pollen. Allergic rhinitis, also known as hay fever, occurs in response to airborne pollen, and causes irritation of the nose, sneezing, and itching and redness of the eyes. Inhaled allergens can also lead to asthmatic symptoms, caused by narrowing of the airways (bronchoconstriction) and increased production of mucus in the lungs, shortness of breath (dyspnea), coughing and wheezing.
Aside from these ambient allergens, allergic reactions can result from foods, insect stings, and reactions to medications like aspirin, and antibiotics such as penicillin. Symptoms of food allergy include abdominal pain, bloating, vomiting, diarrhoea, itchy skin, and swelling of the skin during hives or angiooedema. Food allergies rarely cause respiratory (asthmatic) reactions, or rhinitis. Insect stings, antibiotics and certain medicines produce a systemic allergic response that is also called anaphylaxis; multiple systems can be affected including the digestive system, the respiratory system, and the circulatory system. Depending of the rate of severity, it can cause cutaneous reactions, bronchoconstriction, edema, hypotension, coma and even death. This type of reaction can be triggered suddenly or the onset can be delayed. The severity of this type of allergic response often requires injections of epinephrine, sometimes through a device known as the Epi-Pen auto-injector. The nature of anaphylaxis is such that the reaction can seemingly be subsiding, but may recur throughout a prolonged period of time.
Substances that come into contact with the skin, such as latex are also common causes of allergic reactions, known as contact dermatitis or eczema. Skin allergies frequently cause rashes, or swelling and inflammation within the skin, in what is known as a "wheal and flare" reaction characteristic of hives and angioedema.
Cause
Risk factors for allergy can be placed in two general categories, namely host and environmental factors. Host factors include heredity, sex, race and age, with heredity being by far the most important. There are recent increases in the incidence of allergic disorders, however, that cannot be explained by genetic factors alone. The four main candidate environmental factors are alterations in exposure to infectious diseases during early childhood, environmental pollution, allergen levels, and dietary changes.
Genetic basis
Allergic diseases are strongly familial: identical twins are likely to have the same allergic diseases about 70% of the time; the same allergy occurs about 40% of the time in non-identical twins. Allergic parents are more likely to have allergic children, and their allergies are likely to be stronger than those from non-allergic parents. However some allergies are not consistent along genealogies; parents who are allergic to peanuts, may have children who are allergic to ragweed, or siblings that are allergic to different things. It seems that the likelihood of developing allergies is inherited and due to some irregularity in the way the immune system works, but the specific allergen, which causes the development of an allergy,
The risk of allergic sensitization and the development of allergies varies with age, with young children most at risk. Several studies have shown that IgE levels are highest in childhood and fall rapidly between the ages of 10 and 30 years. The peak prevalence of hay fever is highest in children and young adults and the incidence of asthma is highest in children under 10. Overall, boys have a higher risk of developing allergy than girls, although for some diseases, namely asthma in young adults, females are more likely to be affected. Sex differences tend to decrease in adulthood. Ethnicity may play a role in some allergies, however racial factors have been difficult to separate from environmental influences and changes due to migration. Interestingly, with regards to asthma, it has been suggested that different genetic loci are responsible for asthma in people of Caucasian, Hispanic, Asian, and African origins.
Environmental factors
International differences have been associated with the number of individuals within a population that suffer from allergy. Allergic diseases are more common in industrialized countries than in countries that are more traditional or agricultural, and there is a higher rate of allergic disease in urban populations versus rural populations, although these differences are becoming less defined.
Exposure to allergens, especially in early life, is an important risk factor for allergy. Alterations in exposure to microorganisms is the most plausible explanation, at present, for the increase in atopic allergy. Since children that live in large families or overcrowded households, or attend day care, have a reduced incidence of allergic disease, a relationship has been proposed between exposures to bacteria and viruses during childhood, and protection against the development of allergy, which has been called – the "hygiene hypothesis". Exposure to endotoxin and other components of bacteria may reduce atopic diseases.Endotoxin exposure reduces release of inflammatory cytokines such as TNF-α, IFNÎł, interleukin-10, and interleukin-12 from white blood cells (leukocytes) that circulate in the blood. Certain microbe-sensing proteins, known as Toll-like receptors, found on the surface of cells in the body are also thought to be involved in these processes.
Gutworms and similar parasites are present in untreated drinking water in developing countries, and were present in the water of developed countries until the routine chlorination and purification of drinking water supplies. Recent research has shown that some common parasites, such as intestinal worms (e.g. hookworms), secrete chemicals into the gut wall (and hence the bloodstream) that suppress the immune system and prevent the body from attacking the parasite.This gives rise to a new slant on the hygiene hypothesis theory — that co-evolution of man and parasites has led to an immune system that only functions correctly in the presence of the parasites. Without them, the immune system becomes unbalanced and oversensitive. In particular, research suggests that allergies may coincide with the delayed establishment of gut flora in infants. However, the research to support this theory is conflicting, with some studies performed in China and Ethiopia showing an increase in allergy in people infected with intestinal worms. Clinical trials have been initiated to test the effectiveness of certain worms in treating some allergies. It may be that the term 'parasite' could turn out to be inappropriate, and in fact a hitherto unsuspected symbiosis is at work
Colorectal cancer, also called colon cancer or large bowel cancer, includes cancerous growths in the colon, rectum and appendix. It is the third most common form of cancer and the second leading cause of cancer-related death in the Western world. Colorectal cancer causes 655,000 deaths worldwide per year, including about 16,000 in the UK, where it is the second most common site (after lung) to cause cancer death. Many colorectal cancers are thought to arise from adenomatous polyps in the colon. These mushroom-like growths are usually benign, but some may develop into cancer over time. The majority of the time, the diagnosis of localized colon cancer is through colonoscopy. Therapy is usually through surgery, which in many cases is followed by chemotherapy.
The first symptoms of colon cancer are usually vague, like weight loss and fatigue (tiredness). Local (bowel) symptoms are rare until the tumor has grown to a large size. Generally, the nearer the tumor is to the anus, the more bowel symptoms there will be.
Symptoms and signs are divided into local, constitutional and metastatic.
Local symptoms
* Change in bowel habits
o Change in frequency (constipation and/or diarrhea),
o Feeling of incomplete defecation (tenesmus) and reduction in diameter of stool, both characteristic of rectal cancer,
o Change in the appearance of stools :
+ Bloody stools or rectal bleeding
+ Stools with mucus
+ Black, tar-like stool (melena), more likely related to upper gastrointestinal eg stomach or duodenal disease
* Bowel obstruction causing bowel pain, bloating and vomiting of stool-like material.
* A tumor in the abdomen, felt by patients or their doctors.
* Symptoms related to invasion by the cancer of the bladder causing hematuria (blood in the urine) or pneumaturia (air in the urine), or invasion of the vagina causing smelly vaginal discharge. These are late events, indicative of a large tumor.
Constitutional (systemic) symptoms
* Unexplained weight loss, probably the most common symptom, caused by lack of appetite
* Anemia, causing dizziness, fatigue and palpitations. Clinically, there will be pallor and blood tests will confirm the low hemoglobin level.
Metastatic symptoms
* Liver metastases, causing :
o Jaundice.
o Pain in the abdomen, more often the upper part (epigastrium or right side of the abdomen
o liver enlargement, usually felt by a doctor.
* Blood clots in the veins and arteries, a paraneoplastic syndrome related to hypercoagulability of the blood (the blood is "thickened")
Risk factors
The lifetime risk of developing colon cancer in the United States is about 7%. Certain factors increase a person's risk of developing the disease. These include:
* Age. The risk of developing colorectal cancer increases with age. Most cases occur in the 60s and 70s, while cases before age 50 are uncommon unless a family history of early colon cancer is present.
* Polyps of the colon, particularly adenomatous polyps, are a risk factor for colon cancer. The removal of colon polyps at the time of colonoscopy reduces the subsequent risk of colon cancer.
* History of cancer. Individuals who have previously been diagnosed and treated for colon cancer are at risk for developing colon cancer in the future. Women who have had cancer of the ovary, uterus, or breast are at higher risk of developing colorectal cancer.
* Heredity:
o Family history of colon cancer, especially in a close relative before the age of 55 or multiple relatives
o Familial adenomatous polyposis (FAP) carries a near 100% risk of developing colorectal cancer by the age of 40 if untreated
o Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome
* Long-standing ulcerative colitis or Crohn's disease of the colon, approximately 30% after 25 years if the entire colon is involved
* Smoking. Smokers are more likely to die of colorectal cancer than non-smokers. An American Cancer Society study found that "Women who smoked were more than 40% more likely to die from colorectal cancer than women who never had smoked. Male smokers had more than a 30% increase in risk of dying from the disease compared to men who never had smoked."
* Diet. Studies show that a diet high in red meat and low in fresh fruit, vegetables, poultry and fish increases the risk of colorectal cancer. In June 2005, a study by the European Prospective Investigation into Cancer and Nutrition suggested that diets high in red and processed meat, as well as those low in fiber, are associated with an increased risk of colorectal cancer. Individuals who frequently eat fish showed a decreased risk.However, other studies have cast doubt on the claim that diets high in fiber decrease the risk of colorectal cancer; rather, low-fiber diet was associated with other risk factors, leading to confounding. The nature of the relationship between dietary fiber and risk of colorectal cancer remains controversial.
* Physical inactivity. People who are physically active are at lower risk of developing colorectal cancer.
* Virus. Exposure to some viruses (such as particular strains of human papilloma virus) may be associated with colorectal cancer.
* Alcohol. See the subsection below.
* Primary sclerosing cholangitis offers a risk independent to ulcerative colitis
* Low selenium.
* Inflammatory Bowel Disease. About one percent of colorectal cancer patients have a history of chronic ulcerative colitis. The risk of developing colorectal cancer varies inversely with the age of onset of the colitis and directly with the extent of colonic involvement and the duration of active disease. Patients with colorectal Crohn's disease have a more than average risk of colorectal cancer, but less than that of patients with ulcerative colitis.
* Environmental Factors. Industrialized countries are at a relatively increased risk compared to less developed countries or countries that traditionally had high-fiber/low-fat diets. Studies of migrant populations have revealed a role for environmental factors, particularly dietary, in the etiology of colorectal cancers. Genetic factors and inflammatory bowel disease also place certain individuals at increased risk.
* Exogenous Hormones. The differences in the time trends in colorectal cancer in males and females could be explained by cohort effects in exposure to some sex-specific risk factor; one possibility that has been suggested is exposure to estrogens . There is, however, little evidence of an influence of endogenous hormones on the risk of colorectal cancer. In contrast,there is evidence that exogenous estrogens such as hormone replacement therapy (HRT), tamoxifen, or oral contraceptives might be associated with colorectal tumors.
Alcohol
The WCRF panel report Food, Nutrition, Physical Activity and the Prevention of Cancer: a Global Perspective finds the evidence "convincing" that alcoholic drinks increase the risk of colorectal cancer in men.
The NIAAA reports that: "Epidemiologic studies have found a small but consistent dose-dependent association between alcohol consumption and colorectal cancer even when controlling for fiber and other dietary factors. Despite the large number of studies, however, causality cannot be determined from the available data."
"Heavy alcohol use may also increase the risk of colorectal cancer" (NCI). One study found that "People who drink more than 30 grams of alcohol per day (and especially those who drink more than 45 grams per day) appear to have a slightly higher risk for colorectal cancer." Another found that "The consumption of one or more alcoholic beverages a day at baseline was associated with approximately a 70% greater risk of colon cancer."
One study found that "While there was a more than twofold increased risk of significant colorectal neoplasia in people who drink spirits and beer, people who drank wine had a lower risk. In our sample, people who drank more than eight servings of beer or spirits per week had at least a one in five chance of having significant colorectal neoplasia detected by screening colonoscopy.".
Other research suggests that "to minimize your risk of developing colorectal cancer, it's best to drink in moderation"
On its colorectal cancer page, the National Cancer Institute does not list alcohol as a risk factor: however, on another page it states, "Heavy alcohol use may also increase the risk of colorectal cancer"
Drinking may be a cause of earlier onset of colorectal cancer.
Treatment
The treatment depends on the staging of the cancer. When colorectal cancer is caught at early stages (with little spread) it can be curable. However when it is detected at later stages (when distant metastases are present) it is less likely to be curable.
Surgery remains the primary treatment while chemotherapy and/or radiotherapy may be recommended depending on the individual patient's staging and other medical factors.
Surgery
Surgeries can be categorised into curative, palliative, bypass, fecal diversion, or open-and-close.
Curative Surgical treatment can be offered if the tumor is localized.
* Very early cancer that develops within a polyp can often be cured by removing the polyp (i.e., polypectomy) at the time of colonoscopy.
* In colon cancer, a more advanced tumor typically requires surgical removal of the section of colon containing the tumor with sufficient margins, and radical en-bloc resection of mesentery and lymph nodes to reduce local recurrence (i.e., colectomy). If possible, the remaining parts of colon are anastomosed together to create a functioning colon. In cases when anastomosis is not possible, a stoma (artificial orifice) is created.
* Curative surgery on rectal cancer includes total mesorectal excision (lower anterior resection) or abdominoperineal excision.
In case of multiple metastases, palliative (non curative) resection of the primary tumor is still offered in order to reduce further morbidity caused by tumor bleeding, invasion, and its catabolic effect. Surgical removal of isolated liver metastases is, however, common and may be curative in selected patients; improved chemotherapy has increased the number of patients who are offered surgical removal of isolated liver metastases.
If the tumor invaded into adjacent vital structures which makes excision technically difficult, the surgeons may prefer to bypass the tumor (ileotransverse bypass) or to do a proximal fecal diversion through a stoma.
The worst case would be an open-and-close surgery, when surgeons find the tumor unresectable and the small bowel involved; any more procedures would do more harm than good to the patient. This is uncommon with the advent of laparoscopy and better radiological imaging. Most of these cases formerly subjected to "open and close" procedures are now diagnosed in advance and surgery avoided.
Laparoscopic-assisted colectomy is a minimally-invasive technique that can reduce the size of the incision and may reduce post-operative pain.
As with any surgical procedure, colorectal surgery may result in complications including
* wound infection, Dehiscence (bursting of wound) or hernia
* anastomosis breakdown, leading to abscess or fistula formation, and/or peritonitis
* bleeding with or without hematoma formation
* adhesions resulting in bowel obstruction (especially small bowel)
* adjacent organ injury; most commonly to the small intestine, ureters, spleen, or bladder
* Cardiorespiratory complications such as myocardial infarction, pneumonia, arrythmia, pulmonary embolism etc
Chemotherapy
Chemotherapy is used to reduce the likelihood of metastasis developing, shrink tumor size, or slow tumor growth. Chemotherapy is often applied after surgery (adjuvant), before surgery (neo-adjuvant), or as the primary therapy (palliative). The treatments listed here have been shown in clinical trials to improve survival and/or reduce mortality rate and have been approved for use by the US Food and Drug Administration. In colon cancer, chemotherapy after surgery is usually only given if the cancer has spread to the lymph nodes (Stage III).
* Adjuvant (after surgery) chemotherapy. One regimen involves the combination of infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX)
o 5-fluorouracil (5-FU) or Capecitabine (Xeloda)
o Leucovorin (LV, Folinic Acid)
o Oxaliplatin (Eloxatin)
* Chemotherapy for metastatic disease. Commonly used first line chemotherapy regimens involve the combination of infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) with bevacizumab or infusional 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) with bevacizumab
o 5-fluorouracil (5-FU) or Capecitabine
o Leucovorin (LV, Folinic Acid)
o Irinotecan (Camptosar)
o Oxaliplatin (Eloxatin)
o Bevacizumab (Avastin)
o Cetuximab (Erbitux)
o Panitumumab (Vectibix)
* In clinical trials for treated/untreated metastatic disease.
o Bortezomib (Velcade)
o Oblimersen (Genasense, G3139)
o Gefitinib and Erlotinib (Tarceva)
o Topotecan (Hycamtin)
Radiation therapy
Radiotherapy is not used routinely in colon cancer, as it could lead to radiation enteritis, and it is difficult to target specific portions of the colon. It is more common for radiation to be used in rectal cancer, since the rectum does not move as much as the colon and is thus easier to target. Indications include:
* Colon cancer
o pain relief and palliation - targeted at metastatic tumor deposits if they compress vital structures and/or cause pain
* Rectal cancer
o neoadjuvant - given before surgery in patients with tumors that extend outside the rectum or have spread to regional lymph nodes, in order to decrease the risk of recurrence following surgery or to allow for less invasive surgical approaches (such as a low anterior resection instead of an abdomino-perineal resection)
o adjuvant - where a tumor perforates the rectum or involves regional lymph nodes (AJCC T3 or T4 tumors or Duke's B or C tumors)
o palliative - to decrease the tumor burden in order to relieve or prevent symptoms
Sometimes chemotherapy agents are used to increase the effectiveness of radiation by sensitizing tumor cells if present.
In November 2006, it was announced that a vaccine had been developed and tested with very promising results. The new vaccine, called TroVax, works in a totally different way to existing treatments by harnessing the patient's own immune system to fight the disease. Experts say this suggests that gene therapy vaccines could prove an effective treatment for a whole range of cancers. Oxford BioMedica is a British spin-out from Oxford University specialising in the development of gene-based treatments. Phase III trials are underway for renal cancers and planned for colon cancers.
Treatment of liver metastases
According to the American Cancer Society statistics in 2006, over 20% of patients present with metastatic (stage IV) colorectal cancer at the time of diagnosis, and up to 25% of this group will have isolated liver metastasis that is potentially resectable. Lesions which undergo curative resection have demonstrated 5-year survival outcomes now exceeding 50%.
Resectability of a liver metastasis is determined using preoperative imaging studies (CT or MRI), intraoperative ultrasound, and by direct palpation and visualization during resection. Lesions confined to the right lobe are amenable to en bloc removal with a right hepatectomy (liver resection) surgery. Smaller lesions of the central or left liver lobe may sometimes be resected in anatomic "segments", while large lesions of left hepatic lobe are resected by a procedure called hepatic trisegmentectomy. Treatment of lesions by smaller, non-anatomic "wedge" resections is associated with higher recurrence rates. Some lesions which are not initially amenable to surgical resection may become candidates if they have significant responses to preoperative chemotherapy or immunotherapy regimens. Lesions which are not amenable to surgical resection for cure can be treated with modalities including radio-frequency ablation (RFA), cryoablation, and chemoembolization.
Patients with colon cancer and metastatic disease to the liver may be treated in either a single surgery or in staged surgeries (with the colon tumor traditionally removed first) depending upon the fitness of the patient for prolonged surgery, the difficulty expected with the procedure with either the colon or liver resection, and the comfort of the surgery performing potentially complex hepatic surgery.
Poor pronostic factors of patients with liver metastasis include:
* Synchronous (diagnosed simultaneously) liver and primary colorectal tumors
* A short time between detecting the primary cancer and subsequent development of liver mets
* Multiple metastatic lesions
* High blood levels of the tumor marker, carcino-embryonic antigen (CEA), in the patient prior to resection
* Larger size metastatic lesions
Support therapies
Cancer diagnosis very often results in an enormous change in the patient's psychological wellbeing. Various support resources are available from hospitals and other agencies which provide counseling, social service support, cancer support groups, and other services. These services help to mitigate some of the difficulties of integrating a patient's medical complications into other parts of their life.
Musculoskeletal pain affects the bones, muscles, ligaments, tendons, and nerves. It can be acute (having a rapid onset with severe symptoms) or chronic (long-lasting). Musculoskeletal pain can be localized in one area, or widespread.
Lower back pain is the most common type of musculoskeletal pain. Other common types include tendonitis, myalgia (muscle pain), and stress fractures.
