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Jeffery Hunter Young, M.D., M.H.S.

Associate Professor of Medicine

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Medial ligament rupture to the ulnar collateral ligament is not common in young athletes and is seen more in adults antifungal treatment for thrush generic 250 mg grifulvin v with mastercard. Patients may have medial tenderness for months to years before the ligament is injured antifungal prescription cream buy grifulvin v with amex, usually in a sudden catastrophic event fungus zinc oxide cheap grifulvin v 250mg fast delivery. If the injury is detected early fungus spray buy generic grifulvin v on line, conservative treatment including rest and alternating heat/ice is recommended. It is a self-limiting condition where the capitellum epiphysis essentially assumes a normal appearance as growth progresses. They present with elbow pain and a flexion contracture of greater than or equal to 15 degrees. These patients should be seriously counseled about the dangers of continued throwing and are urged to abstain. Posterior extension and shear injuries are uncommon in young throwers but the incidence increases with age. If there is lack of apophyseal fusion, rest and immobilization can produce good results. Partial avulsion of the olecranon requires surgical reattachment of the olecranon and triceps. They can be seen not just in baseball pitchers but also in quarterbacks, tennis players, volleyball players and javelin throwers. Because the biomechanics of throwing are complex, the physical stresses can cause a group of pathologic entities to include the medial, lateral, and posterior aspects of the elbow. Preventing these types of injuries involves teaching proper throwing mechanics, keeping an accurate pitching count, predetermining a stopping point based on number of pitches thrown, and recognizing early warning signs and stopping once the pain starts. Although many of these injuries have been blamed on throwing curve balls, some studies have shown that a properly thrown curve ball causes no more injuries than the traditional fastball (11,12,13). He was playing in a roller hockey game when a hockey stick was swung high and struck him in the face. Ophthalmology is consulted and further evaluation for the hyphema includes an intraocular pressure measurement, which is found to be normal. The patient and parents are told to limit his activity for the first 72 hours without television or video games. His immunization records are current and the patient is sent home with a narcotic analgesic and follow-up in 3 days. The next season, he is sporting a new pair of safety goggles to every game and practice. Orbital injuries are common injuries in athletes, especially those in high-risk sports with high-speed objects such as sticks, bats, balls, pucks, or aggressive body contact. Males are at higher risk for orbital fractures because of their increased incidence of trauma. The aperture of the bony architecture surrounding the eye does not allow an object with a radius of greater than 5 cm to penetrate the globe (14). The thin orbital floor (maxilla) and the medial wall (ethmoid) are the weakest portions of the orbit. A direct blow to the bony rim may not cause a bony rim fracture, but can be enough to increase intraorbital pressures (as the globe is compressed) resulting in a "blowout fracture" of the weakest point of the orbital wall, which is usually the floor of the orbit. Sphenoid: posterior orbit Related anatomical structures that can be injured during an orbital fracture include the optic nerve, periorbital fat, extraocular muscles, and the inferior orbital nerve. These injuries are multiple and can include corneal abrasion, lens dislocation, iris disruption, choroid tear, scleral tear, ciliary body tear, retinal detachment, hyphema, ocular muscle entrapment, and globe rupture. The patient should be questioned regarding epistaxis or clear fluid from nares or ears, loss of consciousness, visual problems, hearing problems, malocclusion, and facial numbness or tingling. Other specific questions regarding the eye include the presence of diplopia, painful eye motion (entrapment or periorbital edema), photophobia, flashes of light (retinal detachment), or blurred vision (hyphema, vitreous hemorrhage, retinal detachment) (14,16,17). This includes visual acuity, inspection for abrasions, laceration, foreign bodies, changes in pupillary dimension or reactivity to light. Any change in visual acuity, blood in the anterior chamber, or change in the shape of the iris should warrant a consult with an ophthalmologist. They should have their supraorbital ridge and frontal bone palpated for step-off fractures, and their hard palate and teeth palpated for stability. Evaluate the supraorbital, infraorbital, inferior alveolar, and mental nerve distributions for anesthesia. These patients may present with ecchymoses, enophthalmos of the globe (sunken eye), vertical dystopia (a change in vertical position of the pupil in relation to the unaffected side), or numbness in the area on the ipsilateral cheek supplied by the infraorbital nerve. Although a "black eye" was once felt to be a relatively benign injury for which medical attention was often not sought, many instances of periorbital ecchymoses are due to orbit fractures. Radiographically, routine facial views include Waters, Caldwell, and lateral projections (14,15,16). The Waters view is used for identifying inferior orbital rims, nasoethmoidal bones, and maxillary sinuses. The Caldwell projection provides the best view of the lateral rim and ethmoid bone. Lateral views may show air-fluid levels in the posterior maxillary sinus if the patient is lying supine. C-spine films are indicated if the patient complains of neck pain or if a suspected cervical injury cannot be ruled out. A forced duction test can determine if limitation of ocular movements is due to entrapped soft tissues or to edema or contusion of a motor nerve or muscle. This is performed by anesthetizing the affected eye with topical anesthesia, grasping the sclera with a fine toothed forceps at the level of the inferior rectus muscle and moving the eye in a superior/inferior direction. In clinical practice, this test is only rarely performed, since it is more convenient to merely wait to see if diplopia subsides with time. Even patients with signs of entrapment may be discharged home because most entrapment resolves as the swelling goes down. They should; however, return if there is a change in visual acuity, increased pain, or flashing lights. Hyphema occurs more often in males (3:1) and is usually seen in a younger population, less than 30 years old (18). Trauma is the most common cause of hyphema, often seen in baseball or hockey athletes where a blunt compressive force hits the globe causing tears in the ciliary body, iris, and other structures in the anterior segment. Other non-sports related causes of hyphema include microvascular disease such as diabetes causing neovascularization, retinal ischemia, carotid stenosis, or iatrogenic (post-intraocular surgery), sickle cell disease, pupillary microhemangiomas, iritis, or intraocular tumors. Corneal bloodstaining results from blood being forced into corneal endothelial cells. It is an ominous sign and signifies the need for surgical evacuation of the hyphema. This occurs when the clot completely occludes the pupil/lens interface, blocking the flow of aqueous from the posterior to anterior chamber. Historical data important to illicit include the mechanism of injury, type of assaulting object, whether protective eye wear was used, ethnic origin, and past ocular history. Visual acuity, pupillary reaction, extraocular movement, signs of corneal staining, and intraocular pressure are also important aspects of the examination. An exophthalmometer can be used to look for exophthalmos related to ocular trauma. In patients without an increase in intraocular pressure, behavioral modifications begin with limiting activities such as reading, which cause rapid shifts in the globe. Within the first 72 hours, rebleed is most common, therefore, this is the crucial time when children may have to be bedrested. It is especially important to limit activities in infants and children who watch television or play video games. Watching television from a distance greater than 10 feet limits the amount of extraocular movement. In hyperactive children, bilateral patching may be required to minimize activity level. Patching of the affected eye only, is not beneficial because movement of the contralateral eye will cause movement of the affected eye (18). In general, patients should keep activity to a minimum for at least the first 5 days to prevent a rebleed. Cycloplegics and topical steroids, which treat associated iritis may also be used. Cycloplegics are anticholinergic agents that block the response of the iris sphincter muscle and ciliary body to cholinergic stimulation, causing paralysis of accommodation (cycloplegia) and pupillary dilation (mydriasis). Antifibrinolytics such as aminocaproic acid may be used to prevent recurrent hyphemas, but this medication may cause serious adverse effects.

In other virus diseases with skin Arcanobacterium pyogenes and coliforms are com lesions fungus dandruff order genuine grifulvin v online, serial serological samples may provide evi monly found on the normal bovine skin fungus gnats winter purchase grifulvin v online pills, but heavy dence of recent infection fungal rash proven grifulvin v 250 mg. These are particularly useful in the diagnosis of Parasitic causes mange infestation zarin anti fungal cream discount grifulvin v 250mg on-line. The scraping is best taken with a Neoplastic causes scalpel blade to a depth at which signs of capillary Nutritional causes bleeding just appear. The scraping may be examined Toxic causes microscopically directly or after treatment with Physical causes potassium hydroxide. The presence of abnormal ocular or nasal discharges is noted, as are changes or abnor Closer examination of the head and neck is aided malities in the outline and contours of the region. In nervous or difficult animals but drooling of saliva from the mouth is abnormal the patient may be further restrained by holding the and should be investigated; it may be associated with nose either by hand or using bulldogs. The head is normally held vertically upright in the Unilateral swellings of the head in the adult may be undisturbed animal. Persistent head tilting is abnor caused by abscess formation or less commonly by tu mal and may indicate vestibular disease or unilateral mours such as brosarcomas. Unilateral facial swelling over the hension, mastication and swallowing of its food are cheek area in calves is often an external sign of calf normal. Very occasionally the teeth of neonatal calves may be damaged or displaced during birth. They are then externa and foreign bodies in the ears of cattle are pulled out, tearing the ear. If aural discharge is present, seen around recently inserted ear tags, especially the ear canal can be inspected using an auriscope or a in calves. The eye moves to a limited Injury,tag damage,laceration extent within the orbit if the animal is visually fol Infected tag puncture wound lowing a moving object. If the head is tilted upwards Aural discharge the eyes move downwards within the orbit, a move Foreign body ment involving the vestibular system and known as Aural haematoma vestibular eye drop. This will cause the animal to rotate the nent if it is displaced by a tumour mass or infection eyeball upwards with wide open eyelids allowing within the orbit. The eyes may All parts of the eye and eyelids should be carefully also be sunken in severely emaciated animals which and methodically inspected. The eye instilled into the eye will also facilitate a pain-free may appear sunken and have a reduced intraocular examination. Ocular injury, infection and pressure if it has been accidentally penetrated or rup foreign bodies are quite common in cattle. Its vas Examination of ocular re exes cularity is also increased in some cases of meningitis. Fixation, palpebral, corneal, menace and light re Petechial haemorrhages in the sclera may be seen in sponse re exes are checked on both sides. Full details cases of septicaemia and yellow discolouration may of these and the neurological pathways involved are be present in jaundice. If the membrane Intraocular pressure ruptures astaphylomamay form through which some Assessment of ocular/cranial nerve re exes of the interior components of the eye may prolapse Fixation re ex. Fluorescein in the eye passes eventually Pupillary light re ex with the tears into the nasolachrymal duct. Patency of the ducts is demonstrated by the presence of the dye placed in the conjunctiva appearing in the ipsilateral nostril. Even with care, some foreign bodies may be in damage to and in ammation (iritis) of the iris as seen hard to nd and a second search should always be in some cases ofsilage eyecaused by listeria or implemented if the rst is unsuccessful. In this condition, caused by damage to tween the anterior chamber and the vitreous by the the cervical sympathetic trunk, miosis (see below) ciliary bodies, is sometimes displaced into the an and retraction of the eyeball may also be present. The retina is examined revealing the dorsal Abnormal dilation of the pupil (mydriasis) is usually bright tapetal fundus and the darker ventral non accompanied by absence of the pupillary light re ex. Optic disc) may occur in meningitis and vitamin A de nerve damage is seen as papilloedema in some cases ciency. Profuse nasal Air ow through both nostrils haemorrhage may be seen as a terminal event in Smell of the breath cases of thrombosis of the caudal vena cava. Bovine papular stomatitis is frequently accompanied by the development of small papules, which are often horseshoe shaped, on the muzzle and in the mouth. Mouth Air ow through both nostrils should be assessed by holding the hand close to the nose where the pressure the mouth must be carefully inspected in good light of air ow can be appreciated. Note the central pair of permanent incisor teeth in this animal aged 1 year 9 months. Such problems may mandibular joint or degenerative changes affecting arise through local damage to nerves by abscess or its articular surfaces may also result in an inability to tumour formation adjacent to the nerves or in the open the mouth. Facial nerve damage may occur through injury to the the dental pad replaces the incisor teeth in the nerve and surrounding tissues. In adult cattle it may show Inability to move the tongue may arise through small scars sustained when the animal was grazing. Bovine dentition Teeth the arrangement of teeth in cattle is given in Table the teeth may be temporary or permanent and inspec 5. In cases of wooden and larynx tongue caused by Actinobacillus lignieresii the tongue is very rm and in exible to the touch; the animal is Examination of the internal pharynx and larynx unable to advance it through the lips and excessive through the mouth can be achieved by manual pal salivation may be seen. Patency or obstruction of the oesophagus can be de tected using a nasogastric tube or probang. Endoscopy of the nasal passages, pharynx, larynx, trachea and oesophagus Restraint and sedation of the patient the patient should be placed in a crush with its head restrained by a halter. Sedation is not always neces sary but should be used if the animal is at all frac tious. They must always be used with cau tion and the exact whereabouts of the objective part of the instrument checked by frequent observation through the eyepiece. If this is not done the instru ment may bend ventrally behind the soft palate be Figure 5. At other times vision diameter can usually be passed along the ventral may be obscured by the end of the endoscope making meatus of the nasal cavity. In smaller animals a contact with the mucosa at any point during the human paediatric endoscope may be needed. An assistant oor of the nasopharynx and the two small openings passes the endoscope slowly forward as the opera of the Eustachian tubes are visible in the dorsolateral tor views the visible structures. Nasal cavity the mucosa of the ventral meatus and the roof of the pharynx may be depressed by en the ventral turbinate bone is pink in colour. The endoscope may occasionally impinge Larynx this may not be visible until the endoscope on and be obstructed by the ethmoid bone in the has passed well into the pharynx. The endoscope is ad the animal swallows and the soft palate moves vanced further into the trachea. Folds of mucosa are seen passing longitu towards the laryngeal aditus and then further ad dinally down towards the rumen. The trachea appears circular in outline and sophagus by in ation allows better evaluation of the the inside of the cartilaginous tracheal rings are clear mucosa.

Blood-borne and sexual encephalitis in a paediatric bone marrow recipient: successful treatment transmission of human herpesvirus 8 in women with or at risk for human with pharmacokinetic monitoring and high doses of ganciclovir fungus gnats webs grifulvin v 250mg with amex. Risk factors for human thymidine kinase and phosphotransferase homologues confer sensitivity herpesvirus 8 infection among adults in the United States and evidence to ganciclovir antifungal during pregnancy order genuine grifulvin v on line. Infect Dis Obstet Gynecol virus type 1 and type 2 seroprevalence in the United States antifungal ointment for jock itch buy generic grifulvin v 250mg. Natural history of cervico deoxyribonucleic acid persists throughout pregnancy and decreases in vaginal papillomavirus infection in young women fungi kingdom order 250 mg grifulvin v with amex. Int J Gynaecol Obstet 2006;94(Suppl 1): associated oral warts among human immunodeficiency virus S56-64. Oral Surg Oral Med Oral Pathol Oral Radiol and acquired immunodeficiency syndrome. The 1992 National Cancer vaccine against human papillomavirus to prevent anogenital diseases. Oral acyclovir prophylaxis of necrosis caused by varicella-zoster virus in children with acquired varicella after intimate contact. The progressive outer with intravitreal injections and monitoring with quantitative retinal necrosis syndrome. Letters and roman numerals in parentheses after regimens indicate the strength of the recommendations and the quality of evidence supporting it (see Box). Chronic suppressive therapy (secondary prophylaxis) is recommended in children and adults after initial therapy (Table 2). Adverse events that can result weight daily orally divided into 3 doses weight daily orally, divided into 3 doses from use of this drug at treatment doses include every 8 hrs for 7 days. Combination ganciclovir and foscarnet is associated with substantial rates of adverse effects, and optimal treatment for neurologic disease in children is unknown, particularly those receiving optimized antiretroviral therapy. Pretreatment with acetaminophen and/or diphenhydramine may alleviate febrile reactions. Tablets: rash) pain, constipation, diarrhea, 50 mg, 100 mg, anorexia, nausea, vomiting) Requires dose adjustment in patients with Rare impaired renal function. Posaconazole Oral solution: Infrequent Bone marrow suppression Must be administered with meals. Visual disturbances common (>30%) but transient and reversible when drug is discontinued. Use with caution in patients who have hepatic function impairment (biliary excretion main route of elimination). Ciprofoxacin Oral suspension: More frequent More frequent Can be taken without regard to meals. Enhances phosphorylation of didanosine, use with caution because of increased risk for pancreatitis/mitochondrial toxicity. Atovaquone/ Tablets: Less frequent Not for severe renal Pediatric tablets available making dosing easier. Chewable tablet: 200 mg High potential for interaction with many Tablet: antiretrovirals and other drugs. Children less than or equal to 23 months should be vacci percentages less than 15%). Modifed dosing regimens, including doubling of the apart) can be considered for children and adolescents aged 9 through standard antigen dose, might increase response rates. The reporting week concludes at close of business on Friday; compiled data on a national basis are ofcially released to the public on the following Friday. Use of trade names and commercial sources is for identifcation only and does not imply endorsement by the U. Questions with more than one correct answer will instruct you to Indicate all that apply. To receive continuing education credits, please answer all of the following questions. The best approach to reducing the risk for cryptosporidiosis from vaccine drinking water is A. After immune reconstitution while on highly-active antiretroviral receiving highly active antiretroviral therapy. Each note has a different definition for use but they are both similar in that they indicate that codes excluded from each other are independent of each other. The 7th character must always be the 7th character of a code Chapter 1 Certain infectious and parasitic diseases (A00-B99) Includes: diseases generally recognized as communicable or transmissible Use additional code to identify resistance to antimicrobial drugs (Z16. An additional code from Chapter 4 may be used, to identify functional activity associated with any neoplasm. Morphology [Histology] Chapter 2 classifies neoplasms primarily by site (topography), with broad groupings for behavior, malignant, in situ, benign, etc. For multiple neoplasms of the same site that are not contiguous, such as tumors in different quadrants of the same breast, codes for each site should be assigned. A5 Cutaneous T-cell lymphoma, unspecified, lymph nodes of inguinal region and lower limb C84. Z Other lymphoid leukemia T-cell large granular lymphocytic leukemia (associated with rheumatoid arthritis) C91. Z Other myelodysplastic syndromes Excludes1: chronic myelomonocytic leukemia (C93. Z9 Other specified neoplasms of uncertain behavior of lymphoid, hematopoietic and related tissue Histiocytic tumors of uncertain behavior D47.

These critiques are suspicious of identities because they involve the individual in social categories antifungal pills over the counter discount 250mg grifulvin v fast delivery, which are understood to be outside the core self anti fungal wash for dogs cheap 250 mg grifulvin v with amex, to be public fungus gnats kitchen buy generic grifulvin v 250 mg, imposed antifungal therapy cheap 250 mg grifulvin v with mastercard, and never a wholly fair or adequate rep resentation. It is this ontology that makes all substantive representations of the self inadequate and even equates the very attempt to represent with the attempt to op press. It is only the excess that is undetermined by external forces and therefore free, uncontainable, indeterminate, too uid to be characterized in substantive terms. Hegel, however, was himself under no illusions that this is either possible or truly desirable. We need, however, a material and historical accounting of when the look of the Other poses a threat rather than an existential universalizing of this threat to every self/other relationship, and we need an account that can take note of the real differences in the extent and manner of the threat. If the look of the Other generally has a potentially terrifying power, the look of the Other whom one has colonized and enslaved is a special threat, and must be de ected at all costs. Irigaray has shown a similar effect of female presence in a masculine order where masculine subjectivity is predicated on the erasure of women. The power of the Other to constitute the self must lead, in such situations, precisely to the death struggle that Hegel envisioned. The problem for the dominated, by contrast, is, as Hegel said, their lack of recognition: they are car icatured but never truly seen. The problem in accounts of identity has occurred, however, when the threat of the Other to the self is decontextualized, dehistoricized, and then universalized. In classical liberalism, developed against the backdrop of European colonial expan sion, that which originates outside of me must be fought against, it is assumed, else my very selfness, my ownness to my self, will be at stake. The human self is the Philosophical Critique 71 essentially a reasoning self, but according to liberal ideology, reason requires au tonomy or the ability to gain critical distance and to pass independent judgment on anything external. The tradition we have just retraced starts from a different place but effectively ends in the same view. To submit to our being-for-others as if this were an inescapable truth about ourselves is to commit bad faith. The essential self is the capacity to resist, to transcend and to exceed all attempts at representation. For them, as for Sartre, resistance to identity is both metaphysically and politically mandated, in sofar as it is possible (which in their estimation is far less than Sartre imagined). The difference between modern and postmodern accounts is simply in their degree of optimism about the extent to which the individual can negate the given and resist an external power. But in both cases negation, resistance, and destabilization are the privileged tactics because what comes to the individual from the Other is assumed to be ultimately both inaccurate and oppressive. However, there are striking similarities when it comes to their attitude toward social categories of identity. For Foucault, identity is a form of subjection and subjugation in which the individual is interpellated within structures of discourse. Unlike in classical liberalism, Foucault does not posit the existence of a self prior to subjection, a self that is then subordinated to the constraints of social life. It was the disciplinary practices of Christian confessionals and, later, prison procedures that produced the inward re ection necessary for a sense of self as an interior, stable entity. But such selves were the product of dominant power/knowledges involved in the regulation and dissemination of bodies. Only as subjects can we be made subject to the disciplinary strategies that produce docile bodies. Collective categories of identity produce a similar opportunity for disciplinary mechanisms by working through groups rather than individuals. There have been important debates over whether such statements as these should be interpreted as denying the existence of a subject who has agency and an interior life (see Allen 1999, Halperin 1995 for recuperative arguments). One way to reopen the debate would be to distinguish the processes of normalization from the processes by which we adopt or adapt to social identities.

If the balance shifts to homodimers of proapoptotic tosis after irreparable harm has occurred (p53 is discussed in proteins antifungal groin buy 250 mg grifulvin v with amex, the apoptotic cascade is activated (see antifungal iv medications buy grifulvin v. Cytochrome c participates in many mito A delicate balance exists between the stabilization and destruc chondrial processes fungus photos purchase genuine grifulvin v on-line, including electron transport and membrane tion of p53 fungus gnats bonsai order grifulvin v 250mg with amex. The mechanisms by which mitochondria exert while it upregulates transcription of the proapoptotic genes bax such a powerful effect on apoptosis have recently been eluci and bak. A surfeit of proapoptotic con effect that leads to translocation of a number of proapoptotic stituents of the Bcl-2 family leads to the release of Apaf-1. Cytosolic cytochrome c activates Apaf-1, tain oncogenes, such as c-myc, increases the amount of an which in turn converts procaspase-9 to caspase-9. Caspase-9 acti Mdm2-binding protein (p14arf), thereby protecting p53 from vates downstream caspases (3, 6, and 7) in the same manner as Mdm2-induced destruction. The Equilibrium between Pro and Anti-apoptotic Signals Inactivation of p53 Apoptosis can be viewed as a default pathway and the survival of Proteins of a number of oncogenic viruses inactivate p53 by many cells is contingent upon constant anti-apoptotic (prosur binding to it. From an evolutionary perspective, the aging process presents conceptual difficulties. Since animals in the wild do not attain their maximum longevity, how did aging evolve The conse quences of aging arise after the reproductive period and thus should not have an evolutionary impact. Aging must be distinguished from mortality on the one hand and from disease on the other. Death is a random event; an aged person who does not succumb to the most common cause of death will die from the second, third, or tenth most common cause. Al though the increased vulnerability to disease among the elderly is an interesting problem, disease itself is entirely distinct from aging. The schematic at the bottom illustrates the degree of which with vigor may extend to 80. By contrast, it is estimated apoptosis observed in these cells as a function of the concentrations of that the usual age at death of Neolithic humans was 20 to 25 these two agents. This phenomenon lized environments is analogous to that observed between ani is called laddering. For animals in the wild, after an initial high mortality during matu ration, a progressive linear decline in survival is noted, ending at the maximum life span of the species. A popular method involves the demonstration of nucleo dental trauma, infection, starvation, and so on. Since nucleosomes are regularly spaced ingly, the maximum life span attained is not significantly altered by a along the genome, a pattern of regular bands can be seen when protected environment. Apoptotic cells that incorporate the labeled nucleotide are visualized by fluores cence microscopy or flow cytometry. Life span of animals in their natural environment com especially degenerative diseases. Note that both curves reach the lation of apoptosis is an active frontier of drug development. Constituents of the connective tissue matrix are progres additional years, respectively. Lipofuscin (wear and tear) pigment accu Yet the maximum human life span has remained constant at mulates in organs such as the brain, heart, and liver. Even if diseases associated with old age, such as the salient characteristic of aging is not so much a decrease in basal cardiovascular disease and cancer, were eliminated, only a mod functional capacity as it is a reduced ability to adapt to environmental est increase in average life expectancy would be seen. Although resting pulse is unchanged, the maximal in riod of good health and low mortality rate would be followed by crease with exercise is reduced with age and the time required to a precipitously increased mortality owing to aging itself; the life return to normal heart rate is prolonged. Similarly, the aged span would, for practical purposes, remain on the lower side of show impaired adaptation to ingested carbohydrates: fasting 100 years. Given the current life expectancy, the prevention or blood glucose levels are often normal compared with younger cure of the causes of premature death would have little impact people, but they rise higher after a carbohydrate meal and de on mean longevity. The male-to-female ratio is 106:100 at birth, but from that time on, more women the Cellular Basis of Aging Is Studied in Culture than men survive at every age, and at age 75 the male-to-female Although the biological basis for aging is obscure, there is general ratio is 2:3. Interestingly, greater female longevity is almost uni agreement that its elucidation, as in all pathologic conditions, versal in the animal kingdom. Various theories of cellular with the female genotype are no hardier than those with the aging have been proposed, but the evidence adduced for each is male pattern. Factors involved in the difference in average hu at best indirect and is often derived from data obtained in cultured man longevity include the greater male mortality from violent cells. An adequate theory should be parsimonious, compatible causes and greater susceptibility to cardiovascular disease, can with the species-specific differences in life spans and consistent cer, respiratory illness, and cirrhosis in middle and old age. His with the fact that most noncycling cells, such as neurons and my torical differences between the sexes in cigarette smoking and al ocytes, undergo a linear, relatively uniform functional decline cohol consumption are also important in the gender gap in with age. Indeed, smoking alone has been estimated to account troversial field of investigation. Thus, Support for the concept of a genetically programmed life if men escape from these hazards, the gap in longevity between span comes from studies of replicating cells in tissue culture. Cultured human fibro blasts undergo about 50 population doublings, after which they Functional and Structural Changes Accompany Aging are irreversibly arrested in the G1 phase of the cell cycle and no the insidious effects of aging can be detected in otherwise longer divide. The great leaps of imagination in theoretical chemical carcinogen, they may continue to replicate; in a physics and mathematics are almost exclusively made by the sense, they become immortal. In many sports, an athlete in his or her 30s may be re the number of population doublings in fibroblasts and life span ferred to as aged. For example, rat fibro vascular abnormalities, beginning in the fourth decade of life blasts exhibit considerably fewer doublings than do human there is a progressive decline in many physiologic functions. Moreover, cells obtained from persons afflicted with a 1-37), including such easily measurable parameters as muscular syndrome of precocious aging, such as progeria (see below), strength, cardiac reserve, nerve conduction time, pulmonary vi also display a conspicuously reduced number of population tal capacity, glomerular filtration, and vascular elasticity. One is, therefore, left with the apparent paradox Velocity that replicating cells in culture have a limited life span, whereas of nerve aging in vivo seems mainly to affect the functional capacity of conduction postmitotic cells. In other words, persons do not age because cells 80 of the intestinal tract or bone marrow fail to replicate. However, Glomerular filtration if one considers that a function of cells in vitro is to proliferate, 60 then they indeed display a major failure in functional capacity, Cardiac contractility and in many studies cells in culture are used as a model for the study of aging. Decrease in human physiologic capacities as a function mortalized cells with an indefinite capacity to divide, undergo of age. Thus, genes that prolong function(s) encoded by most of them have not been elucidated. An attractive explanation for cell senescence in vitro centers on In experiments with Drosophila, strains of long-lived flies can the genetic elements at the tips of chromosomes, termed telo be readily created by using the oldest flies for breeding. Thus, the polymerase cannot copy the linear chromosomes all the way to original population must have had a set of alleles that yields the tip, the telomeres tend to shorten with each cell division until greater fitness at a young age and decreased fitness at an older a critical diminution in size interfered with replication. To overcome this end-replication problem, most eukary otic cells use a ribonucleoprotein enzyme termed telomerase, Diseases of Premature Aging which can extend chromosome ends. It has thus been proposed In humans, the modest correlation in longevity between related that telomere shortening acts as a molecular clock (replicome persons and the excellent concordance of life span among iden ter), which produces senescence after a defined number of cell di tical twins lend credence to the concept that aging is influenced visions in vitro. The existence of heritable diseases associated reverses the senescent phenotype, and after immortalization of with accelerated aging buttresses this notion. This idea implies of less than 10 years in a genetic syndrome termed Hutchinson that replicative senescence related to telomere shortening did not Guilford progeria. The mutant gene codes for a defective precur telomeres to a critical length activates a p53-dependent check sor of the lamin A protein, which has been termed progerin. Mice that are mutant for an acti this abnormal protein accumulates in the nucleus from one cell vated form of p53 display an early onset of phenotypes associated generation to the next, thereby interfering with the structural with aging, including a shortened life span, generalized organ at rophy, osteoporosis, and diminished tolerance to a variety of stresses. These data are consistent with the observation that mu tant mice that are deficient in telomerase exhibit high levels of activated p53 and also suffer reduced longevity and early senes cence-related phenotypes. Other tumor suppressor genes also ap pear to be activated by telomere shortening and cyclin-dependent kinase inhibitors (p16, p21, and p27) are regarded as the key ef fectors of replicative senescence. There is also evidence for a telomere-independent pathway for growth arrest in humans. In view of these data, current concepts hold that growth arrest sup presses tumorigenesis but that the functional changes contribute to aging.

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