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By X. Kan. Saint Joseph College.

In summary generic 50mg nizagara visa, 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 cheap nizagara 50mg free shipping. Considering aging illuminates the question of how it is that biologic drivers of disease differ in the old compared to the young generic 50mg nizagara amex. 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. Sharpless Oncogenic mutations either increase the gene s normal activity, or confer de novo oncogenic function to the mutated genes. Upon activation, a proto-oncogene becomes an oncogene, gaining the ability to confer growth and survival advantage to normal cells and promote cancer development. Since only one copy of the proto- oncogene needs to be mutated to exert its oncogenic function, activating mutations of proto-oncogenes can follow the one-hit model and often occur early during cancer development. Alternatively, increased expression of the onco- gene protein product can occur as a result of gene amplication or promoter muta- tion (e. Lastly, chromosome rearrangement events involving one or more onco- genes can generate fusion proteins that acquire increased transcript stability or de novo oncogenic function (e. An important concern is whether a given oncogene contributes only to cancer initiation or is it also required for the continued survival and expansion of cancer cells (termed tumor maintenance or oncogene addiction ). Inhibiting oncogenic pathways involved in tumor maintenance from cancer cells causes tumor regression through increased cell death and/or cell cycle arrest [6]. Clearly, oncogenes to which a cancer is addicted make better targets for cancer therapy. However, as with any disease based on clonal evolution, drug resistance frequently emerges in cancer cells. Thus a better understanding of the molecular function of oncogenes and their normal cellular counterparts may help to identify cooperating pathways which, when inhibited, can cause synthetic lethality of the drug resistant cancer cells. While oncogenes are best known for their roles in cancer, dysregulation in their activity may also contribute to aging under physiological or pathological condi- tions. Because many proto-oncogenes are critical regulators of somatic stem cell function and maintenance in adult tissues, insufcient proto-oncogene activity may contribute to age-related functional attrition of somatic stem cells and aging of self- renewing tissues. Telomerase is activated in human cancers through several genetic mechanisms and is critical to transformation in some tissues (e. Loss of telomerase activity with attendant telomere shortening and dysfunction causes attrition of certain self-renewing cells and the manifestation of certain aspects of aging (e. A second way proto-oncogenes can contribute to aging is through the activation of tumor suppressor genes. Oncogene activation can trigger tumor suppressor responses in host cells, resulting in oncogene-induced apoptosis, senescence or differentiation. As activating mutations of oncogenes can accumulate in the stem cell pool over time, this can cause functional attrition of stem cells with age, resulting in reduced regen- erative potential of aging tissues (discussed in detail in the next section). A third and related way whereby oncogenic events can contribute to tissue aging is through the induction of advantaged clones that are defective for normal stem cell function. It is likely that this type of stem cell competition resulting from oncogenic events that cause tissue dysplasia contributes to aging phenotypes in tissues beyond the bone marrow. Tumor suppressors function to either prevent the emergence of neoplastic cells by maintaining genomic stability or to restrict the growth and proliferation of already damaged cells. As both copies of tumor suppressor genes usually need to be inactivated to abolish their function, mutations of tumor suppressor genes in cancer cells often follow the two-hit model. There are some exceptions, as tumor sup- pressor genes can be haploinsufcient, meaning the loss of a single copy of the gene is sufcient to confer growth advantage to mutant cells; in other cases, muta- tion of the tumor suppressor proteins can create dominant negative or a gain-of- function form of the protein that is sufcient to drive neoplastic transformation. In these cases, mutations of tumor suppressor genes can act as an initiating event in malignant transformation.

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Try to go to bed at the same time each night and get up at the same time each morning purchase nizagara 25 mg on line. The most vigorous nizagara 100mg with amex, enthusiastic people I know are generally individuals who are quite consistent in getting their full sleep cheap nizagara 50 mg online. Your body is working less, and the air you breathe is used to restore and rebuild body tissue. Therefore be sure there is a current of fresh air entering the room preferably outdoor air while you sleep. If you do not have that fresh air at night, you will tend to awake tired and exhausted. Keep in mind the words of the wise man: "The sleep of a laboring man is sweet" (Ecclesiastes 5:12). Only those who use their muscles during the day in physical work can enjoy sweet sleep at night. If you have a history of poor tooth structure, that is an indication that taking a little calcium each day will make life more restful for you, and will help you sleep better at night. Pantothenic acid (calcium pantothenate), a vitamin of the B complex, will also help you get to sleep at night. Along with this, take some niacin (best taken in its niacinamide form to avoid face flushing) in your meals to aid in sound sleep at night. Certain nontoxic natural herb teas have been used for years to help folk to go to sleep at night. After only a few hours of sleep loss, the body begins experiencing momentary lapses into sleep, each one of which lasts only a split second. Each micro-sleep is a period of blankness, or it may be filled with wisps of dreams. As the sleep loss increases, the micro-sleeps increase to two or three seconds at a time. Nervous tension, the use of caffeine products, and too much salt in the diet, all are items found to cause sleeplessness at night. Neutral temperature baths for 8 minutes or more are excellent for relaxing and calming the mind, and preparing one for sleep. Gutwirth, in his book, How to Sleep Well, describes a method to help insomniacs learn how to go to sleep. The point here is twofold: to learn what it feels like to relax, and then to do it when you want to so you can go to sleep at night. Going to bed within an hour or so after supper is hard on the heart and other vital organs, and exhausts the brain. There appears to be a positive correlation between going to sleep at night after a big meal and the frequency of heart attacks. Older people need less sleep, but at the same time they may have a harder time getting it. If you tend to be sleepless at night, get some active exercise in the day, and take that outdoor walk before retiring. If you still feel tired from lack of sleep, the midday nap will do much to solve your problem. If you are napping during the day, do not fear some sleeplessness at night, for just by laying there you are having a good rest. During the day, rest your eyes by shutting them occasionally or by gazing outdoors upon the things of nature. Too much talk wears people out: those who do it and those who have to listen to it. Rest your mind by not constantly dwelling upon a particular problem and trying endlessly to solve it. If you cannot solve it in five minutes, forget it is a dictum that has helped this writer. Rest your lungs by going out-of-doors every so often through the day and drinking in the fresh air deeply. If you smoke, stop; if you do not smoke, refuse to work in rooms where people smoke. Few people have it, but it is as near as your silent prayer to your Creator as you go through the day. For these rest, freedom from care, and a spare diet, are essential to restoration of health. Roaming through the fields and the woods, picking the flowers, listening to the songs of the birds, will do far more than any other agency toward their recovery. When every other voice is hushed, and in quietness we wait before Him, the silence of the soul makes more distinct the voice of God. It excites the appetite, and renders the digestion of food more perfect, and induces sound, sweet sleep. The work of digestion should not be carried on through any period of the sleeping hours. We feel confident that disease and great suffering are brought on by sleeping in rooms with closed and curtained windows, not admitting pure air and the rays of the sun. The room may not have had an airing for months, nor the advantages of a fire for weeks, if at all. It is dangerous to health and life to sleep in these rooms until the outside air shall have circulated through them for several hours and the bedding shall have been dried by the fire. Every room in the house should be thoroughly ventilated every day, and in damp weather should be warmed by fires. Every room in your dwelling should be daily thrown open to the healthful rays of the sun, and the purifying air should be invited in. If all would appreciate the sunshine, and expose every article of clothing to its drying, purifying rays, mildew and mold would be prevented. This alone is sufficient to greatly enfeeble the action of the heart and lungs, thereby affecting the whole system. While care may be needful to protect the infant from a draught of air or from any sudden and too great change, especial care should be taken to have the child breathe a pure, invigorating atmosphere. In critical cases this may be necessary; but it is often the case that more harm is done the sick by this practice than good. Attendants upon the sick should, if possible, leave them to quiet and rest through the night, while they occupy a room adjoining. The sick as a general thing are taxed with too many visitors and callers, who chat with them, and weary them. She should have a simple diet, and should be allowed plenty of pure, soft water to drink. The Sabbath was designed to stop our ceaseless turmoil of the week, and draw apart to be with our Creator and with our families. The Bible explains that the Sabbath was also given to remind us that God is our Creator. It is a sign between Me and the children of Israel for ever: for in six days the Lord made heaven and earth, and on the Seventh day He rested, and was refreshed. And God blessed the Seventh day, and sanctified it: because that in it He had rested from all His work which God created and made.

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Cystitis Etiology Urinary bladder inammation and infection occur sec- ondary to bladder paralysis that allows urine stasis 50 mg nizagara sale, dystocia with ascending contamination from the ure- thra purchase nizagara 25 mg free shipping, and chronic irritation from cystic calculi purchase nizagara 50 mg with amex. Dystocia is a major cause of cystitis in dairy cattle because sacral innervation to the bladder may be damaged, thereby decreasing bladder tone, interfering with emptying, and predisposing to infection by either stasis or direct con- tamination through the urethra. In calves, cystitis almost always is associated with urachal or umbilical remnants that act as a nidus of in- fection, or prevent complete bladder emptying by trac- tion from brous adhesions. Urethritis generally accompanies cystitis and may be responsible for some of these signs. Occasionally high-strung cows with cystitis may kick at the abdomen, but this sign is not as common as observed in pyelonephritis. Scalding of the perineum from urine dribbling is observed in some cattle if sacral nerve damage has caused relative bladder atony and subsequent urine dribbling. Umbilical infections in calves frequently produce a mild clinical or occult cystitis. B, Sandlike crystals and stru- microscopic urinalysis may reveal pyuria and bacteruria, vite precipitates removed from the vulvar hair of the but the systemic signs are often mild or attributed to the heifer. Pyelonephri- tis as a consequence of urachal remnant infection and cystitis in calves is extremely rare. Fever is der in cases with sacral nerve damage following dystocia not common and is one means of differentiating cystitis or other neurologic diseases. Affected cows do not act ill, titis without innervation defects, the bladder will be but irritation from the infection may cause enough dis- palpated as a rm, thick-walled structure the size of a comfort to affect appetite and thus production. Elevated tail head and dysuria in a 6-month-old Brown Swiss with a chronic urachal abscess causing the bladder to be adhered to the ventral body wall. The urinalysis was and kidneys will conrm disease of the bladder and rule normal. Culture and sensitivity of urine for and part of the bladder alleviated the clinical signs. Bladder endoscopy can be used to determine the severity of mucosal lesions from through a ventral midline approach to free the bladder cystitis (see video clip 22). In calves with cystitis or recurrent cystitis, ultrasonog- raphy of the abdomen to detect urachal abscesses or Bladder Paralysis (Neurogenic Injury, umbilical remnants adherent to the bladder is impera- Bladder Atony) tive. On occasion calves with recurrent cystitis may have resolved the infection within the umbilicus and urachus It is difcult to discuss bladder paralysis and cystitis but have been left with brous adhesions between the separately because inadequate bladder emptying predis- bladder and abdominal wall, resulting in incomplete poses to cystitis by encouraging ascending infection. Etiology Treatment Sacral nerve injuries causing bladder dysfunction are Bacterial cystitis requires antibiotic therapy based on most commonly caused by dystocia with intrapelvic in- urine culture and antibiotic susceptibility tests. Therapy jury to the nerves or by crushing injuries to the sacrum should be continued for at least 7 days. While awaiting urine culture re- modern facilities with poorly designed free stall dividers sults, penicillin (22,000 U/kg) and ampicillin (11 mg/kg) or partitions. In either event, the bladder dysfunction are excellent choices for initial therapy. When bladder seldom is diagnosed until cystitis develops or a large paresis or atony complicates cystitis, temporary place- bladder is palpated during routine rectal palpation of ment of a Foley catheter may improve bladder emptying the reproductive tract. Adequate salt and water should be available to the paralysis rather than vice versa. Dribbling of urine and voiding of small amounts of Bacterial cystitis associated with cystic calculi requires urine despite efforts at complete urination are the major correction of the calculi problem and will be discussed signs of bladder dysfunction. Urine is normal unless secondary cystitis chal adhesions and infection require abdominal surgery occurs. Prevention Crystalluria may result in sandy calculi formation on the Because the disease is usually fatal, preventing exposure vulvar hair ventral to the vulva. Although other vectors of the virus have been affected cow cannot empty the bladder when stimulated. Enzootic Hematuria Treatment Etiology In acute cases, placement of an indwelling Foley cathe- A progressive noninfectious cystitis with tissue metapla- ter coupled with prophylactic penicillin therapy may sia of the bladder mucosa has been described in cattle prevent urinary retention and cystitis. Spo- dexamethasone (10 to 20 mg once daily for 3 days), or radic cases also have been observed in cattle with no epidural administration of 5 mg of dexamethasone may known exposure to bracken fern or, for that matter, any be worthwhile to reduce edema and inammation pasture. Although several toxic factors have been identi- around the involved sacral nerves. Multiple types of neoplasms are possible in this against the cystitis as outlined above. The prognosis is syndrome, including both epithelial and mesenchymal poor because recurrent cystitis and eventual pyelone- origin tumors. Signs Severe hematuria, strangury, and anemia are found in Hemorrhagic Cystitis Associated affected cattle. Rectal examination in most cases allows palpation Etiology of multiple masses within the bladder wall. In individual pastured near sheep at some time within several months cases, necropsy ndings of anemia, bladder masses, and of disease onset. Fortu- Affected cattle progress rapidly to severe depression and nately pasture diseases, such as enzootic hematuria, inappetence with death occurring in 24 to 72 hours. Bladder Rupture Diagnosis Etiology Necropsy reveals severe hemorrhagic cystitis with a thick- Bladder rupture is rare in cattle but has been reported fol- ened bladder wall and mucosal erosion. A retrospective lowing parturition and in heifers with urachal adhesions diagnosis is made based on lesions of vasculitis in all or traction adhesions resulting from previous abdominal major organs (e. Urolithiasis is uncommon in dairy cattle, thereby exclusion of other causes of hemorrhagic cystitis. Bladder rupture also has oc- curred secondary to urethral obstruction by large blood clots in severe cases of acute pyelonephritis in cattle. Al- though rare in cattle raised for milk production, urolithia- sis may occur in dairy calves raised for veal or dairy steers and will be discussed below. Signs Abdominal distention, depression, inappetence, and a detectable uid wave during ballottement of the abdo- men are typical signs of bladder rupture in cattle. Urine being drained from the abdomen of a steer with ruptured bladder caused by urethral calculi. Diagnosis Failure to palpate the urinary bladder and uid abdom- differentiated easily following cleansing of the organ inal distention arouse suspicion of bladder rupture. The bladder may rarely be in- However, because this problem is rare in dairy cattle, volved in a vaginal prolapse and will prevent normal laboratory aids are essential to diagnosis. Abdominocentesis should result in copious uid that Prognosis is guarded for these conditions. Repair of may be analyzed for cytology, protein content, and creati- eversion is difcult because of rapid congestion and nine levels. The narrow urethra of inal uid creatinine should allow positive diagnosis of the cow makes replacement difcult. One case report urinary bladder rupture because the abdominal uid cre- describes a dorsal urethral incision to aid replacement.

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