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By W. Narkam. Brooklyn College.

Before noise made with the tongue or ophthalmoscope starting the examination micardis 40 mg free shipping, it is useful to gain the to ensure at least temporary stillness buy generic micardis. In fact cheap micardis online mastercard, it is Screening of Children s Eyes sometimes better to ignore the anxious child deliberately during the rst few minutes of the In an ideal world buy micardis discount, all children s eyes would be interview. Once the young patient has summed examined at birth by a specialist and again at six you up, hopefully in a favourable light, then a months to exclude congenital abnormalities and gentle approach in a quiet room is essential for amblyopia. Most children are also this has been done the pupils and anterior part screened routinely in school at the age of six of the eye can be examined, rst with a hand years, and any with suspected poor vision are lens but if possible with the slit-lamp micro- referred for more detailed examination. Fundus examination and measurement further examination is often conducted at the age of any refractive error demand dilatation of of nine or ten years and again in the early teens. The commonest defect to be found is refractive Cyclopentolate 1% or tropicamide 1% are both error,that is simply a need for glasses without any used in drop form for this purpose. The ophthalmological screening ophthalmoscope is a useful tool when examin- is usually performed by a health visitor in the ing the neonatal fundus, the wide eld of view preschool years and a school nurse for older chil- being an advantage in these circumstances. Screening tends to include measurement of the infant is asleep in the mother s arms, this visual acuity alone but checking any available can be benecial because it is a simple matter family history of eye problems would be helpful. In the case of children between the each eye, the screener should suspect the possi- ages of three and six years, fundus examination bility of a treatable medical condition rather than can be more easily achieved by sitting down and just a refractive error. A test of colour vision asking the standing patient to look at some spot should also be included in the screening pro- or crack on the wall while the optic disc is gramme for older children and this can be con- located. It is become too excited or anxious to allow a proper worth remembering that colour blindness affects examination and here one might have to decide 8% of men and 0. It ination for a week or whether the matter seems is also equally important to realise that colour urgent enough to warrant proceeding with an blindness can vary considerably in degree and The Child s Eye 159 can often be so mild as to cause only minimal head tilt and especially if the lid covers the inconvenience to the sufferer. Congenital Eye Defects Congenital Nystagmus Lacrimal Obstruction Children with congenital nystagmus are usually brought to the department because their parents The watering of one or both eyes soon after birth have noticed that their eyes seem to be continu- is a common problem. Such abnormal and per- mally at the lower end of the nasolacrimal duct, sistent eye movements might simply occur where a congenital plug of tissue remains. Infec- because the child cannot see (sensory nystag- tion causing purulent discharge can be treated mus) or they might be caused by an abnormality effectively by the use of antibiotic drops. It is important to distinguish con- charge, the eye continues to water as long as the genital nystagmus from acquired nystagmus tear duct is blocked. This manoeuvre causes mucopurulent material to be expressed from the lower punctum when there is a block- Sensory Congenital Nystagmus age and can be used as a diagnostic test. If The roving eye movements are described as carried out regularly, this helps to relieve the pendular, the eyes tending to swing from side to obstruction. A special general anaesthesia is an effective procedure, kind of retinal degeneration known as Leber s which can be done as a day case. It tends to body or even congenital glaucoma might be mis- lead to near blindness at school age. In Europeans it usually disappears as the bridge of the nose develops, but its impor- The exact cause of this type of nystagmus is tance lies in the fact that it can give the mis- usually never ascertained but a proportion of leading impression that a squint is present. Other Severe epicanthus can be repaired by a plastic abnormalities might be present, such as mental procedure on the eyelids. The nystagmus tends to be Ptosis jerky,with the fast phase in the direction of gaze to the right or left. The distance vision is usually Congenital drooping of the eyelid can be uni- impaired to the extent that the patient might lateral or bilateral and sometimes shows a never be able to read a car number plate at dominant inheritance pattern. Referral usually good, enabling many patients with this for surgery is indicated if there is signicant problem to graduate through university. This strange wobbling movement of the iris used This term refers to a type of pendular nystag- to be seen in the old days after cataract surgery mus, which is present shortly after birth and without an implant, but it is now still seen after resolves spontaneously after one or two years. Like other forms of congenital nystagmus, it can Congenital subluxation of the lens is seen as be associated with head nodding. Congenital glaucoma has already been discussed in the chapter on glaucoma; it can be The lack of pigmentation might be limited to inherited in a dominant manner and is the result the eye, ocular albinism, or it might be gener- of persistent embryonic tissue in the angle of the alised. There is sure is raised in early infancy, the eye becomes often congenital nystagmus. Congenital Cataract Albinos need strong glasses to correct their The lens can be partially or completely opaque refractive error, which is usually myopic astig- at birth. Dark glasses are also usually required and can be seen appearing in a dominant because of photophobia. Tinted contact lenses manner together with a number of other con- can sometimes be helpful. The condition might also be acquired in utero,the Structural Abnormalities best known example of this being the cataract of the Globe caused by rubella infection during the rst trimester of pregnancy: remember the triad of There are many different developmental abnor- congenital heart disease, cataract and deafness malities of the globe but most of these are for- in this respect. Coloboma refers to a failure of cataract are sometimes seen as an incidental fusion of the foetal cleft of the optic cup in the nding in an otherwise normal and symptom- embryo. The nature of the cataract usually helps keyhole-shaped pupil and the defect can extend with the diagnosis. The lens bres are laid down into the choroid, so that the vision might be from the outside of the lens throughout life. Inspection of the fundus reveals an the opaque lens bres are laid down in utero, oval white area extending inferiorly from the this opaque region can remain in the centre of optic disc. Only when the cataract is thick does it (anophthalmos) or with an abnormally small present as a white appearance in the pupil and eye (microphthalmos). It is important to nd out the full extent of this type of abnor- examine the red reex and see whether the mality and if the mother has noticed something darker opaque lens bres show up. The surgeon amiss in the child s eye, referral to a paediatric has to decide whether the vision of the child has ophthalmologist is required without delay. Sometimes the vision can turn out to be sur- Aniridia prisingly good with apparently dense cataracts. Aniridia (congenital absence of the iris) can be The surgical technique is similar to that for inherited as a dominant trait and can be asso- cataract surgery in the adult. The lens can be duction of lens implants, the risk of developing subluxated or dislocated from birth. This might a retinal detachment in later life was high in The Child s Eye 161 these patients. The word amblyopia means this presents a special case because the affected blindness and tends to be used rather loosely by eye tends to be amblyopic, thus preventing a ophthalmologists. Amblyopia of disuse is common and Other Eye Conditions some patients even seem unaware that they have any problem until they suffer damage to their in Childhood sound eye. This weakness of one eye results when the image on the retina is out of focus or Abnormalities of Refraction out of position for more than a few days or months in early childhood or, more specically, Nowadays children whose vision is impaired below the age of eight years. Amblyopia of because they need a pair of glasses are usually disuse, therefore, arises as the result of a squint discovered by routine school testing of their or a one-sided anomaly of refraction, or it can visual acuity. They might also present to the occur as the result of opacities in the optical doctor because the parents have noticed them media of the eye. A corneal ulcer in the centre screwing up their eyes or blinking excessively of the cornea of a young child can rapidly lead when doing their homework. By contrast, even better are the chances of improving the vision slight degrees of myopia, if both eyes are by occlusion. Myopia unlikely that any signicant improvement can does not usually appear until between the ages be achieved by this treatment and, by the same of five and 14 years, and most commonly at token, it is unlikely that amblyopia will appear about the age of 11. An adult could suffer total occlusion of one eye for several months Squint without experiencing any visual loss in the This exceedingly common inherited problem of occluded eye. Leucocoria All cases of squint require full ophthalmological examination because the condition can be asso- This term means white pupil and it is an ciated with treatable eye disease,most commonly important sign in childhood. There is no reason why any number of conditions that can produce this patient,child or adult,should suffer the indignity effect in early childhood. The important thing to of looking squint eyed because the eyes can be realise is that if a mother notices something straightened by surgery. In spite of this, it is not white in the pupil, the matter must never be always possible to restore the full simultaneous overlooked and requires immediate investiga- use of the two eyes together (binocular vision). The differential diagnosis includes con- In general, the earlier in life that treatment is genital cataract, opaque nerve bres in the started, the better the prognosis. This has been dened as a unilateral impair- ment of visual acuity in the absence of any other Retinopathy of Prematurity demonstrable pathology in the eye or visual pathway.

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Etiology The technique for repair of stulas is well accepted Trauma from the patient s hind foot or medial dewclaw order micardis uk, and includes elliptical incision around the stula proven micardis 40mg, de- trauma by a neighboring cow buy cheap micardis on-line, or lacerations from barbed bridement of necrotic or brous tissue (in acquired stu- wire or other sharp objects may induce teat lacerations best order micardis. Associated mucosal damage, avulsion, or detach- severe cicatricial brosis are very difcult because tissue ment may lead to focal or diffuse cisternal obstruction. C, Teat cannula protruding from mucosal defect following en bloc resection of elliptical skin piece and stula tract. The streak canal is often transected, but a portion of the streak canal and sphincter remains proximal to the laceration and sufces for sphincter tone, barring future injury. Depth of laceration and duration of time since injury are important determinants when surgical repair is considered. Full-thickness lacerations may be obvious because of milk leak but sometimes are plugged with brin and B blood clots that mask the extent of the lesion. In fact, the distal ap of tissue is so swollen as to suggest laceration above the sphincter. Fortunately close examination of the wound will often reveal functional streak canal and sphincter muscle above (dorsal) to the swollen ap. Diagnosis The clinical signs and careful cleansing of the wound to allow detailed evaluation of depth sufce for diagnosis. The cow may need to be restrained or sedated to allow cleansing and inspection of the wound. Treatment C Owners neglect many supercial teat lacerations but tend to call veterinarians when the lacerations enter the cistern or cause mechanical interference with milking. Similar to lacerations anywhere on the body, teat lacerations are best approached as soon after injury as possible. A, Milking appears to cause milk to the wound is essential, and gentle debridement with a leak from the teat cistern. In general, vertical lacera- ap conrms the presence of remaining streak canal tions heal better than horizontal or circumferential ones. C, Removal Flaps that transect the streak canal should be clipped off of the ap restores teat function. Bruce Hull, Professor of Large Animal Surgery at the sutured similarly to the repair of teat stulas described Ohio State University, the wound is made with a previously. All principles are identical to repair of a sur- manure-laden foot rather than a sterile scalpel. Careful debridement, aseptic techni- Treatment of brous or membranous obstructions at the que, carefully placed sutures, and absolute closure of base of the gland cistern is not likely to be successful. Use of indwelling cannulas follow- teat and gland cisterns has been successful rarely, but ing surgery will help decrease internal pressure on the most surgical interventions are unsuccessful. The cannula should be left open to drain con- of teat obstruction is as described in diffuse teat-cisternal tinually for several days. Temporary or permanent teat implants of- for 3 to 5 days, and the quarter is infused with antibiot- fer the best success rates for heifers and cows that have ics following repair. Success rates of 50% or more are likely for this type of teat obstruction when Blind Quarters and Membranous implants are used. Stenosis or atresia of the teat end is treated by slow Obstructions dilation of the streak canal when the canal can be seen Etiology or by sharp puncture of the apparent dimple at the teat Blind quarters appear to be laden with milk at freshen- end when a streak canal cannot be identied. Congenital or acquired lesions sharp 14-gauge needle is directed into the teat lumen at that impair milk ow from the gland cistern cause blind the apparent dimple that correlates with where the quarters. After needle puncture, genital, acquired before rst lactation, or acquired as a the stenosis can be opened further with a bistoury. Leaking Teats Degeneration of the gland cistern and connecting ducts is the most common lesion found in freshening Etiology and Signs heifers that have either small amounts or no milk from a Many cows leak milk just before normal milking times quarter that appears to be of normal size. The condition because of intramammary pressure; this is considered is thought to be caused by intramammary infection or normal or physiologic. Such infections can be and that which occurs at times other than milking or that initiated by aggressive nursing of incompletely weaned affects show potential is considered abnormal. At the time the blind quarter is identied, masti- Generally milk leaking is more common in previ- tis is usually not present in the affected quarter. The injury has disturbed normal sphincter tone or integrity of the teat end by brosis or Signs loss of tissue so that leaking occurs. Anticipated quantities of milk cannot usually be obtained from the affected quarter. The teat usually feels abby and Diagnosis meaty rather than turgid, as expected in normal milk ll- Only the history and physical inspection of the teat are ing. The teat may be probed to assess in cases in which congenital or acquired cisternal obstruc- the streak canal diameter but seldom is this necessary. Treatment Injecting about a drop of Lugol s iodine solution with a Diagnosis tuberculin syringe at four equidistant spots in the sphinc- Careful probing of the teat cistern and gland cistern with ter muscles has been reported to correct leaking in ap- a 3- or 4-in (7. This technique also allows assess- Skin Lesions ment of any teat-cistern obstruction and permits milk to be obtained for examination. If the diagnosis is still in Viral Causes question following probing of the quarter or if surgical Bovine Papillomavirus treatment is contemplated, ultrasound examination is Etiology. Salicylic acid (10%) and g spread primarily by milking machines and milkers tree latex applied every 5 days has also been shown to be hands that carry the virus, which then infects the skin in effective. Because of the current concerns about transmission Florid warts that appear as classical papillomas or bro- of prions among cattle, autogenous vaccines cannot be papillomas with epithelial projections may be more recommended. Warts at the teat end The use of common utensils during udder washing sometimes interfere with effective milkout and always and drying should be avoided; udders should be washed predispose to mastitis because of environmental con- and dried with individual paper towels before milking. Herds with endemic instances of this type of Herpes Mammillitis wart can be extremely frustrating because means to stop Etiology. If signs are not pathognomonic, excisional herds where the virus has persisted in recovered older biopsy is conrmatory. The exact means of spread is unknown because numbers of cattle are affected, freezing of the warts by rather deep inoculation of the virus into the teat wall is application of a steel rod chilled to liquid nitrogen required for experimental reproduction of the disease. Several authors suggest an insect mode of transmission, but this theory does not coincide with the peak seasonal (fall-winter) incidence. Types of early lesions vary but may include vesi- cles, edematous plaques, and serum crusts. Initially vesi- cles form on the skin of the teat and udder, and the skin appears edematous. Sizes of lesions range widely from a few millimeters to several inches in diameter and vary in number in infected cattle. After several days, dense crusts and dark-colored scabs cover the ulcerations and persist for 10 to 14 days until healing begins. Other useful tests include biopsy of early skin lesions and the edges of ul- cers to look for intranuclear inclusions that help differen- tiate the disease from pseudocowpox (intracytoplasmic inclusions) and syncytia formation. Some laboratories may offer serology because infection does confer detect- able serum antibodies. Supportive measures include careful milk- ing to minimize mastitis, application of softening creams to the teat lesions, use of iodophor teat dips to inactivate the virus, and milking affected animals last. Vesicles are present on the skin of from the vesicular uid of early lesions from herdmates the teat-gland junction at left, and ulcers and crusts are injected away from the udder probably may work well present on the teat and gland to the right. Dietary measures to control udder edema in rst-calf heifers during the winter months in endemic herds make intuitive sense and can lessen le- sion severity. The cause of pseudocowpox lesions on the teats of cattle is a member of the genus Parapoxvirus within the family Poxviridae. The pseudocowpox virus is very similar to the papular stomatitis virus and the virus that causes contagious ecthyma (orf) in sheep and goats. Pseudocowpox causes painful papules, vesicles, and de- nuded circular raised areas that heal under a thick scab. Cowpox or vaccinia are extremely rare the skin above the right hind teat, and the right front and currently may not be present in the United States. When cowpox or vaccinia is present, cows usually have become infected from a milker recently vaccinated against smallpox with the vaccinia virus. The lesions are the most severe skin lesions that erupt and then are covered by a thick scab. Once the le- autumn, should alert the veterinarian to the diagnosis of sion heals under the scab, it becomes proliferative and herpes mammillitis.

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The proportions of lifetime cases with mood disorders who had made treatment contact within the year of disorder onset ranged from 28 buy micardis canada. The proportion of individuals with mood disorders making treatment contact within 50 years ranged from 63 cheap micardis 80 mg mastercard. Among individuals with mood disorders who made treatment contact discount micardis uk, the median duration of delay was shortest in Belgium cheap micardis generic, the Netherlands, and Spain and longer in France. Out of the six countries, adults from Belgium and France were less likely to consult a mental health specialist. The highest referral rates for mood disorder were found in Italy (65%), followed by the Netherlands and Spain and the lowest was found in France (30%). Observed referral rates were fairly consistent with the availability of general practitioners in the countries. High rates were found in the Netherlands and Spain, countries with a low density of professionals, compared to the lower rates in countries with many general practitioners such as Belgium and France. This relationship did not hold for Germany and Italy, countries with a quite similar density of general practitioners, but with quite different patterns of referral. Half of the individuals suffering from mood disorders made a contact the first year of onset and the delay varied from 1 to 3 years. Although overall rates were similar across the 6 European countries, the differences between providers varied. In northern countries (Belgium, France, Germany and The Netherlands) treatment adequacy was higher in the specialised sector, whereas no difference was found in southern countries (Italy and Spain). Individuals who reported that their mental disorder (whether suffering from depression or another disorder) had interfered a lot or extremely with their lives or their activities and those who had used formal healthcare services for their pathology in the previous 12 months were defined as having a need for mental healthcare services. By combining the prevalence of need for mental health care services and the proportion of respondents with a need for care who did not receive any formal healthcare, it was estimated that 3. Compared with the youngest cohorts (18 24 years), all other age groups had a statistically significant lower risk for unmet need (0. Individuals whose mental disorder had started more than 15 years before had more than twice the likelihood of unmet need for mental care than the rest. Even so, they are not suffering from depressive disorders only, that would represent a few millions of adults out of a total population of 213 million in those countries. This is a fairly high level of unmet need, especially given that the criterion for defining a need as being met was quite conservative. On the other hand the contacts with health system could have been underreported since it implies self recognition of the presence of mental health disorders to be declared, which may inflate the estimated rates of unmet need. In the survey, respondents were asked about suicidality in their lifetime and during the 12 months previous to the interview. The specific question that was asked was: has any of these experiences happened to you? Lifetime prevalence of attempts ranked among the lowest rates obtained in previous population surveys and clinical studies (Paykel et al. Respondents that had been previously married (separated, divorced, widowed) had the highest frequency of lifetime suicidality. It was also much higher among individuals with lifetime major depression, dysthymia, Generalized Anxiety Disorder and alcohol dependence, with prevalences near 30% for suicidal ideas and 10% for suicidal attempts. Differences among the mental disorders appeared to be small, which may be a consequence of comorbidity among them. Although non statistically significant, it was also found that elder individuals tended to show a lower prevalence of suicidality. Previous studies had found higher frequency of suicidal ideation and attempts among the younger individuals and women, and higher frequency of completed suicide among men and the eldest (Mller, 2003). Some country differences were also observed, with Germany and France having the highest rate ratios of suicidal ideation and Belgium and France of attempts, while the lowest risk of ideas was found in Italy and Spain, societies that are generally more traditional and conservative (Hawton et al. The two countries with highest suicide rates are Belgium and France, which were also the countries with largest frequency of suicidal attempts. On the other hand, Italy and Spain, the countries with the lowest rates of suicide, also ranked last in suicidality in our survey. The exception was the Netherlands with a relatively low rate of completed suicide and intermediate rates in suicidal ideation and attempts. Living in a large population was also associated to a higher frequency of suicidality, which may be related to higher frequency of social isolation in cities (Middleton et al. A survival analysis showed that the highest relative risk was found for major depressive episode (2. Factors associated to lifetime suicide attempts among individuals with a lifetime suicidal idea were also analyzed. The analysis of age of onset of suicidal ideas and attempts, showed that suicidal ideas and attempts may appear for the first time at any age, with suicidal ideas having the highest rate of first presentation during teenage years and young adulthood. The number of years from the first suicidal idea to first suicide attempt also had a high variability, but for most individuals it happened within one or few years. Analyses presented here reveal the magnitude of mood disorders in the six European countries. These disorders were frequent, mainly major depression (with or without comorbid dysthymia), affecting more than 28 million people throughout Europe at some time in their lives and more than 9 million every year. A special pattern of risk was found for mood disorders: female, unmarried individuals and individuals having chronic physical conditions were at grater risk. Younger individuals were also more likely to have mood disorders, indicating an early age of onset of the disorder. Comorbidity is highly prevalent, especially with anxiety disorders, highlighting the need for integrated therapies and early intervention in patients with a primary disorder in order to reduce future comorbidity and general psychiatric burden. Substantial levels of disability and loss of quality of life were found among individuals with Major Depression Episode and other mood disorders, with an overall impact similar or stronger than common chronic physical disorders. The consistent relationship found across six European countries underscores the public health significance of these findings. The consequences of the impairment of these capacities make effective prevention and treatment of emotional disorders especially important for the restorement of role function and quality of life. The size of this treatment gap implies that several actions should be taken at service provision level to control mood disorders. An increase in service provision, access, use, effectiveness and efficiency of existing services has been proposed. On the other hand educating individuals in need for mental healthcare may be as important as expanding the services. There is also a need for more qualitative research to improve the knowledge about stigma and other possible reasons for the underuse of mental healthcare services. The data presented here provide an epidemiological basis for promoting a change in mental health policy within Europe. While people s health is no longer judged in terms of mortality statistics exclusively, disability now plays a central role in determining the health status of a population. A proposed improvement of mental health care policy would aim to treat existing cases of mental illness and reduce future cases by means of early detection and early treatment. Given this, our findings highlight some important areas of concern for public mental health policy. A better identification of mood disorders and its risk factors could help mental health professionals in primary and secondary care to recognize and treat these disorders before diagnostic criteria are met. Moreover, by reducing the risk factors by means of more general measures, the proportion of individuals who would ever develop a specific disorder can be altered. Comorbid painful physical symptoms and depression: prevalence, work loss, and help seeking. The relation between multiple pains and mental disorders: Results from the World Mental Health Surveys. Differences in lifetime use of services for mental health problems in six European countries. Mental disorders among persons with heart disease - results from World Mental Health surveys. Mental disorders among persons with asthma: results from the World Mental Health Surveys. Delay and failure in treatment seeking after first onset of mental disorders in the World Health Organization s World Mental Health Survey Initiative. A 12-item short-form health survey:construction of scales and preliminary tests of reliability and validity. Diabetes Diabetes Mellitus (Diabetes) is characterised by an elevated blood glucose level. Type 1 is an autoimmune disease in which the insulin producing cells in the pancreas are destroyed by the immune system.

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The net result is the emergence of a distinct clinical syndrome with a characteristic phenotype that is predictive of a range of adverse clinical outcomes buy micardis online pills. We will rst describe frailty as a prototypical constellation of signs and symp- toms that allows a clinical diagnosis and then generic 40mg micardis with mastercard, working backwards in the causal pathway to etiology purchase 20 mg micardis mastercard, we will consider how what we currently know about frailty informs understanding of aging and accelerated aging order micardis discount. When a critical number of such signs and symptoms occur in the same individual they identify the frailty syn- drome [23]. It is noteworthy that studies have demonstrated that the phenotypic criteria of frailty co-occur in ways that are consistent with the denition of a medi- cal syndrome [24]. That they predict the clinical outcomes associated with being frail provides criterion validity. This susceptibility to adverse outcomes occurs frequently in the context of a stressor, such as illness, hospitaliza- tion or surgery. Clinical frailty develops progressively, so that testing positive for one or two criteria predicts the development of the full syndrome, with weakness and slowed gait being the most common earliest predictors [27]. Studies have found that the greater frailty is associated with greater risk for disability and loss of independence, for example, in the absence of an acute precipitant [28 ]. Clinical frailty is also associated with the presence of specic chronic diseases, particularly those with an inammatory etiology, and the risk of frailty rises with the number of such diseases present [29]. Further, new evidence indicates that obesity and aggregate risk for coronary artery disease in midlife predicts the development of pre-frailty and frailty 26 years later. Together these observations may implicate a shared etiology of aging (the process) and frailty (the clinical syndrome) [29]. Etiological Role of Aging in Chronic Diseases: From Epidemiological Evidence 47 45 Non-frail 40 Pre-frail Frail 35 30 25 20 15 10 5 0 Fig. A large body of evidence indicates that frailty in all its clinical manifestations could be driven by a specic, although complex, pathophysiology that leads to dys- regulation of multiple physiologic systems. Since aging is pervasive across the entire body, the more systems that are dysregulated, the greater the likelihood that the clinical manifestation is the result of accelerated aging or frailty rather than to specic disease. Longitudinal studies have found that dysregulation and loss of function tends to occur harmonically across multiple systems (Fig. Further, the relationship goes beyond any particular dysregulated sys- tem: simply counting the number of systems dysregulated predicts the frailty 48 L. Ferrucci phenotype, and the risk increases exponentially with the number of physiological systems involved [31]. The latter is consistent with the fraying of a complex dynam- ical and adaptive system that is essential for a resilient and robust organism. In other terms, we can hypothesize that some fundamental housekeeping mechanism impor- tant for homeostasis and probably related to energetics becomes impaired and diminishes the functionality of important physiological systems at the organismal level. To generate frailty, the level of physiological impairment should be severe enough to impair other downstream compensatory mechanisms towards a down- ward spiral that leads to the clinical presentation of frailty [23], an emergent state which tends be irreversible. The alteration of specic physiologic functions may be involved in the vulnera- bility to adverse outcomes characteristic of frailty. Further, frail women showed a pattern of elevation in glucose- raising hormones and decrease in glucose-lowering hormones not seen in the non-frail [33]. These ndings indicate that the entire physiological network of signals that regulate glucose homeostasis tends to be altered in frailty. Importantly, the dimin- ished regulation of physiological responses to a stressor identies the frail. This suggests that nd- ings of frailty are at the more severe end of dysregulation associated broadly with aging, and that the dysregulation of aging is interpretable, in this case, as disease [4]. The ndings summarized above suggest that some specic cellular alterations might be key to maintaining the robust complex dynamic system of the human organism which is essential for health and resilience. The case of mitochondrial dysfunction described above is just an example of the many potential mechanisms that could be involved. The true underlying mechanisms of biological alteration that lead to frailty, and aging itself, remain unknown. The existence of a common causal pathway between aging and frailty could explain why the prevalence of frailty increases geometrically with aging and why the criteria used to dene the frailty syndrome clinically include dimensions, such as sarcopenia and mobility, that are strongly modied by aging in all individuals and across species. Etiological Role of Aging in Chronic Diseases: From Epidemiological Evidence 49 4 Conclusion The analogies between aging and frailty may also explain why the clinical manifes- tations, evolution, prognostic implications and response to treatment of many chronic diseases are substantially different according to the age of the affected indi- viduals. The multisystem nature of frailty, and of aging itself, may further offer insights into why many trials of single-agent replacement therapies in older adults have failed to improve targeted health outcomes. Thus, an important area of future research is to determine the physiological links that explain such age-associated differences in the manifestations of chronic morbidity incorporating appreciation of multisystem phenomena and underlying drivers - so that this knowledge can be inserted into new clinical guidelines for the diagnosis and treatment of a series of pathologies in older, complex patients. Knowledge of the change in disease mecha- nisms, as well as the development of multimorbidity and frailty in association with age, offer the framing for breakthroughs in these research areas. In summary, a focus on disease that avoids considering the biological processes of aging can lead to misunderstanding of the full scope of disease etiology in older patients and miss new therapeutic opportunities. Considering aging illuminates the question of how it is that biologic drivers of disease differ in the old compared to the young. Ultimately, it is possible that, as our understanding of the biology of aging grows, a new chapter of geriatric medicine will open. Perhaps the next generation of precision medicine is a disruptive vessel through which to accomplish some of this goal. Precision medicine is an emerging approach for disease treatment and preven- tion that takes into account individual variability in genes, environment, and life- style for each person. The extension of this method to aging and frailty appears to be the natural evolution of this idea and one that synergizes well with the new impetus of the Geroscience initiative. Placing this information in the context of the full human population experience can lead to understanding of the place of aging itself and the generalizable import of processes observed. Acknowledgments Supported in part by the Intramural Research Program of the National Institute on Aging, National Institute on Health. The authors would like to thank Elisa Fabbri, Nida Raja and Maria O Brien for help with nalizing the text. National Heart, Lung and Blood Institute (1998) Morbidity & mortality: 1998 chartbook on cardiovascular, lung, and blood diseases. Arboleda G, Ramrez N, Arboleda H (2007) The neonatal progeroid syndrome (Wiedemann- Rautenstrauch): a model for the study of human aging? Sharpless 1 Introduction In higher organisms, cancer reects the cost of the need for long-lived self-renew- ing somatic stem cells in proliferative tissues functioning throughout the lifespan. Such cells are necessary for the constant production of new cells to replace dam- aged or shed effector cells, thereby maintaining tissue and organ homeostasis. Somatic stem cells and their replicating progeny exhibit a staggering capacity for proliferation, but they also can undergo malignant transformation. These mutations provide the nite number of genetic alterations required for malignant transforma- tion. Given the daily production of immense numbers of new cells, it is actually remarkable that highly replicating tissues only very rarely undergo neoplastic con- version. The nding that oncogenic events that characterize malignancy are very common, even present at birth [2], whereas cancer is an unusual disease mainly affecting the elderly, demonstrates the existence of very effective tumor suppression mechanisms. Specically, we will discuss how time-dependent accumulation of genetic and epigenetic alterations in self-renewing cells as a result of imperfect homeostatic mechanisms can act as a common molecular basis for aging and can- cer; how tumor suppression mechanisms that have evolved to prevent cancer can cause age-related functional attrition of self-renewing cells, which in turn contrib- utes to certain aging-related pathologies; and how aging-associated physiological changes can contribute to cancer initiation and progression. From these discussions, we hope to identify preventive measures that can minimize the risk of cancer while slowing the rate of aging. That is, aberrant expression of proteins that normally regulate cell growth and proliferation cause cancer, either by over- or under-expression of normal versions of cellular proteins, or expression of mutant proteins that acquire de novo oncogenic functions. Cancer-causing muta- tions are grouped into two classes: activating events on oncogenes and inactivating events on tumor suppressor genes (Table 1). Ample evidence suggests that both The Impact of Aging on Cancer Progression and Treatment 55 Table 1 The role of oncogenes and tumor suppressors in cancer and aging Cellular function Role in cancer Role in aging Oncogenes Cell cycle Gain-of-function mutation Loss-of-function impairs stem Cell growth One-hit model cell maintenance (pro-aging) Survival Commonly initiating event Gain-of-function enhances Differentiation Oncogene addiction stem cell self-renewal Apoptosis potential (anti-aging), but can activate tumor-suppressor response to induce senescence or apoptosis, or lead to clonal dominance of stem cells with defective differentiation potential (pro-aging) Gatekeeper Cell cycle Loss-of-function mutation Loss-of-function enhances Tumor Differentiation Two-hits Model stem cell function (anti-aging) Suppressor Apoptosis Inactivation is required for but may induce stem cell tumor maintenance exhaustion (pro-aging) Aberrant activation impairs stem cell function (pro-aging), but physiologically regulated increase in gene dose can in some cases extend lifespan by preventing cancer. They are often mutated or over-expressed forms of normal cellular genes (sometimes termed proto-oncogenes ), but can also be encoded by certain strains of oncogenic viruses and acquired by normal cells following viral infection (e. Cellular proto-oncogenes encode proteins that play essential roles in regulating cell growth, survival, proliferation and differentiation. As a result, many proto-oncogenes are important regulators of embryonic develop- ment [3, 4], while some are specically required for somatic stem cell maintenance and tissue homeostasis in adult mammals [5]. Given their unique ability to regulate cell growth and survival, proto-oncogenes are the targets of oncogenic mutations.

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