Manipulation of such adhesions may lead to dis- semination of infection and subsequent diffuse peritoni- tis generic tadalis sx 20mg with visa. Depending on the size of the cow being explored purchase 20mg tadalis sx mastercard, some of the abdominal viscera may be palpated by extending an arm over or caudal to the rumen buy tadalis sx 20 mg line. When performing a rumenotomy in cases of vagus in- digestion or hardware disease 20 mg tadalis sx otc, the interior of the rumen should be cleared of as much ingesta as possible. C B, A chest trochar was used to drain the liver abscess following a second surgery performed in the right paramedian area to properly place the trochar. The reticulum should be searched If a reticular abscess is identied and is denitely meticulously for foreign bodies. The wall of the reticulum adhered to the wall of the reticulum, aspiration to con- should be grasped and inverted to detect adhesions. The rm abscess formation followed by incisional drainage distal esophagus should be entered to detect neoplastic or of the abscess into the reticulum should be performed. The reticuloomasal orice should If an abscess is identied but is found not to be adher- be entered with several ngers or the whole hand to pal- ent to the forestomach, it should be located carefully pate the interior of the omasum. In smaller cows, the and approached by a second abdominal surgery for de- surgeon may be able to advance through the omasum nitive drainage or marsupialization, assuming the into the abomasum at this time. Abdominal abscesses associated with the reticu- cation of the reticular adhesions helps conrm diagnosis lum, liver, or umbilical remnants likewise may be identi- and directs the surgeon s search for the causative foreign ed by palpation through the rumen wall. This to identify the object until aided by a more experienced pain has been confused with pain caused by peritonitis surgeon. In these instances, the foreign body has been when the affected cow s cranial nerve decits were not found lying ush to the reticular wall, having perforated observed, leading to misdiagnosis of peritonitis. Certainly many foreign bodies have been found to have fully penetrated and exited the reticulum to lie out- This syndrome also has been called rumen collapse side the organ. In these instances, efforts to retrieve tiny and is observed sporadically in cattle suffering from se- metallic objects are futile unless a ventral exploratory pro- vere inammatory diseases such as septic metritis, septic cedure is deemed possible. On rare occasions, it has been mastitis, or severe pneumonia causing complete an- possible to retrieve foreign bodies from a ventral ap- orexia of several days duration. Physical examination proach when previous rumenotomy or ultrasound has usually identies the primary inammatory disease and identied the object and its surrounding brous tissue. Simultaneous percussion however, because of diffuse adhesions making removal of and auscultation reveal a ping localized to the dorsal the foreign body impossible or the creation of diffuse one half to one third of the left abdomen. The abdomen is not distended on the left side, but this Cows showing signs of vagus ingestion that are found ping creates great confusion because differential diag- to have primary reticuloperitonitis almost invariably nosis of left displacement of the abomasum, ruminal have had perforation of the right or medial wall of the tympany, and pneumoperitoneum must be considered. Rectal exa- indirect damage to the ventral vagal nerve branches on mination is necessary to conrm the problem and will the medial wall of the reticulum. Therefore the me- reveal a collapsed dorsal sac of the rumen with no pal- thodical search for the foreign body should be directed pable rumen in the dorsal left quadrant and the left to the right wall of the reticulum. Rumenotomies have had to be pressed around the examiner s arm, ruling out pneumo- performed to retrieve balling guns, parts of balling guns, peritoneum. Standing laparotomies were performed on Fricke specula, stomach tubes, and other pieces of equip- several cattle with pings caused by rumen collapse be- ment swallowed by cows during the administration of fore the syndrome was recognized. In some instances, it may be indicated to transfaunate the cow by giving rumen juices from a healthy cow into the rumen of the patient. Listeriosis Occasional cattle affected with meningoencephalitis caused by Listeria monocytogenes show rumen stasis and vomition as early signs. Buffering by feeding roughage before the offending grain or silage or adding alkalinizing buffer to the feed- stuff usually stops the problem. Vomiting also may be observed in those with trau- matic reticuloperitonitis resulting from repetitive irrita- tion of the reticulum, especially in the cranial reticulum near the cardia or when the foreign body is free in the ventral abdomen. Whether this irritation triggers recep- tors involved in regurgitation is unknown. In addition to vomiting, these cattle usually are ill with signs consistent with traumatic reticuloperitonitis. Regurgitation may be associated Once a diagnosis of rumen collapse has been made with the release of a large amount of liquid rumen ingesta and other causes of left-sided abdominal pings have that cannot be retained in the oral cavity and therefore been ruled out, treatment should be directed toward the appears as vomition. Systemic antibiotics are indicated for regurgitation in the presence of greatly increased intraru- septic metritis, septic mastitis, or pneumonia. Sup- tion of the vagus nerve caused by inammation of the portive therapy for hypocalcemia or ketosis should be vagal nucleus or inability to retain regurgitated ingesta used if indicated. Although unusual, when it occurs, af- If therapy for the primary inammatory disease is fected calves also may have dysphagia resulting from successful, the affected cow will begin to eat. The ventral pharyngeal muscular dysfunction and may not be able extent of the ping will be located more dorsally each to control regurgitated material. This may also be seen successive day during recovery as the rumen begins to in calves with otitis media/interna. Inhalation pneumo- ll and return to its normal position in the left upper nia is a common sequela in calves so affected. Prognosis is excellent if the primary disease is ous plants or toxins may cause vomiting in dairy cattle managed successfully because rumen collapse is merely exposed to Eupatorium rugosum, Hymenoxys sp. Because of modern management systems, however, dairy cattle are exposed to these plants only infrequently except in accidental exposure. Vomition is observed sporadically in dairy cattle and Dairy cattle with severe hypocalcemia resulting from may result from dietary or physical conditions. The parturient hypocalcemia may vomit as a result of in- most common cause of vomition is hyperacidity of the creased intraruminal pressure and loss of smooth mus- diet that usually affects only one cow in the herd. These animals are at greater risk of inhalation only one animal is affected is unknown. Such cows re- pneumonia because of their comatose condition than main healthy, continue to eat, and do not show signs of cattle that vomit because of other causes. It is im- Passage of stomach tubes, especially large-diameter portant to determine when the vomiting has occurred stomach tubes (4. This mass acted as a valve to interfere with eructation and create signs of vagus indigestion in a cow. Vomiting and depression were the most noticeable The other major neoplasm of the forestomach com- clinical signs in this adult cow with listeriosis. Although more commonly found in the abomasum, lymphosarcoma may form sin- gular or multiple lesions in the wall of the forestomach vomiting in dairy cattle. In these in- geal or reticular irritation or be associated with the stances, forestomach dysfunction characterized by bloat cow s primary disease (i. If this be suspected if other target organs, peripheral lymph repeatedly occurs and the cow needs to be tubed for nodes, or visceral masses palpated per rectum are identi- feeding, a smaller tube passed through the nasal cavity ed by cytologic examination. In most cases, however, the lesions are identied on ultrasound examination or at Forestomach Neoplasia the time of abdominal exploratory laparotomy. Treat- Fibropapillomas are common in the distal esophagus, ment is rarely attempted. Large bropapillomas located in the distal such that the cow survives long enough to deliver a term esophagus or cardia region may act as an impediment to calf. Although this has been successful in a few cases, the eructation, thereby causing intermittent or chronic bloat. This virus causes bropapillomata in the oral cavity, esophagus, and fore- Rumen Fistulas as a Therapeutic Tool stomach. In some parts of the world, ingestion of car- cinogens such as bracken fern may encourage malignant Rumen stulas have been used as a surgical means of transformation of bropapillomas to carcinomas or treatment for chronic or recurrent free-gas bloat in dairy squamous cell carcinomas. For this procedure to be most effective, otherwise and have normal appetites when not bloated. Therefore rumenotomy often precedes surgical removal in such cases and has been performed the rumen stula procedure in cows. Thus if passage of a the rst 6 weeks of lactation, but they may occur spo- stomach tube easily relieves free-gas bloat in the patient radically at any stage of lactation or gestation. Some studies show an in- benet from this procedure if their pneumonia responds creased incidence in mature cattle over rst-calf heifers. Excessive production of volatile fatty acids caused time for the animal and avoiding frequent passage of a by modern diets consisting of highly acid feed stomach tube to relieve the free-gas distention.
It does not chelate lead in soft tissue order tadalis sx 20mg otc, more extensive and macrophages will accumulate order tadalis sx 20 mg on line. These and continued treatment depends on soft tissue lead lesions are similar to those caused by thiamine de- equilibrating with the decreasing bone levels buy cheap tadalis sx 20mg online. Both diseases Thiamine should be administered as well at a dosage cause cortical blindness with intact pupil function cheap tadalis sx 20mg on-line, and of 2 mg/kg body weight or higher. Thiamine does not both may lead to depression, head pressing, bruxism, protect against or remove lead accumulation in tissue and other signs. Rabies must be considered in all differ- thiamine levels or metabolism to some degree and that ential diagnoses, but blindness is not as common with some of the cerebrocortical lesions are in fact the result rabies as with lead poisoning. Unless history conrms the source of lead, prevention When recent ingestion of a known lead-containing of further exposure must be the primary concern of the material has occurred, a rumenotomy offers the best op- veterinarian. When the history conrms that the laxatives are indicated to cause formation of insoluble only affected cow is the one who got loose and was lead suldes that can be passed in the feces. Cattle that are having sei- outbreaks with multiple cattle affected and no known zures or showing opisthotonos, blindness, and demen- means of exposure. Some Salt intoxication (water deprivation) or hypernatremia clinicians recommend dividing the dose and giving half is an occasional cause of neurologic signs in calves or of the total daily dose twice daily. Most cases in calves go undiag- may result in hypernatremia because calves seem willing nosed in the eld because of lack of laboratory data. Groups of calves or cows that are affected usually stimu- Failure to provide access to water for milk replacer fed late greater diagnostic efforts. Adult cattle have suffered salt intoxication primarily as Rations and water should be analyzed for salt con- a result of water deprivation that was accidental or brought tent when adult dairy cattle or heifers are affected with on by natural disasters or droughts. When calves are affected, investigation outbreak of salt poisoning in replacement heifers during into feeding protocols, dilution rates of fed milk re- freezing weather when both their water source and walk- placer or oral electrolyte solutions, and the availability ways were covered with ice; salt was sprinkled on the of ad libitum access to fresh water is required. Excessive salt in the ration Treatment generally is not a problem as long as plenty of fresh water Treatment should be designed to produce a slow, grad- is available to cattle. Beware that the signs of cerebro- much more rapidly than brain intracellular osmolarity. Ideally correction of hypernatremia rologic signs tend to be directly proportional to serum should be 2 mEq/hr. Diarrhea caused by saline catharsis and dehydration exists because the patient needs intensive enteric pathogens in calves contributes to dehydration, uid therapy for dehydration but will likely suffer neuro- which worsens the electrolyte problems. Supportive therapy with thiamine may be of to hypernatremic patients decreases extracellular uid os- benet and is unlikely to be harmful. If the sodium has molarity faster than intracellular osmolarity in the brain returned to normal but the calf has not responded appro- cells; the net result is imbibition of water into brain cells, priately, a dose of mannitol (0. Adult cattle that are water deprived tend to show Nervous Ketosis gastrointestinal signs, including anorexia, diarrhea, and vomiting. Neurologic signs ini- Etiology tially reect the prosencephalic cerebrocortical lesion Nervous ketosis is simply an encephalopathic form of depression, blindness, and seizures. More severe lesions metabolic ketosis and may occur at any time during the will involve the brainstem and cerebellum, causing cer- rst 8 weeks of lactation. The reason for the neurological signs in ner- vous ketosis are not known but may be caused simply by hypoglycemia, acetoacetic acid levels that are toxic to the brain, or through the production of isopropyl alcohol A from acetoacetic acid breakdown in the rumen. A degree of hepatic encephalopathy could contribute to neuro- logic signs in these cattle, but we are unaware of studies to conrm or deny this theory. Signs Signs observed in cattle affected with nervous ketosis vary from recumbency to aggression. Many cows having ner- vous ketosis act demented, constantly licking one or more spots on their own body or on inanimate objects. Other cows, if conned, show pro- pulsive tendencies by constantly leaning into a stanchion or tie stall. Cattle not conned to tie stalls may wander about, appear ataxic, blind, and will head press. Some severely affected cattle become recumbent as their degree of hypoglycemia B worsens. Once recumbent, the patient may appear simi- lar to hypocalcemic or hypomagnesemic patients. Overly fat periparturient cows may develop severe ketosis and signs of nervous ketosis within days following calving. There- fore if recumbent, these cows are often assumed to be hypocalcemic or hypomagnesemic but may have nervous ketosis or combined metabolic problems. This cow appeared demented Cattle showing irritation or aggression are obviously and repeatedly licked her side and stall pipes, and bit the more dramatic and can be dangerous to handlers, vet- water cup. Irritability resulting from hypoglycemia, just as in people, can worsen if the pa- tient is stressed. Diagnosis Blindness is observed occasionally in cattle having ner- Diagnosis depends on identication of ketonuria in vous ketosis. Most cattle regain vision following treat- cattle showing bizarre neurologic signs. Ketonemia and ment, which has caused many authors to describe this ketonuria are usually dramatic, and test tablets quickly blindness as transient or apparent. However, not all patients have strongly posi- ness may persist and be permanent in some nervous keto- tive urine ketones. This may be a dilutional effect if the sis patients, even though all other signs have resolved with cow has been drinking large quantities of water or chew- treatment. This bilateral blindness, rst described by Fox, ing on a salt block because of a depraved appetite. There- is a cerebrocortical blindness with intact pupillary func- fore some variation in the degree of ketonuria exists in tion and is most likely caused by permanent damage to nervous ketosis patients. In addition to dextrose, low- dose corticosteroids usually are used as therapy for keto- sis. An initial dose of 10 to 20 mg of dexamethasone is followed by 10 mg daily for 3 to 4 additional days. Dexa- methasone treatment is contingent on the fact that the patient has no contraindications to use of this drug. Most clinicians use propylene glycol or glycerol at 6 to 8 oz, usually twice daily, as a supplemental energy source. It is important not to use these products in exces- sive doses because they may contribute to decreased ru- minal activity and diarrhea. Chloral hydrate (30 g orally in gelatin capsules) may be extremely helpful as initial therapy in very agitated only acetoacetate and do not detect acetone or beta- patients because of the sedative properties of the drug. More bizarre signs Periparturient patients with nervous ketosis have a cause the clinician to consider a wider differential diag- guarded prognosis. Despite the broad differen- Vitamin A Deciency tial diagnosis, the triad of early lactation, positive (usu- ally strongly) urine or milk ketones, and nervous signs Etiology and Signs generally allow accurate diagnosis. An absolute or relative deciency of vitamin A may cause Occasionally cows with other neurologic diseases a multitude of abnormalities in growing cattle. Mature cattle may Overly fat periparturient cows with nervous ketosis show blindness and gastrointestinal, neurologic, and re- require further workup, including acid-base electrolyte productive abnormalities. Dex- nial pressure secondary to meningeal thickening and trose should be repeated in 6 to 12 hours in eld settings. If this is not practical, re- meningeal broplasia and a narrowing of the caudal peat treatments with dextrose should be suggested at cranial fossa and foramen magnum result in caudal cer- 12-hour intervals for at least three treatments. Optic disc edema must be severe to result in blindness because many decient cattle will remain visual despite mild-to-moderate edema. In severe cases, this causes dilated pupils with decient pupillary responses to light. Nyctalopia or night blindness also is associated with vitamin A deciency and, although it is one of the earliest signs, may be difcult to assess in eld settings. Vitamin A is essential for rhodopsin regen- eration required for photoreceptor activity during dark adaptation. Rod photoreceptors may be more affected than cones, thus contributing to nyctalopia. This may be repeated, and dietary supple- only offered coarse roughage in addition to pasture may mentation should begin immediately with sufcient become decient.
There is a considerable variation in the incidence and mortality rates around the world tadalis sx 20 mg sale. Squamous cell cancer of the posterior lateral border of the tongue in a 28-year-old woman discount tadalis sx 20mg with amex. In a very general overview purchase tadalis sx 20 mg online, the balance between tu mor suppressor genes and those genes that induce cell cycle is altered tadalis sx 20mg free shipping. Allowing cells to es cape cell cycle control and developing an unpredictable biological behavior. Subsequently, the cells express molecules that allow them to acquire an invasive phenotype, a phenomen on known as epithelial-mesenchymal transition. Free radicals are products of the oxidation-reduction systems of the cell and its participation in cellular metabolic functions is essential for cell survival. The involvement of free radicals in cancer development has been studied for 3 decades, and there is sufficient evidence that implicates theirs in the multistage theory of carcinogenesis. It should be added that oxidative protein damage participates in facilitating the development of cancer. The results agree that there is an imbalance between the high amount of free radicals and insufficient antioxidant system activity. Added to this, some researchers have observed that high levels of lipid-peroxidation combined with low levels of thiols and anti oxidant status, correlate with poor survival rate in patients with oral cancer . It is considered that the smoke from cigarettes have 4000 chemicals, 40 of which have carcinogenic potential. It has been shown that ciga rette smoke contains pro-oxidants that are capable of initiating the process of lipid-peroxida tion and deplete levels of antioxidants from the diet [17,18]. In contrast, there is epidemiological evidence that demonstrates the protective effect of diet on some populations [19-21]. For example in Greece, which has the lowest rates of oral can cer among European countries,its population is exposed to latent risk factors such as alcohol intake and smoking; micronutrients consume such as riboflavin, magnesium and iron corre lated inversely with oral cancer . Consequently, several authors have proposed the ingestion of diverse exogenous antioxi dants; supporting in those epidemiological studies, where the diet offers protection for the development of cancer, and taking into account that the endogenous antioxidant systems have been overwhelmed by oxidative stress. For example, vitamin C is one of the most extensively evaluated antioxidants in oral cancer alternative co-therapies. Low or even undetectable levels of vitamin C correlate with the presence of oral cancer [17, 22]; in contrast, is one of the micronutrients that have a consis tent inverse correlation in different studies . Vitamin C acts as a scavenger of free radicals and impedes the detrimental chain reactions triggered by the free radicals. The l-glutamine is administered in the diet as a complementary ther apy; the proposal is that restores glutathione cascade system . Even more,when them are administered together during the cycles of radiotherapy . Author details Mario Nava-Villalba, German Gonzlez-Prez, Maribel Lian-Fernndez and2 3 Torres-Carmona Marco4 *Address all correspondence to: marionava23@gmail. AutonomousUniversity of Quertaro, Quer taro, Mxico 3 Dentistry Department, School of Medicine. AutonomousUniversity of Quertaro, Quer taro, Mxico 4 Dentistry Department, School of Medicine. Periodontitis in individuals with diabetes treated in the public health system of Belo Horizonte, Bra zil. The effect of intensive oral hygiene care on gingivitis and periodontal de struction in Type 2 diabetic patients. Relationship of oxidative stress with periodontal disease in older adults with type 2 diabetes mellitus. Por phyromonasgingivalis Peptidoglycans induce excessive activation of the innate im mune system in silkworm slrvae. Oral cancer prevention and control- The approach of the World Health Organization. Evaluation of oxi dative stress and nitric oxide levels in patients with oral cavity cancer. Oxidative stress in lymphocytes, neutrophils, and serum of oral cavity cancer patients: modulatory ar ray of l-glutamine. Lipid peroxidation, total antioxidant status, and total thiol levels predict overall sur vival in patients with oral squamous cell carcinoma. Status of serum vitamin C level and peroxidation in smokers and non-smokers with oral can cer. Erythrocyte malonilaldheyde and antioxidant status in oral squamous cell carcinoma patients and tobacco chew ers/smokers. Diet in the etiology of oral and pharyngeal cancer among women from the southern United States. Ef fect of oral antioxidant supplementation on lipid peroxidation during radiotherapy in head and neck malignancies. Introduction Aging is an extremely complex and multifactorial process that proceeds to the gradual dete rioration in functions. Traditionally researchers focused primarily on understanding how physiological functions decline with the increasing age; almost no research was dedicated to investigation of causes or methods of aging intervention. If scientists would discover a drug for healing all major chronic degenerative diseases, the average lifetime would be increased for just 12 years. Defects formed in human body as a consequence of the aging process start to arise very ear ly in life, probably in utero. In the early years, both the fraction of affected cells and the aver age burden of damage per affected cell are low . The signs of aging start to appear after maturity, when optimal health, strength and appearance are at the peak. Aging theories Scientists estimated that the allelic variation or mutations in up to 7,000 relevant genes might modulate their expression patterns and/or induce senescence in an aging person, even in the absence of aging specific genes [4, 5]. As these are complex processes they may result from different mechanisms and causes. Consequently, there are many theories trying to ex plain the aging process, each from its own perspective, and none of the theories can explain all details of aging. The aging theories are not mutually exclusive, especially, when oxida tive stress is considered . Mild oxidative stress is the result of normal metabolism; the resulting biomolecular damage cannot be totally repaired or removed by cellular degradation systems, like lysosomes, pro teasomes, and cytosolic and mitochondrial proteases. Since extensive research on the relation between polymorphisms likely to accelerate/decelerate the common mechanisms of aging and resistance to the oxidative stress has been neglected in almost all scientific stud ies, the data do not allow us to conclude that the oxidative theory supports the theory of programmed aging so far . However, the most recent studies support the idea that oxida tive stress is a significant marker of senescence in different species. Resistance to oxidative stress is a common trait of long-lived genetic variations in mammals and lower organisms [5, 12]. Free radical theory, oxidative stress theory and mitochondrial theory of aging Denham Harman was first to propose the free radical theory of aging in the 1950s, and ex tended the idea to implicate mitochondrial production of reactive oxygen species in 1970s, . According to this theory, enhanced and unopposed metabolism-driven oxidative stress has a major role in diverse chronic age-related diseases [13, 14, 7]. Harman first proposed that normal aging results from random deleterious damage to tissues by free radicals  and subsequently focused on mitochon dria as generators of free radicals . Halliwell and Gutteridge later suggested to rename this free radical theory of aging as the oxidative damage theory of aging , since aging and diseases are caused not only by free radicals, but also by other reactive oxygen and ni trogen species. Increases in mitochondrial energy production at the cellular level might have beneficial and/or deleterious effects . On the other hand, enhanced mitochondrial activity may increase the pro duction of superoxide, thereby aggravating the oxidative stress and further burdening the antioxidant defence system. The mitochondria are the major source of toxic oxidants, which have the potential of reacting with and destroying cell constituents and which accumulate with age. The result of this destructive activity is lowererd energy production and a body that more readily displays signs of age (e. Damaged mitochondria can cause the energy crisis in the cell, leading to senescence and aging of tissue. The gradual loss of energy experienced with age is paralleled by a decrease in a number of mitochondria per cell, as well as energy- producing efficiency of remaining mitochondria. How 334 Oxidative Stress and Chronic Degenerative Diseases - A Role for Antioxidants ever, whether this damage affects mitochondrial function or significantly modulates the physiology of aging has remained controversial [27, 28].
As the stimulated B cell clones divide rapidly order tadalis sx 20mg without a prescription, they also mu- tate their antibody-binding regions at a high rate purchase tadalis sx 20mg on-line. Mutant lineages that bind with higher anity to the target antigen divide more rapidly and outcompete weaker-binding lineages order 20 mg tadalis sx amex. This mutation and selection pro- duces high-anity antibodies cheap tadalis sx 20mg otc,typically of type IgA or IgG. Natural antibodies from dierent B cell lineages form adiverseset thatbindswithlowanity to almost any antigen. By contrast, in vivo inoculations with several dierent patho- gens showed that the initial binding by natural antibodies lowered the concentrations of pathogens early in infection by one or two orders of magnitude. Poor binding condi- tions cause low-anity binding to be highly specic because detectable bonds form only between the strongest complementary partners. By contrast, favorable binding conditions cause low-anity binding to de- velop a relatively broad set of complementary partners, causing rela- tively low specicity. Early stimulation of B cells appears to depend on the equilibrium binding anity for antigens. By contrast, competition between B cell clones for producing anity-matured anti- bodies appears to depend on the dynamic rates of association between Bcellreceptors and antigens. The sixth section compares the cross-reactivity of an in vivo, poly- clonal immune response with the cross-reactivity of a puried, mono- clonal antibody. Polyclonal immune responses raise antibodies against many epitopes on the surface of an antigen. Cross-reactivity declines lin- early with the number of amino acid substitutions between variant anti- gens because each exposed amino acidcontributes only a small amount to the total binding between all antibodies and all epitopes. By contrast, amonoclonal antibody usually binds to a single epitope on the antigen surface. Cross-reactivity declines rapidly and nonlinearly with the num- ber of amino acid substitutions in the target epitope because a small number of amino acids control most of the binding energy. The seventh section discusses the specicity and cross-reactivity of Tcellresponses. The eighth section lists the ways in which hosts vary genetically in their responses to antigens. The germline genesthatcontribute to the T cellreceptor have some poly- morphisms that inuence recognition, but the germline B cell receptor genes do not carry any known polymorphisms. Each specic subset of an antigenic molecule recognized by an antibody or a T cell receptor denes an epitope. For example, insulin, a dimeric protein with 51 amino acids, has on its surface at least 115 antibody epitopes (Schroer et al. Nearly the entire surface of an antigen presents many overlapping domains that antibodies can discriminate as distinct epitopes (Benjamin et al. Epitopes have approximately 15 amino acids when dened by spatial contact of antibody and epitope during binding (Benjamin and Perdue 1996). Almost all naturally occurring antibody epitopes studied so far are composed of amino acids that are discontinuous in the primary se- quence but brought together in space by the folding of the protein. The relative binding of a native and a mutant antigen to a puried (monoclonal) antibody denes one common measure of cross-reactivity. C50mut is the concentration of the mutant antigen required to cause 50% inhibi- tion of the reaction between the native antigen and the antibody. Simi- larly, C50nat is the concentration of the native antigen required to cause 50% inhibition of the reaction between the native antigen and the an- tibody (self-inhibition). Then the relative equilibrium binding constant for the variant antigen, C50nat/C50mut,measurescross-reactivity (Ben- jamin and Perdue 1996). Site-directed mutagenesis has been used to create epitopes that vary by only a single amino acid. Studies dier considerably in the methods used to identify the amino acid sites dening an epitope, the choice of sites to mutate, the amino acids used for substitution, and the calculation of changes in equilibrium binding constants or the free- energy of binding. Benjamin and Perdue (1996) discuss these general issues and summarize analyses of epitopes on four proteins. First, approximately 5 of the 15 amino acids in each epitope strongly inuence binding. Certain substitutions at each of these strong sites can reduce the relative binding constant by two or three orders of magnitude. These strong sites may contribute about one-half of the total free-energy of the reaction (Dougan et al. Second, the other 10 or so amino acids in contact with the antibody may each inuence the binding constant by up to one order of magni- tude. Third, the consequences of mutation at a particular site depend, not surprisingly, on the original aminoacidandtheamino acid used for substitution. Fourth, theoretical predictions about the free-energy consequences of substitutions based on physical structure and charge can sometimes be highly misleading. This problem often occurs when the binding location between the antibody and a particular amino acid is highly accessible to solvent, a factor that theoretical calculations have had diculty incor- porating accurately. Fifth, antibodies raised against a particular epitope might not bind optimally to that epitope the antibodies sometimes bind more strongly to mutated epitopes. In addition, antibodies with low anity for an antigen can have higher anity for related antigens (van Regenmortel 1998). Each antibody binding site denes a paratope, composed of the particular amino acids of that antibody that physically bind to a specic epitope. Approximately 50 variable amino acids make up the potential binding area of an antibody (van Regenmortel 1998). However, in both epitope and paratope, substitutions both in and away from the binding site can change the spatial conformation of the binding region and aect the binding reaction (Wedemayer et al. The antibody s 50 or so variable amino acids in its binding region dene many overlapping groups of 15 amino acids. A paratope does not dene asinglecomplementary epitope; rather it presents certain molecular characteristics that bind antigenic sites with varying anity. First, an antibody can have two completely independent binding sites (paratopes) for unrelated epitopes (Richards et al. Bhattachar- jee and Glaudemans (1978) showed that two puried mouse antibodies (M384 and M870) each bind methyl D-galactopyranoside and phos- phorylcholine at two dierent sites in the antigen-binding region of the antibody. Second, an antibody presumably has many overlapping paratopes that can potentially bind to a variety of related or unrelated epitopes. I did not, however, nd any studies that dened for a particular antibody the paratope map relative to a set of variable epitopes. The potential distribution of paratopes may change as a B cell clone matures in re- sponse to challenge by a matching antigen I take this up in the next section (4. Third, a single paratope can bind two unrelated epitopes (mimotopes, Pinilla et al. X-ray diraction of three competing peptides showed that they all bound to the same site on the antibody (Keitel et al. Fourth, a particular epitope can be recognized by two dierent par- atopes with no sequence similarity. The two antibodies also have dierent patterns of cross- reactivity with other antigens. Experimental studies of specicity frequently compare pairwise ani- ties between an epitope and various paratopes or between a paratope and various epitopes. In these pairwise measures, one rst raises anti- body to a monomorphic (nonvarying) antigenic molecule and then iso- lates a single epitope-paratope binding in other words, one raises a monoclonal antibody that binds to a single antigenic site. Variations in anity are then measured for dierent epitopes holding the paratope constant or for dierent paratopesholding the epitope constant. Alternatively, one can challengeahost with a polymorphic popula- tion of antigens. One controlled approach varies the antigens only in asmall region that denes a few epitopes (Gras-Masse et al. If exact replicas of each epitope occur rarely, then antibodies will be se- lected according to their binding anity for the aggregate set of varying epitopes (mixotopes) to which they match. This method may be a good approach for nding antibodies with high cross-reactivity to antigenic variants of a particular epitope. An antibody is a secreted form of a receptor that occurs on the surfaces of B cells. Each B cell clone makes IgM with dierent binding characteristics that is, the variable binding regions of the IgMs dier.