By W. Asam. Central Bible College.

Mecha nism of the conversion of xanthine dehydrogenase to xanthine oxidase: identification of the two cysteine disulfide bonds and crystal structure of a non-convertible rat liver xanthine dehydrogenase mutant discount avana online. Multiple antioxidants and L-arginine modulate inflammation and dysli pidemia in chronic renal failure rats best order for avana. Identification and characterization of a functional mitochondrial angiotensin system order avana 50 mg visa. Measuring reactive species and oxidative damage in vivo and in cell culture: how should you do it and what do the results mean? Effects of combina tion tocopherols and alpha lipoic acid therapy on oxidative stress and inflammatory biomarkers in chronic kidney disease. Role of oxidants/ inflammation in declining renal function in chronic kidney disease and normal ag ing. Effect of N-ace tylcysteine on serum creatinine and kidney function: results of a randomized control led trial. The effect of N-acetylcysteine on proteinuria and markers of tubular in jury in non-diabetic patients with chronic kidney disease. N-acetylcysteine for the management of anemia and oxidative stress in hemodialysis patients. Effect of oral N-acetylcysteine treatment on plasma inflammatory and oxidative stress markers in peritoneal dialysis patients: a placebo-controlled study. Chronic treatment with N-acetylcysteine improves cardiac function but does not prevent progression of cardiomyopathy in Syrian cardiomyopathic hamsters. Free radical recycling and intramembrane mobility in the antioxidant properties of alpha-tocopherol and alpha-tocotrienol. A quantitative approach to the free radical interaction between alpha-tocopherol or ascorbate and flavonoids. Recycling and antioxidant activity of tocopherol homologs of differing hydrocarbon chain lengths in liver microsomes. Ascorbate-dependent recycling of the vitamin E homologue Trolox by dihydrolipoate and glutathione in murine skin homogenates. Management of oxidative stress by heme oxygenase-1 in cisplatin-induced toxicity in renal tubular cells. Kinetics of tissue alpha-tocopherol uptake and depletion fol lowing administration of high levels of vitamin E. In crease in oxidative stress but not in antioxidant capacity with advancing stages of chronic kidney disease. The effect of vitamin E supplementation on antioxidant enzyme activities and lipid peroxidation levels in hemodialysis pa tients. Supplementation of diets with alpha-tocopherol reduces serum concentrations of gamma- and delta-tocopherol in humans. Effects of coenzyme Q10 and alpha-tocopherol admin istration on their tissue levels in the mouse: elevation of mitochondrial alpha-toco pherol by coenzyme Q10. Effect of coenzyme Q(10) and alpha-tocopherol content of mito chondria on the production of superoxide anion radicals. Role of mitochondrial electron transport complex I in coenzyme Q1 reduction by intact pulmonary arterial endothelial cells and the effect of hyperoxia. Coenzyme Q(10) - its role as a prooxidant in the for mation of superoxide anion/hydrogen peroxide and the regulation of the metabo lome. Ubiquinol-10 is an effective lipid-soluble antioxidant at physiological concentrations. Electron transport-linked ubiquinone-dependent recycling of al pha-tocopherol inhibits autooxidation of mitochondrial membranes. Healthy aging: regulation of the metabolome by cel lular redox modulation and prooxidant signaling systems: the essential roles of su peroxide anion and hydrogen peroxide. Effects of coen zyme Q(10) administration on its tissue concentrations, mitochondrial oxidant gener ation, and oxidative stress in the rat. Coen zyme Q10 attenuates diastolic dysfunction, cardiomyocyte hypertrophy and cardiac fibrosis in the db/db mouse model of type 2 diabetes. Osteopontin defi ciency protects against aldosterone-induced inflammation, oxidative stress, and in terstitial fibrosis in the kidney. Nutritional compounds influence tis sue factor expression and inflammation of chronic kidney disease patients in vitro. Docosahexaenoic acid enhan ces the antioxidant response of human fibroblasts by upregulating gamma-glutamyl- cysteinyl ligase and glutathione reductase. Antioxidative and anti-inflammatory actions of docosahexaenoic acid and eicosapentaenoic acid in renal epithelial cells and macrophages. Short- time infusion of fish oil-based lipid emulsions, approved for parenteral nutrition, re duces monocyte proinflammatory cytokine generation and adhesive interaction with endothelium in humans. Dietary omega-3 polyunsaturated fatty acids inhibit phosphoinositide formation and chemo taxis in neutrophils. Omega-3 fatty acid supplementation attenuates oxidative stress, inflammation, and tubulointerstitial fibrosis in the remnant kidney. The effects of dietary fish oil on inflam mation, fibrosis and oxidative stress associated with obstructive renal injury in rats. The use of ome ga-3 poly-unsaturated fatty acids in heart failure: a preferential role in patients with diabetes. Effects of omega-3 polyunsaturated fatty-acid supplementation on redox status in chronic re nal failure patients with dyslipidemia. In sights into the inhibition of platelet activation by omega-3 polyunsaturated fatty acids: Beyond aspirin and clopidogrel. Effects of purified eicosapentaenoic and docosahexaenoic acids on glycemic control, blood pressure, and serum lipids in type 2 diabetic patients with treated hypertension. Eicosapentaenoic acid improves imbalance between vasodilator and vasoconstrictor actions of endo thelium-derived factors in mesenteric arteries from rats at chronic stage of type 2 dia betes. Effect of hypouricaemic and hyperuricaemic drugs on the renal urate efflux transporter, multidrug resistance protein 4. Role of xanthine oxidase inhibitor as free radical scavenger: a novel mechanism of action of allopuri nol and oxypurinol in myocardial salvage. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Effect of treatment of hyperuricemia with allopurinol on blood pressure, creatinine clearence, and pro teinuria in patients with normal renal functions. The effects of lower ing uric acid levels using allopurinol on markers of metabolic syndrome in end-stage renal disease patients: a pilot study. Relationship between serum carnitine, acylcarnitines, and renal function in pa tients with chronic renal disease.

Large and numerous systemic to pulmonary arterial collateral vessels will cause excessive pulmonary blood flow and as a result no significant cyanosis but significant pulmo- nary edema cheap avana 200mg without a prescription. On the other hand purchase avana once a day, limited or small systemic to pulmonary arterial collaterals with hypoplastic pulmonary arteries will restrict blood flow to the lungs purchase generic avana, resulting in significant cyanosis and no pulmonary edema. Most patients are born with adequate or excessive systemic to pulmonary arterial collaterals resulting in mild cyanosis and significant pulmonary edema, however, as time passes, systemic to pulmonary arterial collaterals become stenotic and pulmonary blood flow becomes inadequate resulting in less pulmonary edema and worsening cyanosis. Patients with ductus arteriosus which remains patent, or those with multiple and/or large systemic to pulmonary arterial collaterals providing adequate or excessive pulmonary blood flow, will have near normal oxygen saturation. The latter subset of patients can even present in heart failure with tachypnea and minimal cyanosis due to the excessive pulmonary blood flow. However, within weeks or months these patients will outgrow their source of pulmonary blood flow as the collaterals develop stenosis resulting in progressive hypoxemia. On physical examination, the degree of cyanosis is inversely related to the extent of pulmonary blood flow. Therefore, these patients will present with shortness of breath and easy fatigability. The precordium in these patients is hyperactive with prominent right ventricular impulse. Patients with small systemic to pulmonary arterial collaterals will present pre- dominantly with cyanosis. There may be tachypnea due to low oxygen saturation; however, there are no significant symptoms of pulmonary edema or congestive heart failure. Single second heart sound and continuous murmur are again heard in 17 Pulmonary Atresia with Ventricular Septal Defect 207 Fig. The continuous murmur reflects systemic to pulmonary arterial col- laterals that are present, but restrictive. Chest X-Ray Typical radiologic features are similar to those seen in classic tetralogy of Fallot. A boot-shaped heart is seen due to elevation of the apex of the heart because of right ventricular hypertrophy and concavity in the area of the main pulmonary artery because of hypoplasia or atresia of this artery. An absent thymus shadow can also sometimes be appreciated in these latter patients. In those patients with excessive pulmonary blood flow secondary to extensive systemic to pulmonary arterial collaterals, there might be left atrial enlargement and biventricular hyper- trophy due to the increase in blood return from the pulmonary veins. Echocardiography can also be helpful to evaluate the size of the pulmonary arteries and determine whether they are conflu- ent or discontinuous. It can also help detect the presence of systemic to pulmonary arterial collaterals, although it is not a sufficient test to completely define these tortuous vessels. Additional information such as patency of the ductus arteriosus, presence of a right aortic arch and additional lesions can also be clearly assessed. Therefore, cardiac catheterization continues to be a helpful procedure to delineate the distribution of the true pulmonary arteries and of the collaterals. In those patients with more exten- sive atresia of the outflow tract and more complex systemic to pulmonary arterial 17 Pulmonary Atresia with Ventricular Septal Defect 209 collaterals, cardiac catheterization is important in the long-term follow up of these patients to relieve stenotic areas in these vessels. This is often obtained prior to surgical repair in newly diag- nosed newborn children unless those patients will undergo an interventional cath- eterization, in which case cardiac catheterization will provide the information needed. Infants relying on the patent ductus arteriosus for adequate pulmonary blood flow, require immediate institution of prostaglan- din infusion after birth. Rare cases where pulmonary blood flow is excessive, secondary to extensive collaterals might require anticongestive heart failure therapy with diuretics. The main goal of therapy is to establish a reliable source of pulmonary blood flow by creating a communication between the right ventricle and the pulmonary arteries. These patients benefit from opening the atretic pulmonary valve in cases of membranous pulmonary valve atresia and patent main pulmonary artery with or without placement of a systemic to pulmonary arterial shunt. On the other hand, if pulmonary atresia is more extensive, affecting the pulmonary valve and main pulmonary artery, then a systemic to pulmonary arterial shunt is necessary to maintain a reliable source of pulmonary blood flow till the child is about 4 6 months of age when a right ventricle to pulmonary arterial conduit can be placed with closure of the ventricular septal defect. Children with multiple systemic to pulmonary arterial collaterals typically have poorly developed pulmonary arteries and numerous collateral vessels feeding different segments of the two lungs. Management in such cases is chal- lenging and requires multiple staging of operative repair. Repair starts by good understanding of the pulmonary arterial and collateral anatomy. The initial surgical step brings together as many collaterals and the pulmonary artery on one 210 K. This procedure is known as unifocalization since it connects all blood vessels supplying the lung to a single source of blood supply. After few weeks, the same surgical procedure is performed for the other side of the chest. A third surgical procedure is then performed to bring the two unifocalized sides together and connect to the right ventricle through a conduit (homograft). Those patients with abnormal pulmonary artery anatomy and extensive systemic to pulmo- nary arterial collaterals have poorer prognosis with less certain long-term results. Case Scenarios Case 1 A female newborn was noted to be severely cyanotic shortly after birth. The child was transferred to the neonatal intensive care unit for further evaluation. Physical Exam On physical examination, the patient was cyanotic, but did not otherwise appear sick. Heart rate was 148 bpm, respiratory rate 50, blood pressure was 62/38 mmHg, oxygen saturation 74% while breathing room air. On ausculta- tion, the first heart sound was normal and the second heart sound was single. The pulmonary vascular markings are decreased, suggesting decreased pulmonary blood flow. The differential at this juncture should include pulmonary pathology, cardiac pathology, as well as sepsis. A systolic murmur in the upper sternal border in a cyanotic new- born is suggestive of a congenital cyanotic heart defect. In this case, pulmonary blood flow depends on a patent ductus rather than numerous systemic to pulmonary arte- rial collaterals. Management The patient should be immediately initiated on prostaglandin infusion to keep the ductus arteriosus patent and maintain an adequate source of pulmonary blood flow. This can be done in the cardiac catheterization laboratory; however, if not possible, surgical reconstruction of the right ventricular outflow tract can then be performed. Case 2 A 16-month-old boy presented to the emergency department because of increased work of breathing and progressively turning blue during the prior recent months. In his first months of life, he was tachypneic and struggled with weight gain, but then improved until a few months ago when cyanosis developed. Physical Exam On physical examination, the patient was cyanotic and in respiratory distress. Cardiac auscultation revealed a single second heart sound and a blowing continuous murmur was heard over the precordium as well as over the back. Heart disease becomes more apparent once you examine this child and hear the continuous murmur over the precordium and back.

A pre-planned compari- son between treatments was performed separately for each group of pesticide to determine within group treatment eVects order cheapest avana and avana. Xoridana sporulation was higher when the cadavers were immersed into pesticides than when sprayed (F35 discount avana 200 mg fast delivery,324 =11 discount 50mg avana amex. When cadavers were sprayed with the pesticides, Methomyl, Lambda-Cyhalothrin, Propargite and Abamectin had no eVect on sporulation at neither of the concentrations. Leaf treatment Cadavers placed on leaf discs that were immersed into Lambda-Cyhalothrin sporulated and produced as many conidia as the control (Table 3). In general, sporulation was signiWcantly higher when leaf discs were sprayed than when immersed in both Mancozeb and Captan (F11,108 = 11. Propargite and Mancozeb totally inhibited germination of conidia after immersion of coverslips. When coverslips were sprayed, germination was totally inhibited by Mancozeb and only 7. Lambda-Cyhalothrin and Captan also reduced germination in both application methods. Methomyl was the only pesticide that did not aVect germination when coverslips were either immersed or sprayed. Overall, germination of primary conidia was signiWcantly higher on coverslips that were sprayed than immersed (F29,60 = 22. More than half of the mites transferred to leaf discs treated with Propargite, Abamectin, Mancozeb or Lambda-Cyhalothrin died after 1 day indicating a direct eVect of the products on the mites and therefore these products were not used in the infectivity test (Table 5). Methomyl and Captan were the only pesticides used to test infectivity when leaf discs were either immersed or sprayed. Lower mortality of fungus- inoculated mites was observed when leaf discs were immersed rather than sprayed with Methomyl and Captan (F9,39 = 10. Neither Methomyl nor Captan aVected infectivity when leaf discs were sprayed with the pesticides. When cadavers were either immersed or sprayed, all pesticides except Mancozeb (not tested due to insuYcient sporulation) were used to test pathogenicity of the sporulating fungus. However, when cadavers were sprayed, mite mortality was higher than when immersed 294 J. Mean mortality of mites that were placed onto leaf discs contaminated with Methomyl, Captan or water (=control) before transfer to leaf discs with sporulating cadavers of N. Discussion The detrimental eVects of pesticides used to control insects, mites and fungal diseases in commercial tomato production on sporulation, germination and infectivity of N. Xoridana varied as a function of the methods of contamination, chemical nature and concentration. The fungicides Mancozeb and Captan that resulted in the most negative eVects on sporula- tion and germination of N. Xoridana in Tetranychus urticae Koch Diseases of Mites and Ticks 295 in peanut Welds. Acaricides such as Propargite, which do not inhibit sporulation but aVect primary conidia germination, may have a moderate eVect on the fungus in the Weld compared to those pesticides that inhibit sporulation because the life span of a primary conidium is much shorter than the life span of a mummiWed mite. However, any pesticide that inhibits the formation of capilliconidia, the only infective spores of N. No eVects on infectivity of the capilliconidia was observed from the pesticides after exposure. Seemingly, some pesticides inhibit sporulation or germination of primary conidia, but the capilliconidia produced under the exposure of these pesticides mantain the potential to infect their hosts. Viability of conidia is very important because the power of the fungus to kill its hosts depends on this factor as only viable conidia have the capacity to germinate and adhere to healthy hosts. It was expected that once the mites feed on pesticide contaminated leaves, they could ingest and accumulate the pesticides that may inhibit vegetative growth of the fungus and reduce mite mortality due to infection. Since the control mites were not subjected to pesticide contaminated leaf discs, higher mortality due to the fungus was anticipated. However, mor- tality in treatments with the insecticide Methomyl and the fungicide Captan was similar to the mortality in the controls suggesting that the pesticides did not aVect fungal development. Xoridana was higher when immersed than sprayed and this is probably associated with the amount of the product that the fungus is exposed to, despite being of equal concentration. DiVerences between the controls observed in the germination study were attributed to independent incubation of control lots together with each pesticide group. It is also possible that Tween 80, the surfactant used in the two controls, could have been the cause of diVerential germination because more of the products could be retained on the coverslips when they were immersed than sprayed. Although the spray tower method may give comparable results to Weld application of pesticides, the equipment may not be readily available in many laboratories, as a result, its use in pesticide testing may be limited. However, the eVect of direct immersion of leaf discs or cadavers into pesticide solutions is stronger and may not reXect a Weld situation, but it represents a rapid method to assess both direct and indirect eVects of these pesticides on the fungus and may assist in making quick decisions on the pesticides to be applied during pest attack. Also, if a product is considered compatible with the pathogen in this laboratory method (worst scenario) it may warrant selectivity in the Weld. The same line of thought applies to diVerences observed between maximum concentration and half the concentrations recommended for Weld application. A higher concentration in the laboratory that does not aVect the fungi has higher chances of being non-toxic in the Weld than a low concentration that is toxic under laboratory conditions. An important consideration in the use of laboratory methods is the determination of how accurately they represent Weld conditions. However, it is unlikely that pesticides which aVect the fungus at low concentrations in in vitro tests will fail to produce eVects under recommended Weld concentrations. Given that high toxicity of chemical products in labora- tory experiments does not always reveal high toxicity in the Weld, the laboratory tests are useful and indicate the possibility of the eVects that may occur in the Weld (Alves et al. Field applications of pesticides usually achieve less-than-perfect coverage, perhaps providing spatial refugia for entomopathogenic fungi. Field studies are usually limited to a small number of products and it takes a long time to reveal any diVerences in the infection levels or the density of propagules in the soil. For this reason, there is need for the generation of labora- tory data on the eVect of pesticides on speciWc aspects of the fungus such as sporulation, germination and viability. However, this has been hampered by lack of a deWned protocol to test this fungus without growing it on artiWcial media. The laboratory tests described here simulate an in vivo situation and allow the Xexibility of dosing a pesticide under con- trolled conditions. The results obtained using these methods indicate that the insecticide Methomyl, and the acaricide Abamectin produced varied eVects on N. Methomyl also reduces infectivity when leaf discs are immersed and not when sprayed. Xoridana in the Weld and may be compatible with conservation strategies of pest control. Xoridana when the coverslips are immersed and this eVect substantially reduces when they are sprayed.

Lumpy jaw is a debilitating disease of cattle result- ing from infection of the mandible or maxilla by A safe avana 200mg. The organism has been described as a normal inhabitant of the oral ora and digestive tract of cattle purchase avana mastercard. The organism also may penetrate around the alveoli of the teeth or contami- nate skin wounds in common feed and water troughs purchase avana 100mg visa. Rebhun observed one herd with an epidemic of lumpy jaw, with 7 of 60 cows affected. The point source cow had a large, draining, lumpy jaw lesion, and all cows ate silage twice daily from a feed bunk made of coarse boards. Discharge of the organism from the point source cow certainly contaminated the sideboards and bunk. Whether the organism had gained access through the oral cavity, injury to the oral cavity by wood splinters, or skin puncture from wood slivers on the sideboards could not be ascertained. Lumpy jaw usually is a sporadic infection but, as in the aforementioned herd, can be an epidemic or endemic herd problem. External swelling is merely the tip of the iceberg as established by skull radiographs that conrm severe osteomyelitis with multifocal radiolucencies caused by rarefaction of bone. Because of distortion, malocclusion, or loss of teeth, eating becomes more difcult for severely affected cows. Salivation, reduced appetite, hesitant at- tempts to chew, and dropping food from the mouth may be observed. Draining tracts discharge copious quantities of serous or mucopurulent pus that should be considered infectious to other cows. Diagnosis Absolute diagnosis requires a tissue core biopsy or uid aspirate to identify the causative organism. Discussion of treatment also must allow for the tre- mendous variation in severity of osteomyelitis caused by A. Recently we have also been injecting antibiotic-coated (penicillin or eryth- romycin) beads into the lesion. Long-term antibiotic therapy has resulted in a surprising cure in a few ad- vanced cases. Surgery has been suggested and still is used by some as treatment for lumpy jaw of the maxillae. Surgical debulking or removal of large pyogranulomas project- ing from the skin of advanced cases may reduce the size of the lesion. In addition, the affected bone may be further compromised or fractured if overzealous debridement and curettage are performed. Loose teeth may require extraction, and stulous tracts may be ushed with iodine solution as ancillary aids. Ironically when this same un- Each of these major types may be further subdivided into treated cow eventually becomes ill as the lesion enlarges, subtypes. Therefore other treatments will need to usually occurs during the summer and fall, but one large be considered. In one comparative study, erythromycin epidemic developed during the late fall and early winter was active against A. Therefore cases to occur in the summer and fall is suggestive of an erythromycin may be a good choice. When epidemics occur, morbidity fed at 30 g/450 kg body weight once daily until iodism is high especially in dense populations of animals occurs. Fever may Bluetongue precede the more obvious signs because viremia is short-lived. Obvious problems with whereas sheep suffer a more apparent clinical disease mastitis occur when teat lesions are widespread. These acute signs in sheep progress to crust- naled by a few animals with obvious lesions, physical ing, erosions, and ulcers of the mucous membranes. In examination of other animals on the premises fre- addition, affected sheep are lame, resulting from both quently will reveal small erosions or ulcers resulting coronitis and myositis. Many of these signs cannot be distin- and other ocular anomalies or skeletal malformations. Oral lesions cause infected addition, there are at least nine serotypes of epizootic cows to eat less, thereby affecting production. Lame- hemorrhagic disease viruses a similar orbivirus that ness, if present, further deters appetite and access to primarily affects whitetail deer but can affect cattle caus- feed. Infection in cattle, goats, and possibly other wild ruminants can remain subclinical, but infected Treatment and Control hosts can act as reservoirs of disease. Sheep are the Common sense measures such as milking cows with major species to show clinical signs of disease. Multiple serotypes require specic testing rather in the milking parlor, reducing animal density, attempt- than group antigen testing for best detection. Softened feeds may be more fections in cattle thereby not arousing clinical sus- easily ingested by affected animals. Salivation is com- neutralization antibody tests primarily detected group mon, and swelling of lips may occur. Affected cattle should be kept out of sunlight if sistent infection of immunotolerant fetuses, and con- possible. If sheep reside on the premises, clinical signs may ern states, Great Plains, and West. Failure of laypeople to lubricate im- plements, judge appropriate depth of the oral cavity, or hold the animal s head and neck straight when adminis- tering oral medication are the most common errors. Small punctures may have few acute conse- quences but eventually result in cellulitis or pharyngeal abscesses. Local effects include pain, reluctance or inability to swallow, salivation, and cellulitis. Therefore early clinical Diagnosis signs of pharyngeal injury may be thought to represent Frequently the clinical signs, coupled with a manual failure of response or worsening of the primary condi- examination of the oral cavity to palpate the pharyngeal tion. Pharyngeal trauma is common in dairy cattle and laceration, are sufcient for diagnosis. Severe lacerations also may damage the soft palate or Clinical Signs proximal esophagus. Administered boluses or magnets The chief complaint in cattle with pharyngeal trauma is may still be embedded in the retropharyngeal tissues in anorexia and a suspected abdominal disorder that has some cases. An oral speculum and focal light examina- not responded to medication (including orally admin- tion also may allow a view of pharyngeal injuries. Direct tissue trauma is quickly Endoscopy and radiology are very helpful ancillary complicated by cellulitis or phlegmon of the retropha- aids, especially when a manual examination of the oral ryngeal tissue. Dysphagia may be present in severe cases and may lead to dehydration because of inability to drink.

Moreover buy avana 100 mg without a prescription, in only 5 of 16 pos- sible cases (4 longevity mutations 4 health measures) was healthy life extended discount 50 mg avana fast delivery, and in all of these the unhealthy period of life was also extended 100mg avana sale. In 7 of 16 possible cases, the period of healthy life was actually shortened compared to wild-type and the unhealthy period extended. Research into laboratory rodent health has a much longer history, is considerably easier to assess, and is undoubtedly more relevant to what we might expect in humans. Moreover, what is known about the health consequences of life-extending interventions in mice is considerably more promising than evidence to date from the invertebrates (see below). However, functional metrics are performed (or at least reported) haphazardly and it is never clear whether all investigated metrics have been reported or there was a selection for reporting those that improved. What is needed in rodent aging research is a widely-agreed upon panel of functional indica- 22 S. Although various drugs and supplements have been reported to extend the lives of laboratory rodents at least since the early 1960s [128 132], until recently none had withstood the test of inde- pendent replication. A difcult problem with rodent longevity studies is that the cost and time involved in doing them makes replication rare. However, this is essential, so that scientists do not spend years pursuing dead ends arising from anomalous experimental results. A recent example is the 1999 report that a targeted mutation in the mouse p66shc gene increased lifespan by 30 % [133], a nding that was never independently validated until 15 years later when it could not be replicated [134 ]. Some of the compounds have been tested at several doses and/or initiated at several different ages. One major result is that none of the compounds tested to date has signicantly shortened mouse lifespan. Another rather astonishing result is that so far 5 of the 16 compounds have signicantly extended life in either males alone or in both sexes. Aspirin is a familiar nonsteroidal anti-inammatory drug with anti-thrombotic and antioxidant proper- ties. At the single dose tested, there was a small (8 %) but statistically signicant lengthening of median lifespan in males but no signicant effect in females and no effect on maximum longevity (last surviving 10 %) in either sex [135]. Further investigation indicated that females had less bioactive plasma levels of aspirin and its metabolites. Austad male survival of those getting the drug is 8 10 % greater than controls and at no dose do females appear to be living longer [138 ]. A nonfeminizing estrogen with little or no afnity for the classical estrogen receptors, 17-estradiol has been repeatedly reported to have neuroprotective and antioxidant properties [139]. An interesting aspect of the 17-estradiol studies is that there was a dramatically larger effect (28 % increase in median longevity) at one facility than either of the others (a nonsignicant 3 % at each). The larger effect was not due to longer-lived treated mice at that site but to shorter-lived controls [138]. So this general result should be treated somewhat cautiously until more research is done. Acarbose is not metabolized, it inhibits -glucosidases in the intestines and therefore slows the breakdown of dietary carbohydrates into glucose. The pooled data showed a 5 % increase in median female longevity, which reached statistical signicance (p = 0. However, there was essentially no absolute median difference at one site, a non- signicant 7 % increase at another site, and a marginally signicant (p=0. As no statistical corrections were done for multiple compari- sons, this result, like the female 17-estradiol results, should be interpreted with caution. Surprisingly, maximum longevity of females was increased at all sites in absolute terms, by 9 % overall, a highly signicant (p=0. Recall that these are genetically heterogeneous mice, so the puzzling results where there are large inter-site differences or a marginal result in median longevity but a more sig- nicant result in maximum longevity could be a consequence of that genetic hetero- geneity. Four of 16 drugs tested have shown highly statistically signicant effects on median male longevity, only one of those four (acarbose) showed a statistically signicant increase in median female longev- ity and there is reason to interpret that one result cautiously. Only one of the four drugs again, acarbose increased maximum longevity signicantly, and it did so in both sexes. Measured from the time at which rapamycin feeding had begun though, males lived 28 % longer than controls and females lived 38 % longer than controls. Follow-up studies with mice begun on the same dose of rapamycin at 9 months of age found a highly signicant 10 % increase in median lifespan in males and an 18 % increase in females as well as 16 and 13 % increases in maximum longevity, respectively. On top of these improvements in mouse models of various human diseases, rapamycin also improves a number of mouse health indicators. In sum, rapamycin administered to mice increases longevity, prevents or delays many diseases, and preserves many aspects of health. Are any of these side- effects severe enough to eliminate it from consideration as a potential senescence- retarding intervention in humans? Because it has been in clinical use for years already, we know quite a bit about rapamycin s side-effects in people with various serious diseases. However because it is typically used in combination with other drugs and never given to completely healthy people, we know little about its side- effects in healthy people. However, in a genetically heterogeneous mouse stock, these effects were seen in young male mice during the rst 6 weeks of rapamycin treatment but were substantially diminished and even reversed in some cases by 5 months of treatment [168]. So at least in male mice, metabolic changes pro- duced by chronic rapamycin treatment disappear quickly when treatment is halted 26 S. It will be enlightening to see whether these effects also occur in female mice and in both sexes of other species. The use of rapamycin as a component of anti-rejection therapy following organ transplant suggests that if used chronically it may enhance susceptibility of infec- tious diseases. However, it enhances other aspects, and consequently has been termed an immunomodulator rather an immunosuppressant [148, 172]. Chronic enteric rapamycin administration has been found to enhance resistance to pneu- mococcal pneumonia in elderly mice [173], although no such protection and possibly reduced protection was found against West Nile virus [174]. Moreover, a 6 week course of injected rapamycin prior to inuenza vaccination has been found to enhance protection again inuenza in both mice and humans [148, 172]. Therefore, the impact of chronic rapamycin on disease susceptibility in healthy humans is far from clear and should not by itself discourage trials in species other than mice. Where do we go from here if we are serious about ultimately discovering new ways to prolong human health? That means replicating and optimizing successful interventions for both health and longevity in both sexes in other geno- types and other species. That also means evaluating interventions that have not already been approved for human use in other mammal species. Mice, particularly laboratory mice, are not an acceptable stand-in for all mammals. They have dis- played a notable lack of success in predicting therapeutic efcacy in human diseases such as Alzheimer s disease, stroke, or even cancer.