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Cardiovascular Disease and Aging 129 3 Cardiovascular Aging in Mammalian Models 3 purchase 160mg super viagra with mastercard impotence zinc. Cardiac aging responses have been characterized in multiple animal models super viagra 160mg line erectile dysfunction protocol guide, including nonhuman primates, dogs, rats and mice. However, due to the different species, strains and definitions of age groups used by different studies, the results should be interpreted cautiously. While the rodent heart is different from those of primates and other larger mammals (particu- larly the electrical conduction system), in general, cardiac aging in rodents closely recapitulates the cardiac aging phenotypes seen in humans without overt cardiovas- cular diseases [31]. Dai and colleagues showed in a mouse longevity cohort that there were significant age-dependent linear trends for several cardiac parameters [32]. They showed by echocardiography that left ventricular mass index and left atrial dimension significantly increased with age. Diastolic function measured by tissue Doppler echocardiography revealed an age-dependent decline in the ratio of early to late diastolic mitral annular velocity (Ea/Aa) and the frequency of diastolic dysfunction [33 ], defined as Ea/Aa <1, was increased in C57B6 mice over 24 months of age. The proportion of mice with atrial dilation also significantly increased with age [32]. The aging-asso- ciated changes in different phases of the cardiac cycle are summarized in Fig. This suggests that the hypertrophic growth of the myocytes in middle-age and old mice becomes decompensated in senescent mice, consistent with myocyte loss [34]. At a histopathological level, the aged hearts display inter- stitial fibrosis, cytoplasmic vacuolization and hyalinization, increased variation in myocyte fiber size, collapse of sarcomeres, mineralization, arteriosclerosis and arte- riolo sclerosis [ 40 ]. The relatively short lifespan and the availability of genetically modified mice also make mouse models useful tools for study of the molecular mechanisms of cardiac aging. In addition, the general absence of common cardiovascular risk fac- tors such as diabetes and hypertension [32 , 41], allows intrinsic cardiac aging changes to be distinguished from disease-induced changes. These include endothelial dysfunction [42], structural remodeling, arterial stiffening, vascular oxidative stress and inflammation [43], vascular calcification, microvascular rarefaction [44], autoregulatory dysfunction and impaired functional adaptation to hypertension [45, 46], blood brain barrier disruption [45 ], neurovascu- lar uncoupling [47], impaired cellular stress resistance [48], increased susceptibility for vascular injury, and mitochondrial dysregulation [49 , 50]. Thus, laboratory rodents are well-suited models for studying these aspects of aging-induced vascular pathologies. In contrast, laboratory rodents are not ideal models for age-related increases in blood pressure [51]. Aged wild type mice and rats also do not develop atherosclerotic plaques spontaneously (in the absence of genetic depletion of Ldlr or Apoe) similar to those observed in aged primates. The age-related damage of the arterial tree in non-human primates is of particu- lar interest, as these species are physiologically and phylogenetically closer to humans than the more commonly studied rodent models. With age, non-human pri- mates exhibit increased arterial stiffness [52], increased central arterial pulse pres- sure, increased carotid intima-media thickness, hypertension [53], activation of processes involved in atherogenesis [54], development of aneurysms [55 ], vascular oxidative stress and inflammation [56, 57], endothelial dysfunction and apoptosis [16], alterations of the blood brain barrier [58] and cellular mitochondrial content [59] and impaired cellular stress resistance [57], mimicking the human vascular aging phenotype. Using genetic models and interventions targeting different pillars of geroscience, research- ers have revealed several critical molecular mechanisms of cardiac aging in the past decade that have the potential to translate into cardiovascular healthspan interven- tions (summarized in Fig. Multiple pathways and molecules have been demonstrated to play critical roles in cardiac and vascular aging. Although cardiac failure was not the major cause of death in these mice, they exhib- ited great attenuation of many cardiac aging phenotypes, including left ventricular hypertrophy, diastolic dysfunction and impaired myocardial performance, as well as significant amelioration of age-dependent cardiomyocyte hypertrophy, interstitial fibrosis and mitochondrial ultrastructural changes [32, 65]. Middle age Polgm/m mice display cardiac hypertrophy, impaired systolic and diastolic function to an extent that is even more severe than wild type mice 24–30 months old. In addition to the decline in cardiac function with age, increased susceptibility of the aged heart to stress is also likely related to mitochondrial dysfunction. Rapamycin has been demonstrated to extend lifespan in model organ- isms including yeast, fly, and mouse [85–87]. Long-term rapamycin treatment for 1 year initiated at mid-life reduced hypertrophy but failed to restore systolic function in aged male mice [88]. This was accompanied by restoration of proteomic and metabolic profiles to more youthful phenotypes. It functions to maintain protein abundance and quality and supports normal physiological function. Failure to maintain protein homeostasis, leading to accumulation of defective proteins, has been observed in several age-related dis- eases [91], including neurodegenerative diseases [92], cardiac dysfunction [93, 94], cataracts [95], and sarcopenia [96 , 97]. Several protein degradation pathways have been implicated in these failures, including autophagy and the ubiquitin-proteosome system. One of the hallmarks of aging hearts is the accumulation of myocardial lipofuscin. This “wear and tear” pigment is membrane-bound cellular waste that can neither be degraded nor ejected from the cell and is composed of incomplete lysosomal degradation products, predominantly from damaged mitochondria [99]. In normal physiology, removal of damaged mitochondria occurs primarily through fusion and fission, autophagy and lysosomal degradation.

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In dairy cattle cheap super viagra 160 mg overnight delivery erectile dysfunction grand rapids mi, “creeper” cows that have had hypocalcemia are most at risk for femoral nerve injury buy cheap super viagra 160 mg online impotence in men. Slippery concrete surfaces in some free stalls also contribute to possible femoral nerve injury because it is not at all rare to see cows fall in free stall alleys with their hind limbs extended caudally. Such cows are lying on the ventral abdomen, udder, and cra- nial surface of the stifles. Occasionally these animals have difficulty getting their hind limbs back under them and risk femoral nerve injury. Signs The femoral nerve supplies motor innervation to the Figure 12-44 quadriceps femoris to extend the stifle and a portion of A calf with femoral nerve paresis of the right pelvic the iliopsoas muscle to help flex the hip. This was believed to be caused by a difficult deliv- nerve also gives rise to the saphenous nerve, which ery and “hip lock” while passing through the maternal supplies skin sensation to the medial aspect of the limb pelvis. Chapter 12 • Neurologic Diseases 547 moveable, and the cause of limb dysfunction may be drugs in the gluteal region or too close to the course of misdiagnosed as patellar luxation. These reactions or Treatment injuries seldom cause complete or permanent loss of Medical therapy of femoral nerve paralysis should be sciatic function in adult cattle but may do so in calves. The cow Although irritating injectables are most risky, direct in- should be moved to a well-bedded box stall or an area jury through needle puncture is possible because of the where good footing is available. Slippery floors must be paucity of gluteal and caudal thigh musculature in dairy avoided, lest the condition be worsened or the cow expe- calves. Placing the cow’s Pelvic fractures involving the ilium or femoral frac- hind limbs in proper position and rolling her onto her tures may do severe damage to the sciatic nerve as well. Warm compresses applied to the In a prolonged dystocia, compression of the ventral quadriceps femoris may be helpful, as may massage. Ap- branch of the L6 spinal nerve where it courses caudally propriate dosages of vitamin E and selenium are recom- over the ventral surface of the sacrum will cause a pero- mended empirically. The cow may only need manual assistance by tail lifting or judicious use of mechanical aids, such as well-padded Signs hip slings. When mechanical aids are used, it is impor- Complete sciatic nerve paralysis results in slight lower- tant not to further damage the quadriceps femoris mus- ing or “dropping” of the hip and hock with overflexion cles. The animal can advance bilateral femoral nerve paralysis has occurred in a cow, the limb by hip flexion and support weight, but the the prognosis is guarded to poor, but some cows so af- digit may drag as the limb is advanced, and the animal fected can be slowly nursed back over a 2- to 3-week usually stands on the dorsum of the digit and fetlock convalescence with assistance in rising. Symptomatic therapy should be intense as outlined for adult cattle, and vitamin E/selenium should be given at recommended dosages. Good bedding and footing are especially im- portant to avoid decubital sores in calves. Sciatic Nerve Paralysis Etiology Injury to the sciatic nerve and its branches are the most common peripheral nerve injuries affecting limb func- tion in dairy cattle. When the characteristic clinical signs are observed, the neuroanatomic diagnosis includes the origin of the sciatic nerve from spinal cord segments L6, S1, and S2, their nerve roots and spinal nerve ventral branches and their distribution to the caudal thigh, and distal to the stifle through the peroneal (L6, S1) and tibial (S1, S2) nerve branches. Direct injury through needle laceration or indirect injury through an irritating drug placed adja- cent to nerve branches is possible. Even well-placed injections into the caudal thigh muscles occasionally cause sciatic or tibial nerve injury in calves. Acute injuries may be treated symptomatically with antiinflammatory drugs and hydrotherapy. A support wrap or gutter-pipe splint may need to be applied to the lower limb if buckling and walking on the dorsum of the fetlocks occurs. Further injections into the affected limb should be avoided, and the animal should be placed on the best footing available to minimize further complications. Tibial Nerve Injury Etiology Injury to the tibial nerve in dairy cattle and calves may result from injection of an irritant drug or a large volume of drugs distally in the caudal thigh muscles. Note contribute to the tibial nerve and cause a tibial nerve the dropped hock and dorsal buckling of the fetlock. Signs for because laypeople may not always volunteer such The tibial nerve supplies motor innervation to the gas- information in the history (Figure 12-46). Sciatic nerve trocnemius, popliteus, superficial digital flexor, and deep injuries must be differentiated from tibial nerve injury, digital flexor muscles. Therefore tibial nerve paralysis or peroneal nerve injury, partial rupture of the gastrocne- partial injury will affect function of these muscles, caus- mius tendon or muscle, and sacral root and sacral nerve ing a dorsal buckling of the fetlock and reduced exten- injuries associated with vertebral and spinal cord sion or increased flexion of the hock (Figure 12-47). The cow is not observed to stand on the dorsum of the Fortunately most peripheral sciatic nerve injuries are digit nor does she drag the digit when walking, as in partial rather than complete. The limb bears giving injections in the gluteal region of adult dairy full weight during walking but may be favored slightly cattle is imperative. Dairy cattle, on the from partial sciatic nerve injury (and doing so may be other hand, have a “dished out” gluteal area with little difficult), partial rupture of the gastrocnemius and/or muscle protection for sciatic nerve branches.

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Physical activity is defined as any bodily movement produced by skeletal muscles and resulting in energy expenditure (1) super viagra 160mg sale impotence at 75. It is planned cheap 160mg super viagra impotence 27 years old, structured, and repetitive, and produces an improvement or maintenance of one or more facets of physical fitness (e. Historically, exercise science investigated healthy, active, young males or athletes. Consequently, much of the information about fitness testing and the recommenda- tions for exercise prescription to improve physical fitness indicated intensive exercise regimens were needed. However, studies are beginning to show that less fit, healthy people or people with musculoskeletal impairment and rheumatic disease do not need to participate in intense exercise programs to obtain health benefits (2,3). For people with rheumatic conditions, physical activity is as important as it is for the healthy population. Maintaining activity retains and restores physiological and pyschosocial function and health, so exercise forms an essential element for the management of rheumatic conditions. This chapter provides a brief overview of the importance of exercise in the management of common rheumatic conditions. Our aim is to present general advice regarding exercise, and to show how exercise should be adapted to address an individual’s specific problems and goals. It is important to remember that all patients with rheumatic disease are different, starting from a different baseline and with different needs. Nonetheless, safety is always a concern that should be discussed with patients, without raising (usually unnecessary) fears and anxiety. People with joint problems or not used to exercising should always seek professional advice prior to starting an exercise regimen. Most people will find benefits, without adverse side effects, that will far outweigh the risks of inactivity. Many individuals associate activity with pain and believe that this indicates that the activity is damaging their joints; consequently, they begin to avoid physical activity, which leads to muscle and general fitness de-conditioning. However, there is a growing body of research suggesting that exercise is safe for people with rheumatic conditions. Early fears that exercise would exacerbate the symptoms of rheumatic disease, particularly in people with inflammatory arthritis, have been challenged by research demonstrating improvements in aerobic fitness, muscle strength, functional status, and disability following dynamic exercise programs (4,5). Furthermore, these improvements were achieved with no exacerbation in joint symptoms or increase in biochemical markers of disease activity (6,7). Additionally, no detrimental effects on joint structure in those with mild to moderate rheumatic disease have been identified (8,9). It is important that patients are advised that initially, they may experience some discomfort during or following exercise. Advice for managing the increased symptoms and the resumption of exercise (see Patient Point 1) is needed. Teaching the principles of pacing and joint protection may be useful in preventing unnecessary pain that sometimes results from physical activity, which can discourage an individual from persevering with an exercise program. Patient Point 1:General Exercise Advice There are a few basic principles that need to be remembered when completing any form of exercise. Once these goals have been achieved, set more challenging targets • Safety: Always ensure you are stable and safe when doing any exercise. Wear clothing that is appropriate to the climate and type of exercise you are doing (usually loose clothing is preferable). Complete a few warm-up exercises to get your body ready to exercise—this may include some stretching or flexibility exercises, too. Progress slowly, gradually increasing the time, frequency, and intensity of exercising, do a little more each time. However, if an activity causes pain, discomfort, or swelling for more than a couple of days, rest for a few days. As the pain or swelling settles, resume exercising gently, gradually building up the exercises as before and taking care to monitor the quality of the exercises. Leave out any specific activities that caused pain initially then add them back into the exercise program cautiously. People with joint problems or those not used to participating in regular exercise should discuss what, when, and how they should exercise with a health care professional (physical or exercise therapist, nurse, physician). A person’s current activity level, fitness, and general health should be considered when setting realistic and achievable goals. The level of exercising and 72 Part I / Introduction to Rheumatic Diseases and Related Topics these goals should be low at first and then gradually increased, for comfort, safety, and to prevent the patient from becoming disillusioned if he or she does not quickly reach unrealistic targets. Assessment Existing levels of physical activity can be assessed using measurement tools such as the Minnesota Leisure Time Physical Activity Questionnaire (12) or the Rapid Assessment of Physical Activity (13).

Stepwise changes can occur by first changing at one site and attacking a subset of the population with a dominant response against that site buy discount super viagra 160mg on line impotence of organic nature. However discount super viagra 160mg fast delivery erectile dysfunction drugs free sample, the immunodominance of individual hosts for particular epitopes and the population variability of immune profiles can create important se- lective pressures on parasites. Suppose, however, that a host first de- velops a memory response to a particular antigen, and then is exposed secondarily to a variant ofthatantigen. If the secondary variant cross- reacts with memory cells, then the host may produce a memory response to the first antigen rather than a primary response to the second antigen. Amemoryresponse to the first antigen rather than a primary response to the variant is called original antigenic sin. Amemoryresponse based on previously encountered, cross-reactive antigens has three consequences for the immunological structure of host populations. First, cross-reaction may aid protection or clearance against secondary challenge. This occurs if the cross-reactive memory effectors have sufficient affinity for the variant antigen (Kaverin et al. This occurs when cross-reactive memory effectors do a poor job of clear- ing secondary challenge but respond sufficiently to repress a new, pri- mary response against the variant antigen (Good et al. Third, the host may fail to develop an increasingly broad memory profile over the course of repeated exposures to different variants. Ihavealready mentioned the immunodominance of individual immune profiles and the tendency for the pattern of immunodominance to vary among individuals. I also discussed how cross-reactivity can affect clear- ance of secondary challenge and the development of memory over a host’s lifetime. In this section, I add a few more factors that affect the distribution of immune profiles. Thus, older individuals typically have a broader memory profile than do younger individuals. Age-related pat- terns have been measured by serological surveys, which describe the presence or absence of circulating antibodies to a particular strain of parasite or to a particular antigen. Many surveys have been published forawide variety of parasites and hosts (Anderson and May 1991, pp. Here are just a few example pathogens for which broader immunolog- ical profiles have been reported in older hosts compared with younger hosts: influenza (Dowdle 1999), Plasmodium (Gupta and Day 1994; Bar- ragan et al. Most neutralizing antibodies against influenza bind to hemag- glutinin, the virus’s dominant surface molecule (Wilson and Cox 1990). Three major subtypes of hemagglutinin have circulated in human pop- ulations since about 1890, labeled H1, H2, and H3. Although antibodies to a partic- ular variant do not always protect against infection by other variants of the same subtype, the antibodies to variants of a subtype do often cross-react to some extent. The strains labeled A/strain des- ignation (subtype) were used to test for antibodies to a particular subtype by measuring the degree to which blood samples carried antibodies that reacted significantly against the test strain. These patterns of cross-reaction allow one to measure immunological profiles of individuals with regard to previous exposure to each of the three subtypes. By measuring individuals of different ages, a picture emerges of the past history of exposure and immunity to the different subtypes. The 1957 pandemic was caused by an H2 subtype and the 1968–69 pandemic was caused by an H3 subtype. Original data from Housworth and Spoon (1971), with permission from Oxford University Press. Note that antibodies against H1 occur in 80–90% of individuals who were less than twenty years old during the pandemic years, suggesting widespread dis- tribution of the disease. The drop in the seropositive level for individu- als born before 1900 may be explained by the typically lower percentage of adults than children infected by influenza epidemics (Nguyen-Van- Tam 1998). The largedropinseroprevalence after 1922 suggests that H1 declined in frequency after the pandemic. Perhaps because of widespread immunity to H1, variants of this subtype had difficulty spreading between hosts. Cohorts born in the years before the pandemic had very high seroprevalence, suggesting widespread infection. Seropreva- lence declined sharply in those born just after the pandemic, implying that H3 had nearly disappeared from circulation. Older people often suffer higher mor- tality from influenza than do younger people (Nguyen-Van-Tam 1998), so the pattern in 1957 appears to be typical. The contained mortality among older individuals in 1968–69 may have been caused partly by immunological memory to the H3 pandemic of 1890 and consequent protection against this subtype. The age structure of immunity profiles has probably influenced the waxing and waning of the various influenza A subtypes over the past 110 years.