Clinical Pharmacist in Hematology/Stem Cell Transplantation, Indiana University Health, Indianapolis, Indiana
The investigators conducted a validation study of the questionnaire and found low to moderate correlations (0 antimicrobial laundry additive quality zyvox 600mg. Both studies used sample selection methods to minimize selection bias antibiotics price generic zyvox 600 mg otc, and one89 compared baseline characteristics by exposure level course of antibiotics for sinus infection purchase 600mg zyvox free shipping. Only one study88 reported that the dementia diagnosis was assigned blind to the exposure level antibiotics for sinus infection webmd 600mg zyvox fast delivery, but since this type of exposure is not typically discussed as part of the dementia assessment and diagnosis process antibiotic treatment for lyme disease purchase 600mg zyvox with visa, it is assumed here that the diagnosis was assigned blind to exposure in both studies antibiotics for dogs after dog bite buy generic zyvox 600 mg line. Exposure was determined based on self-reported information from a semi-quantitative food frequency questionnaire antibiotic weight loss cheap zyvox 600mg with amex. The validity of the questionnaire used in this study was assessed previously in a subsample of individuals using two 7-day food records as the criterion antibiotic cheat sheet 600 mg zyvox mastercard. The study used sample selection methods to minimize selection bias and it compared baseline characteristics by exposure level. It was not reported whether the dementia diagnosis was assigned blind to the exposure level, but it is unlikely that this type of information would have been discussed during the diagnostic process. Factors considered under this heading include diabetes mellitus, metabolic syndrome, hypertension, hyperlipidemia, and homocysteine. Studies were selected that were longitudinal, had subjects recruited at the population level, and where the incidence of dementia could be compared between subjects with and without diabetes mellitus. Studies that included people with cognitive impairments but not dementia were excluded, as were studies of the prevalence of diabetes in patients with dementia. The review authors reported that the quality for cohort designs was fair to good, with 9 of 11 studies receiving a score of at least 6 points out of 10 using a scale that judged population selection and recruitment, participation at followup, dementia assessment and diagnosis, and data analysis. Six studies relied on medical history or medication use and did not assess blood glucose concentration in all participants. Six studies also assessed diabetes only at baseline, making it likely that a number of subjects who developed incident diabetes were assigned to the non-diabetic group. Studies did not distinguish between type 1 and 2 diabetes, but since all participants were middle-aged or older adults and type 2 diabetes predominates in this age group, almost all were likely to have type 2 diabetes. Data for diabetes duration, hemoglobin A1c, and microvascular complications were not regularly reported. Covariates commonly considered included age, sex, education, and, in some studies, baseline cognitive performance and cardiovascular risk factors. Adjustment for vascular risk factors was examined in five studies; four of the five reported a relative risk or hazard ratio greater than 1 (range in all studies 0. Longitudinal studies in which diabetes and dementia were assessed in late life demonstrated fairly consistent results. A test for heterogeneity did not reveal significant heterogeneity between studies (-squared Q-test statistic 3. The risk for subjects with diagnosed diabetes was not statistically different from the risk for non-diabetics. Limitations of the included studies include 58 variable criteria for diagnosis of diabetes, failure to consider duration of diabetes, and degree of glycemic control. Additional research examining the age of diabetes onset (mid-life versus latelife onset), comorbid conditions (such as vascular risk factors), type of treatment (diet versus oral versus insulin), and the role of hyperinsulinemia on dementia risk is needed. Comparisons are further limited because of sex and ethnic differences between the two studies. Both studies adjusted for important confounders, such as age, sex, education, and baseline cognitive performance. These conclusions are limited by the small number of published studies, differences in the study populations, and the lack of uniform criteria used to diagnose metabolic syndrome. Additional analysis of subsets of risk factors included in metabolic syndrome may provide better insight into the validity of metabolic syndrome as a clinically valid construct for predicting dementia risk. These studies are summarized in Table 14; detailed evidence tables are provided in Appendix B. Seven studies were derived from community cohorts in the United States, of which two dealt specifically with subjects of Japanese descent. Two other studies103,109 did check for interactions between antihypertensive medications and hypertension and stated that the change to reported results was minimal. The Religious Orders Study108 followed a cohort of retired catholic clergy and used blood pressure as a continuous variable. These two populations, however, were followed for a considerably longer period of time than the other cohorts. Three of the studies used cholesterol measured in mid-life, one used the average of multiple cholesterol measurements over 30 years, and four used cholesterol measured in later life; for this reason, the studies were considered too heterogeneous to combine in a single analysis. If mid-life but not late-life cholesterol is related to increased risk, then averaging cholesterol over decades of life, as was done with the Framingham cohort, would not be expected to show a relationship. Three of the four cohorts analyzed frozen plasma from fasting subjects, which may give a better estimate of bioavailable folate than non-fasting samples. Two studies57,120 compared the highest quartiles of homocysteine in their samples to the lowest quartile, one examined log-transformed homocysteine,119 and one compared those subjects whose homocysteine doubled over 2. Three studies reported adjusted results for baseline homocysteine using approximately the same threshold (> 14 or >15 µmol/L). A test for heterogeneity suggested significant variability among studies (Q statistic = 6. Point estimates for the relative risk varied substantially across studies, from modest (1. However a pooled estimate using a common classification of elevated homocysteine did not reach statistical significance. Homocysteine levels rise with age, renal insufficiency, use of coffee, tobacco, and the sequelae from heavy alcohol use. Differences in the cohorts studied with regard to these factors may have contributed to variable findings, but there were not adequate numbers of studies to evaluate this possibility formally. All participants were 65 years of age at the time of cognitive testing; however, age at baseline ranged from 40 to 45 years old to more than 77 in some studies. Studies were combined for meta-analysis using a fixed-effect model, as the heterogeneity among the four studies was not statistically significant. A funnel plot that included all studies did not reveal significant publication bias. The first study was conducted in a community in Sweden where 1255 participants who were enrolled in the Kungsholmen Project were followed for 9 years. Two of the three studies compared baseline characteristics by weight,125,126 while one examined baseline characteristic only by sex. These conflicting results could be explained by the differences in age in the different study populations. For these reasons, we decided to include the meta-analyses described here in our review. As expected in case-control studies, the cases were demented at baseline and the controls were not demented. Six of the studies were conducted in the United States, six in European countries, and one each in Canada, Australia, and China. The authors did not conduct a structured quality assessment of the studies reported in this systematic review; however the inclusion/exclusion criteria provided a limited indirect assessment of quality. The review did not provide information on the length of followup, followup rates, or the analytical covariates used in the studies. Standard 2 tests using a pvalue of 5 percent were used to examine heterogeneity; results of these analyses showed no significant heterogeneity was present (actual p values were p 0. Studies were combined using fixed-effect meta-analyses since there was no evidence of heterogeneity. Publication bias was not assessed formally, but the authors did attempt to assess for recall bias, a potential major weakness of case-control studies on individuals with dementia. When limiting the analyses to those cases and controls for whom the informant type was the same. Quality ratings of the studies were not provided, but the selection criteria may have increased the likelihood that higher quality studies were included in the review. They also advised that future studies should use medical records to document head injury and should use population-based cohort designs to avoid the limitations associated with case-control studies. Due to the limitations inherent in case-control studies, we supplemented the above-described systematic review46 with a search for cohort studies. This search identified two eligible prospective cohort studies104,142 and one retrospective cohort study. Two of the studies drew samples from the community,104,142 and one drew its sample from military hospitalization records in the early 1940s;143 this latter study included both community residents and institutionalized individuals. One study was conducted in the United States,143 one in Canada,104 and the third in Europe. Two of the studies used sample selection methods to minimize selection bias;104,142 due to the retrospective nature of the third study,143 it only partially met criteria for sample selection methods that minimize selection bias. Only one of the studies143 compared baseline characteristics to assess differences between exposed and unexposed. Only one study143 reported that the cognitive diagnoses were assigned blind to exposure status; the other two did not report this information. Analyses were appropriate and controlled for relevant potential confounders, but none of the studies reported a priori sample size calculations. Several studies used hospitalization for depression as an indicator of clinical depression, and these studies may not be applicable to individuals with milder depression. A test for heterogeneity suggested significant variability between studies that persisted when the analysis was limited to studies using a cohort design (p = 0. The authors conducted stratified analyses for prospective versus retrospective study designs and specific or non-specific exposure and outcome assessments (Table 19). We identified five additional eligible studies involving 4961 subjects published since the beginning of 2005 (Table 20). Two studies were conducted in the United States, one in Canada, one in the United States and Canada, and one in Europe. The significance of such a single assessment for depressive symptoms is uncertain. Two studies150,151 went further and established a clinical history of depression requiring medical attention. All studies adjusted for some important confounders, but other potentially important confounders, such as comorbid psychiatric conditions, were not evaluated. All studies drew samples from the community, five in the United States and one in the Netherlands, and then followed patients from 3 to 17 years. All but one study153 selected samples using methods to minimize selection bias and baseline differences between exposed and unexposed groups. Statin use was determined only at baseline a crude measure of exposure in two studies. Study name Hazard Lower Upper ratio limit limit Arvanitakis 2008 Haag 2009 Li 2004 Rea 2005 Sparks 2008 Zandi 2005 0. Subgroup analysis by length of followup (< 5 years versus 5 years) did not show important differences in summary effect. Exposure information came from self-report and/or inspection of pill bottles, except in the study by Haag et al. It is not known if as much detail was provided when a questionnaire with multiple risk factors was used, as in Lindsay et al. When controlled for current blood pressure, statistical significance was lost, although a significant result remained when the analysis was restricted to a cohort who self-reported hypertension. Antihypertensive use for 0 to 5 years and 5 to 12 years was associated with a non-statistically significant reduced risk. However, the confidence interval was wide and does not exclude a clinically significant difference. Use of antihypertensives for ranges of duration was significant only for use between 1. However, most studies found a decreased risk albeit a statistically non-significant decreased risk with use of antihypertensive medication, suggesting a possible reduction in risk. Our own search of the literature identified four eligible cohort studies published after the systematic review described above. All four studies had community-based populations, with a total of more than 8200 subjects. Two of the papers reported that examining duration of use or a lagging time (to account both for difficulty by cognitively impaired subjects in accurately reporting exposure and for the possible lagging effects of exposure on risk) did not change the results, but the actual hazard ratios for these calculations were not included. In their analysis, benefit was apparent only in those with at least one e4 allele. It is possible that studies that failed to find an association did so for different reasons. For example, it is possible the duration of followup was too brief in Cornelius et al. The most strikingly positive findings involved longer duration of use in relatively younger cohorts. Analyses examining the effect of duration and level of exposure did not explain the heterogeneity. A sensitivity analysis removing one study at a time found that when the study by Breitner et al. Any use is associated with a moderate statistically significant decreased risk, but studies are heterogeneous. The review included 2 cohort studies (1596 subjects) and 10 case-control studies; 10 were from the United States, 1 from European countries, and 1 from Australia. Study quality for cohort designs was fair; one study had limitations because it did not maintain comparable groups and did not report loss to followup. The other cohort study was limited because it did not assemble comparable groups at baseline. Length of followup and level of covariate adjustment ranged from 1 to 16 years, and results were adjusted for education, age, and ethnicity. The duration of estrogen use was not stated in one cohort study and ranged in duration from 2 months to 49 years (average 6. A test for heterogeneity suggested that the studies were not heterogeneous (p > 0. The review authors conducted stratified analyses for cohort versus case-control study designs; results are summarized in Table 24. The authors of the meta-analysis concluded that hormone replacement therapy decreased risk of dementia, but most studies had important methodological limitations. Further limitations included a wide range of different estrogens, presence or absence of progestins, timing of estrogen treatment (perimenopausal versus early or late post-menopausal), and duration of use. Self-reported information on variables related to childhood socioeconomic status was collected when the participants were an average of 75 years old. The sample selection method only partially minimized selection bias because as part of the enrollment criteria participants were required to agree to post-mortem autopsy, which may have resulted in some selection bias. The study did not report comparison of baseline characteristics between those exposed and unexposed. The authors did not report whether the diagnosis was blind to exposure status; however, it is unlikely that details like those used as part of this childhood socioeconomic index would be discussed during the diagnostic process. Because of their close association, education and occupation are considered together here. The nine cohorts included 22,726 subjects; four studies were from the United States, four from European countries, and one from Japan. Exposure was determined by self-report and categorized as high, medium, or low levels of education. The definition of these three levels of education appeared to differ across studies. Studies were combined using both fixed-effect and random-effects models to calculate pooled relative risks. When results from the two approaches differed, only the random-effects models were reported, as they represent more conservative estimates. To assess the potential effect of publication bias on the pooled relative risk, the authors conducted sensitivity analysis using three assumptions: (1) published studies included only half of all studies conducted; (2) the unpublished studies found null associations; and (3) the unpublished studies included as many cases and controls as the average of the published studies. Analyses were not conducted to allow for assessment of a dose-response association. However, when the lowest and medium level education groups were combined, the relative risk decreased compared to the findings from the analysis using just the lowest level education group. Both the funnel plot and the sensitivity analyses assessing extreme assumptions concerning unpublished studies showed that the findings were robust and that no publication bias was evident. One study used a community sample,182 and one used a religious order sample in the United States. The studies used sample selection methods to minimize selection bias; however, one study required that participants agree to brain donation at the time of death, and this may have introduced some selectivity into the sample. It is not clear whether education is a surrogate for other factors such as occupation, baseline intelligence, or socioeconomic status. Two of the cohort studies included in the systematic review discussed above address some of these points. Two of the studies used community samples in the United States,176,184 and three used community samples in Europe. The studies used different scales to categorize occupational characteristics, making it difficult to make direct comparisons. Social engagement as a risk factor was defined by different exposures in the studies, including objective measures such as marital status, living situation, number of people in social network, as well as subjective measures such as feelings of loneliness and perceptions of social support. Although five social engagement studies were identified, the measurement of exposure and reporting of outcomes varied among the studies. Hence, results were not combined to provide a single summary statistic; rather, qualitative descriptions of the studies are provided in what follows.
Hypertensive subjects (defined by direct measurement but not use of antihypertensives) had faster decline in reasoning tests infection control training zyvox 600 mg overnight delivery, while memory taking antibiotics for sinus infection while pregnant buy cheap zyvox 600mg on-line, speed of processing antimicrobial labs discount zyvox 600mg on-line, and global cognition composite scores were not significantly affected antibiotic resistance debate safe zyvox 600 mg. The authors found no meaningful (or statistically significant) interactions between the cognitive training intervention and the effect of hypertension on cognitive decline antibiotic kill curve protocol buy generic zyvox 600 mg on line. If there is a pattern to these isolated positive results antibiotics for sinus infection and uti purchase zyvox 600 mg visa, it is that they tended to be in tests associated with frontal lobe functioning (reasoning antibiotics gram negative order zyvox 600 mg online, working memory antibiotic quick reference cheap zyvox 600mg with mastercard, etc). This is an area of the brain thought to be vulnerable to vascular insults, which could be expected to be more likely in hypertensive subjects. Duration of this substudy was only 1 year, and all subjects were hypertensive at trial initiation. No relationship was noted between blood pressure analyzed as a continuous variable and cognitive decline, defined by a global score from combining multiple tests, over 6 to 15 years. It is possible that individuals with hypertension selectively died prior to inclusion in this cohort, or that the limited variability of blood pressure levels prevented detection of any association. In summary, while multiple cohorts have been examined for an association between hypertension and cognitive decline using various tests, the samples are as heterogeneous as are the outcomes, definitions of hypertension, and results. The strongest results were associated with subjects whose hypertension was untreated and whose cognitive decline was relatively severe. Some studies found results when multiple tests were compared individually with hypertension at baseline, raising the possibility that a positive result could arise by chance. In data not shown this is limited to individuals over the median age of the cohort (> 56 years) at the first visit considered here. We identified one good quality systematic review that examined the relationship between total cholesterol and cognitive impairment and cognitive decline. Two studies examined the relationship between a mild cognitive impairment diagnosis and total cholesterol. Of the studies examining cognitive decline included in the systematic review, only two would have met our inclusion criteria. Our own independent search identified two additional papers (Table 49; detailed evidence tables are provided in Appendix B). There was a trend toward a lower risk of cognitive decline with higher late-life cholesterol in one study,266 but a lack of association in four others. We identified four cohort studies120,238,285,286 and a nested case-control study237 involving 3409 subjects that examined the association between homocysteine and risk of cognitive decline (Table 50). Among the five studies, three were conducted in European communities,237,285,286 and two in U. Three studies237,238,286 used non-fasting homocysteine samples that may not measure bioavailable folate as well as fasting samples. Rather than specifying abnormal homocysteine levels a priori, all studies set thresholds based on population levels. In the nested case-control study, 51 percent of survivors agreed to participate when approached at 10-year followup, and of these, only 68 percent provided blood for analysis. Decline was evaluated as a continuous measure or using different thresholds for decline. The other two studies used multiple cognitive tests to compute a single summary score238 or summary scores for several domains of cognitive function. Analyses of other cognitive outcomes showed inconsistent associations with baseline homocysteine values. The variability in subjects studied, classification of exposure, outcomes measured, and duration of followup may explain the variability in observed associations. However, given the small number of studies and the variability across multiple dimensions, no clear pattern can be determined. In summary, we identified five studies that examined the relationship between baseline homocysteine and cognitive decline. Four of the five studies did not find an association between cognitive decline and homocysteine levels, and two studies found associations using differing definitions of exposure. There is no consistent association between homocysteine levels and cognitive decline. We did not identify any good quality systematic reviews or primary studies that evaluated the association between sleep apnea and risk of cognitive decline. We did not identify any good quality systematic reviews that examined the relationship between weight and cognitive decline. We identified three prospective cohort studies that examined the effects of obesity on cognitive decline. Two of these were conducted in the United States,258,287 while the other was conducted in Australia. There was no a priori calculation of the sample size in any of the studies, but all did control for potential confounders in the analysis. This latter analysis is of greatest relevance to our study question; however, it is important to bear in mind that this is a secondary analysis. In conclusion, all three prospective cohort studies that have examined the association between weight and cognition are inconclusive. A possible explanation for this could be that the effect of weight on cognitive decline is small. It could also be the case that the extremes of weight have an adverse outcome which might be masked by considering weight to be single continuous variable. Future studies are needed to clarify the relationship between weight and cognitive decline and these studies need to consider age at exposure as well as change in weight. Factors considered under this heading include depression, anxiety, and resiliency. We identified 13 cohort studies, involving 32,969 subjects, evaluating the association between depression and categorical outcomes for cognitive impairment. An additional nine studies evaluated the association between depressive symptoms and changes on 26 different measures of cognition analyzed as a continuous measure. Because of the heterogeneity of continuous outcome measures and the similar results to studies using categorical outcomes, these studies will not be discussed in detail. All studies assessed current depressive symptoms using a validated severity measure; two257,296 also assessed antidepressant use at baseline. However, only one study reported an a priori sample size calculation,294 few controlled for psychotropic medication use, and followup rates were low or not reported in over half the studies. Because of the variability in how studies categorized significant depressive symptoms, we did not compute a summary estimate of effect. One study that found no association with depressive symptoms296 found that antidepressant use increased risk. Three of the six studies showed an elevated risk for cognitive decline among those with depressive symptoms at baseline, one showed an elevated risk only for those with persistent depressive symptoms, and two showed no association. The variability in findings is not explained by differences in study population, exposure measurement, or study design. We identified four prospective cohort studies, involving 6297 mid- to late-life adults, examining the association between anxiety and cognitive decline. Subjects with dementia at baseline or either of the two followup assessments were excluded from analyses. A baseline measure of neuroticism was used as a proxy for anxiety, and cognitive outcomes were assessed using 11 different measures. Analyses were adjusted for age, sex, and education level, but not for other psychiatric symptoms. There was no association between the 9-item neuroticism measure and change in cognition for any of the 11 different measures. Analyses were adjusted for age, sex, education, chronic disease count, depressive symptoms, alcohol consumption, and benzodiazepine use. There was no association between anxiety symptoms and cognitive decline for any of the cognitive measures. Only those with baseline anxiety scores and followup (n = 1160, 48 percent) were included in the analyses. There were multiple baseline demographic and clinical differences between those with and without followup, potentially biasing the estimate of association. Analyses were adjusted for age, education, marital status, cognitive function, and vascular risk factors. A sensitivity analysis excluding those with cognitive impairment at baseline showed a stronger association. Cherbuin and colleagues257 followed 2082 cognitively normal adults for 4 years; followup exceeded 80 percent. Anxiety was measured using the Goldberg Anxiety/Depression Scale but a threshold for an abnormal result was not specified. A sample size or power calculation was not reported, but the study likely had low powered to exclude a clinically significant association. In summary, four prospective cohort studies failed to find a consistent association between anxiety symptoms and cognitive decline. One study309 was strengthened by a validated scale for anxiety, measured at multiple time points, but no study used a clinical or criterion-based diagnosis of anxiety disorders. We did not identify any good quality systematic reviews or primary studies that evaluated the association between psychological resiliency and risk of cognitive decline. Prescription and non-prescription drugs considered under this heading include statins, antihypertensives, anti-inflammatories, gonadal steroids, cholinesterase inhibitors, and memantine. Our search identified four cohort studies examining the relationship between statin use and cognitive decline. All studies were conducted in the United States; three drew samples from the community. Three of the four studies reported measures of global cognition, while the fourth312 reported executive function. The fourth study312 recruited a consecutive sample of veterans from primary care settings, with a mean age of 75 years old, but did not screen for dementia. Only one study selected subjects in a manner that minimized selection bias and baseline inequalities between exposed and unexposed groups. Due to incomplete reporting and heterogeneity in study designs, a summary estimate of effect was not calculated. In summary, a limited number of observational studies, some with important methodological limitations, do now show a consistent association between statin use and cognitive decline in older adults. Two studies were identified examining the impact of antihypertensives on cognitive decline (Table 54). Cognitive decline would be expected to be fairly uncommon under these circumstances and definitions of decline. In summary, the limited evidence from observational studies does not support an association between antihypertensive use and lower risk for cognitive decline. Five studies used community cohorts from the United States and one used a cohort from Amsterdam. Three studies restricted analysis to subjects without cognitive impairment at baseline. Cognitive impairment among participants could differentially bias the recollection of exposure. However, a sensitivity analysis eliminating subjects with baseline cognitive scores in the bottom 10 percent was performed and did not show substantially different results. Jonker and colleagues found lowered odds ratio for decline on tests of delayed recall but confidence intervals were wide and included no effect. Only among those using all three were there significant findings: Among e4 carriers, there was maintenance (0. We identified a single good quality systematic review that examined the association between hormone replacement therapy and cognitive decline. Ten studies were from the United States, four from European countries, and three from Canada. Of the eight cohort studies, six were rated as having fair quality and two as poor. The cohort studies included 15,298 subjects ranging in age from 59 to 77 years, with duration of followup ranging from 1. The formulation of estrogen varied in composition, dose, and method of administration. Studies were not combined because more than 40 different tests were used to assess cognitive function. Thirty of these tests were used in a single study, and seven tests were used in more than two studies, but test administration was not always uniform. Verbal memory using the immediate verbal recall test was examined in four studies and showed a benefit of estrogen treatment in one study. Delayed verbal recall was improved by estrogen treatment in two of three studies, while visual memory improved in one of two studies. Attention tasks were divided into complex attention (0 of 3 positive studies) and mental tracking (0 of 3 positive studies). Most of the studies reporting benefit noted an effect of estrogen on attention tasks and involved women with menopausal symptoms. Abstract reasoning was shown to be improved by estrogen treatment in one of two studies, and mental status, as measured by an improved score in a dementia screening examination, was improved in two of five studies. Verbal fluency was reported to be improved in one of four studies, with users of estrogen more fluent in naming than non-users. Our search identified one new observational study published since 2001 (Table 56; a detailed evidence table is provided in Appendix B). In the fully adjusted model which accounted for age, education, and baseline test performance, the authors found no association of estrogen use with cognitive change. In summary, there may be a slight benefit for symptomatic postmenopausal women in tests of verbal memory, vigilance, reasoning, and motor speed, which could be mediated by symptom relief. Available data does not support a consistent benefit of estrogen use in modifying cognitive decline. There is insufficient evidence to determine the optimal formulation of estrogen; the dose, duration, and onset of treatment; or if progestins attenuate the effect of estrogen. We did not identify any systematic reviews or primary studies that evaluated the association between cholinesterase inhibitors and risk of cognitive decline. We did not identify any systematic reviews or primary studies that evaluated the association between memantine and risk of cognitive decline. We identified three eligible cohort studies that examined the association between childhood factors and cognitive decline in later life. One of the studies reported a categorical outcome;321 the other two reported continuous outcomes of cognitive decline. All three of the studies used community samples in the United States, and one of the studies included individuals residing in religious order facilities. One study320 included all participants who completed cognitive testing at a minimum of two time points, so some individuals may have had dementia at baseline. The other two studies173,321 included only individuals who were non-demented at baseline. All of the studies at least partially used sample selection methods to minimize selection bias. All of the studies collected exposure data using self-report of a range of childhood factors; one study also used public records. The studies did not compare baseline characteristics between those exposed and unexposed, but one compared baseline differences by outcome groups. Two studies found no association between early life socioeconomic status or childhood cognitive milieu and cognitive decline in later life. The differences in the sample characteristics and the childhood factors examined among these three studies make drawing conclusions difficult. The authors of the Japanese-American cohort study point to a number of differences between the Japanese and American cultures that may explain their findings. Based on the two studies using predominantly individuals born and raised in the United States, there does not appear to be a strong influence of childhood socioeconomic status or childhood cognitive milieu on cognitive decline in later life. Confounding adjustment Educational level Baseline cognitive status Followup time Results 0. As described above (under Key Question 1), we consider educational and occupational factors as subcategories under a single heading. The studies are summarized in Table 58; detailed evidence tables are provided in Appendix B. Seven of the studies used community samples in the United States,258,323-325,327-329 one used a health maintenance organization sample in the United States,330 three used community samples in Europe,322,326,332 one used a sample in Europe that included participants from both the community and institutions,267 one used a community sample in Australia,331 and one used a religious order sample in the United States. Exposure was determined based on self-reported information about years of education completed; this is a standard and well-accepted method of data collection for this information. One study examined the association between literacy level as measured by a standard neuropsychological test and cognitive decline. In all but one study331 analyses were appropriate and controlled for relevant potential confounders. Among the eight studies that had categorical outcomes, four reported that having fewer years of education was associated with an increased risk of cognitive decline on at least some of the cognitive measures used,258,323-325 and the odds ratio for the fifth study326 was in the same direction but did not reach statistical significance. In the one study that did not find a significant association between education level and cognitive decline, the education level for the sample was quite low. Four studies reported no association between years of education and rate of cognitive decline in their total samples. The sixth study327 reported that after controlling for education, participants with lower literacy were more likely to have faster decline in cognition. The three studies that reported results comparing ethnic subgroups showed few differences across the subgroups. The study by Wilson and colleagues328 showed no differences between whites and African-Americans for the association between level of education and cognitive decline. Manly and colleagues327 reported no significant differences between whites, Hispanic and AfricanAmericans regarding the association between literacy level and rate of cognitive decline. The study by Karlamangla and colleagues329 reported only one difference among multiple ethnic groups. They found that among non-Mexican Hispanic Americans, a greater number of years of education was associated with less cognitive decline over time. This latter study did not control for baseline cognitive performance or age; it also reported many statistical comparisons without adjustment for multiple comparisons.
They appear at precisely the same time in which that weaker type vyrus 987 c3 2v buy zyvox 600 mg on-line, with its desire to rest antibacterial essential oils zyvox 600 mg amex, steps into the foreground: both types belong together and arise from the same causes antibiotics for acne buy zyvox 600mg. For example infection precautions generic 600 mg zyvox amex, an act of compassion is not in the best days of the Romans called either good or evil bacteria kingdom classification buy discount zyvox 600 mg line, either moral or immoral; and even if the act is praised antibiotic 5440 generic 600 mg zyvox free shipping, this praise is still most consistent with a kind of grudging disdain as soon as it is compared with an act which serves to promote the res publica antibiotic resistance questions and answers purchase zyvox 600mg on-line. After the structure of society as a whole appears determined and secure against external dangers antibiotics origin buy discount zyvox 600mg line, it is this fear of the neighbour which creates new perspectives of moral evaluation. Certain strong and powerful drives like the enterprising spirit, daring, vengeance, cunning, rapacity and the desire to dominate, which in the sense of social usefulness not only had to be honoured under names different, of course, from the ones chosen above but also had to be trained and cultivated (because when the whole was in danger they were always needed against its enemies), are now felt as dangerous with increased intensity now, when their proper channels have disappeared and are step by step branded as immoral and given over to vilification. Now the opposite drives and inclinations come to receive moral honours; step by step the herd instinct draws its conclusion. How much or how little that is dangerous to the community, dangerous to equality, lies in an opinion, in a state [Zustand] and affects, in a will, in a talent, that is now the moral perspective: here, too, fear is again the mother of morality. When the highest and strongest drives, erupting passionately, drive the individual far beyond and above the average range of the herd conscience, they destroy the self-confidence of the community, its belief in itself, breaking as it were its spine: consequently it is just these drives which are branded and vilified most. There comes a point in the history of a society that has become pathologically rotten and soft, when it even sides with its attacker, the criminal, and indeed, in a genuine and serious way. Assuming one could completely get rid of the danger, the reason for being afraid, one would have got rid of this morality at the same time: it would no longer be necessary, it would no longer regard itself as necessary any more! Now it must sound harsh and jar on the ear when we repeatedly insist: that which here believes it knows, which here glorifies itself with praise and blame, which calls itself good, is the instinct of the herd animal, man: as such it has come to a breakthrough, preponderance and dominance over other instincts and will continue to do so more and more in line with a growing physiological approximation and assimilation of 150 Beyond Good and Evil which it is a symptom. Morality today in Europe is herd-animal morality: so only, as we understand it, one kind of human morality beside which, before which, after which many others, above all higher moralities are possible or ought to be. It is the image of such leaders which floats before our eyes: dare I say it out loud, you free spirits? These are the heavy distant thoughts and thunderstorms that pass over the firmament of our life. Whoever has once thought these possibilities through to the end knows one form of nausea more than other people do and perhaps also a new task!. What constitutes the painful ecstasy of tragedy is cruelty; what is pleasantly at work in so-called tragic pity, indeed, in basically everything that is sublime right up to the highest, 3 Schiller, Wilhelm Tell Iv. There is a master morality and a slave morality; I add at once, that in all higher and more mixed cultures attempts to mediate between the two moralities also appear, even more often a confusion of the same and mutual misunderstanding, even, on occasion, their harsh juxtaposition indeed, in the same person, within one soul. The moral value-distinctions have either arisen among a ruling section that was pleasurably aware of being different from the ruled, or among the ruled, the slaves and dependents of every degree. The noble man distances himself from men in whom the opposite of such elevated, proud states finds expression: he despises them. Everyone who is cowardly, timid, petty and thinks only of narrow utility is despised; as is the mistrustful person with his unfree glances, the person who abases himself, the dog-like man who lets himself be maltreated, the fawning flatterer, above all, the liar: it is a fundamental belief of all aristocrats that the common people are all liars. It is clear that the moral valuedistinctions everywhere first referred to people, and only afterwards, derivatively and late, were they applied to actions: which is why it is a grave mistake for historians of morality to start from such questions as `Why have acts of compassion been praised? He honours everything which he knows pertains to himself: a morality like this is self-glorification. To the fore is the feeling of richness, of power ready to overflow, the happiness of high tension, the consciousness of wealth which would like to give and share: the noble man, too, helps the unfortunate, but not from compassion, or almost not, but more from an urge produced by the abundance of power. The noble man honours the powerful man in himself, as well as the one who has power over himself and knows when to speak and when to remain silent, who practises severity and harshness on himself with relish and honours everything that is severe and harsh. Assuming that the violated, the oppressed, the suffering, unfree, unsure-of-themselves and tired should moralize: what would their moral valuations have in common? Probably a pessimistic suspicion towards the whole human condition would find expression, perhaps a condemnation of man together with his condition. Conversely, those qualities are stressed and highlighted which serve to ease the existence of the suffering: here compassion, the obliging helping hand, the warm heart, patience, diligence, humility, friendliness are honoured , because here these are the most useful qualities and almost the only means of enduring the pressure of existence. Would it not be the beginning of the discipline of the scientific spirit to allow itself no more convictions? This is probably true: it only remains to ask whether a prior conviction has to exist in order for this discipline to begin, such an imperative and unconditional conviction, indeed, that it sacrifices all others to itself. Is not-wanting-to-be-deceived really less harmful, less dangerous, less calamitous: what do you know, in advance, of the character of existence, to be able to decide whether the greater advantage lies on the side of absolute mistrust or absolute confidence? But in case both should be needed, a great deal of confidence and a great deal of mistrust: where could science find its absolute faith, its conviction on which it rests, that truth is more important than any other thing, even than any other conviction? Precisely this conviction could not have come into being if both truth and untruth were continually to prove themselves useful: as is the case. But what if precisely this becomes more and more unbelievable, when nothing any longer turns out to be divine except for error, blindness and lies and what if God himself turned out to be our oldest lie? Is there any reason to suppose that a Latin could not easily have thought up this reversal of appearances? A fourth question would be whether Schopenhauer with his pessimism, that is, with his problem of the value of existence,5 had to be a German. The event, after which this problem was to be expected with certainty, so that an astronomer of the soul could have calculated the day and hour for it, the decline of faith in the Christian God, the victory of scientific atheism, is a pan-European event in which all peoples should have their share of merit and honour. Hegel, Encyclopedia of Philosophical Sciences (1830 edn), §368 (especially Zusatz). This is where his whole integrity is located: unswerving, straightforward atheism is, quite simply, the precondition for posing his problems, representing, as it does, a victory of the European conscience, won at last and with difficulty, the most momentous act of a two-thousandyear-long discipline in truth which ultimately forbids itself the lie of faith in God. You see what actually conquered the Christian God; Christian morality itself, the concept of truthfulness which was taken more and more seriously, the confessional punctiliousness of Christian conscience, translated and sublimated into scientific conscience, into intellectual rigour at any price. What Schopenhauer himself answered to this question was if you forgive me something precipitate, youthful, just a compromise, a standstill and deadlock in precisely those Christian-ascetic moral perspectives, from which faith had been withdrawn along with faith in God. But he asked the question as a good European, as I have said, and not as a German. The fact that even in Germany, people are pondering and publishing on the problem posed by him albeit belatedly! Or could we count such dilettantes and old maids as the sugary apostle of virginity, Mainlдnder, amongst the true Germans? In the final analysis, a Jew will turn out to be the only true German ( all Jews become sugary when they moralize). And Schopenhauer was a pessimist, I repeat, as a good European and not as a German. But to justify the claim of work to be honoured, existence itself, to which work is simply a painful means, would, above all, have to have somewhat more dignity and value placed on it than appears to have been the case with seriousminded philosophies and religions up till now. What can we find, in the toil and moil of all the millions, other than the drive to exist at any price, the same all-powerful drive which makes stunted plants push their roots into arid rocks! Only those individuals can emerge from this horrifying struggle for existence who are then immediately preoccupied with the fine illusions of artistic culture, so that they do not arrive at that practical pessimism that nature abhors as truly unnatural. Nowadays it is not the man in need of art, but the slave who determines general views: in which capacity he naturally has to label all his circumstances with deceptive names in order to be able to live. Such phantoms as the dignity of man, the dignity of work, are the feeble products of a slavery that hides from itself. These are illfated times when the slave needs such ideas and is stirred up to think about himself and beyond himself! Plutarch says somewhere,3 with ancient Greek instinct, that no youth of noble birth would want to be a Phidias himself when he saw the Zeus in Pisa or a Polyklet when he saw the Hera in Argos: and would have just as little desire to be Anacreon, Philetas or Archilochus, however much he delighted in their poetry. However, when the compelling force of artistic inspiration unfolds in him, he has to create and bow to the necessity of work. His pleased astonishment at beauty did not blind him to its genesis which, like all genesis in nature, seemed to him a powerful necessity, a thrusting towards existence. That same feeling that sees the process of procreation as something shameful, to be hidden, although through it man serves a higher purpose than his individual preservation: that same feeling also veiled the creation of the great works of art, although they inaugurate a higher form of existence, just like that other act inaugurates a new generation. Shame, therefore, seems to be felt where man is just a tool of infinitely greater manifestations of will than he considers himself to be, in his isolated form as individual. We now have the general concept for categorizing the feelings the Greeks had in relation to work and slavery. Both were looked on by them as a necessary disgrace that aroused the feeling of shame, at the same time disgrace and necessity. In this feeling of shame there lurks the unconscious recognition that these conditions are required for the actual goal. In that necessity lies the horrifying, predatory aspect of the Sphinx of nature who, in the glorification of the artistically free life of culture [Kultur], so beautifully presents the torso of a young woman. Culture [Bildung], which is first and foremost a real hunger for art, rests on one terrible premise: but this reveals itself in the nascent feeling of shame. At their expense, through their extra work, that privileged class is to be removed from the struggle for existence, in order to produce and satisfy a new world of necessities. Accordingly, we must learn to identify as a cruel-sounding truth the fact that slavery belongs to the essence of a culture: a truth, granted, that leaves open no doubt about the absolute value of existence. This truth is the vulture which gnaws at the liver of the Promethean promoter of culture. The misery of men living a life of toil has to be increased to make the production of the world of art possible for a small number of Olympian men. If culture were really left to the discretion of a people, if inescapable powers, which are law and restraint to the individual, did not rule, then the glorification of spiritual poverty and the iconoclastic destruction of the claims of art would be more than the revolt of the oppressed masses against drone-like individuals: it would be the cry of compassion tearing down the walls of culture; the urge for justice, for equal sharing of the pain, would swamp all other ideas. But there are also examples of powerful religions fossilizing certain stages of culture over long periods of time, and mowing down, with their merciless sickle, everything that wants to continue to proliferate. For we must not forget one thing: the same cruelty that we found at the heart of every culture also lies at the heart of every powerful religion, and in the nature of power in general, which is always evil; so we shall understand the matter just as well, if a culture breaks down an all too highly raised bulwark of religious claims with the cry for freedom, or at least justice. Every moment devours the preceding one, every birth is the death of countless beings, procreating, living and murdering are all one. Therefore, we may compare the magnificent culture to a victor dripping with blood, who, in his triumphal procession, drags the vanquished along, chained to his carriage as slaves: the latter having been blinded by a charitable power so that, almost crushed by the wheels of the chariot, they still shout, `dignity of work! The enormous social problems of today are engendered by the excessive sensitivity of modern man, not by true and deep pity for that misery; and even if it were true that the Greeks were ruined because they kept slaves, the opposite is even more certain, that we will be destroyed by the lack of slavery: an activity which 4 Goethe, Faust 11 line 11906. What an elevating effect on us is produced by the sight of a medieval serf, whose legal and ethical relationship with his superior was internally sturdy and sensitive, whose narrow existence was profoundly cocooned how elevating and how reproachful! Whoever is unable to think about the configuration of society without melancholy, whoever has learnt to think of it as the continuing, painful birth of those exalted men of culture in whose service everything else has to consume itself, will no longer be deceived by that false gloss the moderns have spread over the origin and meaning of the state. For what can the state mean to us, if not the means of setting the previously described process of society in motion and guaranteeing its unobstructed continuation? However strong the sociable urges of the individual might be, only the iron clamp of the state can force huge masses into such a strong cohesion that the chemical separation of society, with its new pyramidal structure, has to take place. But what is the source of this sudden power of the state, the aim of which lies far beyond the comprehension and egoism of the individual? The Greeks have given us a hint with their instinct for the law of nations that, even at the height of their civilization and humanity, never ceased to shout from lips of iron such phrases as `the defeated belong to the victor, together with his wife and child, goods and blood. Here again we see the degree to which nature, in order to bring society about, uses pitiless inflexibility to forge for herself the cruel tool of the state namely that conqueror with the iron hand who is nothing but the objectification of the instinct indicated. The onlooker feels, from the indefinable greatness and power of such conquerors, that they are just the means of an intention revealing itself through them and yet concealing itself from them. It is as though a magic will emanated from them, so curiously swiftly do weaker powers gravitate to them, so wonderfully do they transform themselves, when that avalanche of violence suddenly swells, and enter into a state of affinity not present till then, enchanted by that creative kernel. One should really assume that a person investigating the emergence of the state would, from then on, seek salvation only at an awestruck distance from it; and where we do not see monuments to its development, devastated lands, ruined towns, savage men, consuming hatred of nations! The state, of ignominious birth, a continually flowing source of toil for most people, frequently the ravishing flame of the human race and yet, a sound that makes us forget ourselves, a battle-cry that has encouraged countless truly heroic acts, perhaps the highest and most revered object for the blind, egoistic mass which wears the strange expression of greatness on its face only at tremendous moments in the life of the state! This urge is so overcharged amongst the Greeks that it continually and repeatedly starts to rage against itself, sinking its teeth into its own flesh. This bloody jealousy of one town for another, one party for another, this murderous greed of those petty wars, the tiger-like triumph over the corpse of the slain enemy, in short, the continual renewal of those Trojan battle-scenes and atrocities which Homer, standing before us as a true Hellene, contemplated with deep relish what does this naпve barbarism of the Greek state indicate, and what will be its excuse at the throne of eternal justice? The state appears before it proudly and calmly: leading the magnificently blossoming woman, Greek society, by the hand. For this Helen, he waged those wars what grey-bearded judge would condemn this5? Now, after states have been founded everywhere, that urge of bellum omnium contra omnes is concentrated, from time to time, into dreadful clouds of war between nations and, as it were, discharges itself in less frequent but all the stronger bolts of thunder and flashes of lightning. But in the intervals, the concentrated effect of that bellum, turned inwards, gives society time to germinate and turn green everywhere, so that it can let the radiant blossoms of genius sprout forth as soon as warmer days come. With regard to the political Hellenic world, I will not remain silent about those present-day phenomena in which I believe I detect dangerous signs of atrophy in the political sphere, equally worrying for art and society. With this idea in their heads, they will promote that policy that offers greatest security to these interests, whilst it is unthinkable that, contrary to their intentions, they should sacrifice themselves to the state purpose, led perhaps by an unconscious instinct, unthinkable because they lack precisely that instinct. All other citizens are in the dark about what nature intends for them with their state instinct, and follow blindly; only those who stand outside this know what they want from the state, and what the state ought to grant them. Therefore it is practically inevitable that such men should win great influence over the state, because they may view it as means, whilst all the rest, under the power of the unconscious intention of the state, are themselves only means to the state purpose. To this end, they first have to cut off and weaken the specifically political impulses as much as possible and, by establishing large state bodies of equal importance with mutual safeguards, make a successful attack on them, and therefore war in general, extremely unlikely: whilst on the other hand they try to wrest the decision over war and peace away from the individual rulers, so that they can then appeal to the egoism of the masses, or their representatives: to do which they must in turn slowly dissolve the monarchical instincts of the people. They carry out this intention through the widest dissemination of the liberal-optimistic world view, which has its roots in the teachings of the French Enlightenment and Revolution i. I cannot help seeing, above all, the effects of the fear of war in the dominant movement of nationalities at the present time, and in the simultaneous spread of universal suffrage, indeed, I cannot help seeing those truly international, homeless, financial recluses as really those whose fear stands behind these movements, who, with their natural lack of state instinct, have learnt to misuse politics as an instrument of the stock exchange, and state and society as an apparatus for their own enrichment. The only countermeasure to the threatened deflection of the state purpose towards money matters from this quarter is war and war again: in the excitement of which at least so much becomes clear, that the state is not founded on fear of the war-demon, as a protective measure for egoistic individuals, but instead produces from within itself an ethical momentum in the love for fatherland and prince, indicating a much loftier designation. If I point to the use of revolutionary ideas in the service of a self-seeking, stateless money aristocracy as a dangerous characteristic of the contemporary political scene, and if, at the same time, I regard the massive spread of liberal optimism as a result of the fact that the modern money economy has fallen into strange hands, and if I view all social evils, including the inevitable decline of the arts, as either sprouting from that root or enmeshed with it: then you will just have to excuse me if I occasionally sing a pжan to war. His silver bow might sound terrifying; but even if he does swoop in like the night,7 he is still Apollo, the just god who consecrates and purifies the state. But first, as at the beginning of the Iliad, he shoots his arrows at mules and dogs. So let it be said that war is as much a necessity for the state as the slave for society: and who can avoid this conclusion if he honestly inquires as to the reasons why Greek artistic perfection has never been achieved again? Whoever considers war, and its uniformed potential, the military profession, in connection with the nature of the state as discussed so far, has to conclude that through war, and in the military profession, we are presented with a type, even perhaps the archetype of the state. The unconscious purpose of the whole movement forces every individual under its yoke, and even among heterogeneous natures produces, as it were, a chemical transformation of their characteristics until they are brought into affinity with that purpose. In the higher castes, it becomes a little clearer what is actually happening with this inner process, namely the creation of the military genius whom we have already met as original founder of the state. I would have thought the war-like man was a means for the military genius and that his work was, again, just a means for the same genius; and that a degree of dignity applies to him, not as absolute man and non-genius, but as means of genius who can even choose his own destruction as a means to the masterpiece which is war, that dignity, then, of being acknowledged as worthy to be a means for genius. The actual aim of the state, the Olympian existence and constantly renewed creation and preparation of the genius, compared with whom everything else is just a tool, aid and facilitator, is discovered here through poetic intuition and described vividly. Plato saw beyond the terribly mutilated Herm of contemporary state life, and still saw something divine inside it. The fact that he did not place genius, in its most general sense, at the head of his perfect state, but only the genius of wisdom and knowledge, excluding the inspired artist entirely from his state, was a rigid consequence of the Socratic judgment on art, which Plato, struggling against himself, adopted as his own. This external, almost accidental gap ought not to prevent us from recognizing, in the total concept of the Platonic state, the wonderfully grand hieroglyph of a profound secret study of the connection between state and genius, eternally needing to be interpreted: in this preface we have said what we believe we have fathomed of this secret script. His dreadful capabilities and those counting as inhuman are perhaps, indeed, the fertile soil from which alone all humanity, in feelings, deeds and works, can grow forth. Thus the Greeks, the most humane people of ancient time, have a trait of cruelty, of tiger-like pleasure in destruction, in them: a trait which is even clearly visible in Alexander the Great, that grotesquely enlarged reflection of the Hellene, and which, in their whole history, and also their mythology, must strike fear into us when we approach them with the emasculated concept of modern humanity. With the same sensation, we observe the bloody and insatiable mutual laceration of two Greek factions, for example in the Corcyrean revolution. Why did the Greek sculptor repeatedly have to represent war and battles with endless repetition, human bodies stretched out, their veins taut with hatred or the arrogance of triumph, the wounded doubled up, the dying in agony? Only into night and horror, into the products of a fantasy used to ghastly things. What earthly existence is reflected in these repellingly dreadful legends about the origins of the gods: a life ruled over by the children of the night alone, by strife, lust, deception, age and death. The Hellenic genius had yet another answer ready to the question `What does a life of combat and victory want? In order to understand it, we must assume that Greek genius acknowledged the existing impulse, terrible as it was, and regarded it as justified: whereas in the Orphic version there lay the thought that a life rooted in such an impulse was not worth living. Combat and the pleasure of victory were acknowledged: and nothing severs the Greek world so sharply from ours as the resultant colouring of individual ethical concepts, for example Eris and envy. No mortal likes her, but the yoke of necessity forces man to honour the heavy burden of this Eris according to the decrees of the Immortals. Black Night gave birth to this one as the older of the two; but Zeus, who reigned on high, placed the other on the roots of the earth and amongst men as a much better one. She drives even the unskilled man to work; and if someone who lacks property sees someone else who is rich, he likewise hurries off to sow and plant and set his house in order; neighbour competes with neighbour striving for prosperity. Even potters harbour grudges against potters, carpenters against carpenters, beggars envy beggars and minstrels envy minstrels. But another ethic, not a Hellenic one, must have inspired them to this: for Aristotle makes no objection to referring these verses to the good Eris. The Greek is envious and does not experience this characteristic as a blemish, but as the effect of a benevolent deity: what a gulf of ethical judgment between him and us! Because he is envious, he feels the envious eye of a god resting on him whenever he has an excessive amount of honour, wealth, fame and fortune, and he fears this envy; in this case, the god warns him of the transitoriness of the human lot, he dreads his good fortune and, sacrificing the best part of it, he prostrates himself before divine envy. This idea does not estrange his gods at all from him: on the contrary, their significance is made manifest, which is that man, whose soul burns with jealousy of every other living thing, never has the right to compete with them. However, the greater and more eminent a Greek man is, the brighter the flame of ambition to erupt from him, consuming everyone who runs with him on the same track. Aristotle once made a list of such hostile contests in the grand style: amongst them is the most striking example of how even a dead man can excite a living man to consuming jealousy. We do not understand the strength of this attack on the national hero of poetry unless we construe the root of the attack to be the immense desire to take the place of the fallen poet and inherit his fame, as later with Plato, too. Every great Hellene passes on the torch of the contest; every great virtue strikes the spark of a new grandeur. Three cases of humans who tried unsuccessfully to compete with the gods, Thamyris and Marsyas in artistic accomplishment and Niobe in philo-progenetiveness. Because with that, the contest would dry up and the permanent basis of life in the Hellenic state would be endangered. That is the kernel of the Hellenic idea of competition: it loathes a monopoly of predominance and fears the dangers of this, it desires, as protective measure against genius a second genius.
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Actually antibiotic resistance new zealand quality zyvox 600 mg, he defends his sick herd well enough antimicrobial jeans 600 mg zyvox amex, this strange shepherd virus mp3 buy zyvox 600 mg with visa, he even defends it against itself and against the wickedness antibiotics for uti with renal failure generic 600mg zyvox amex, deceit antibiotics yom kippur generic zyvox 600mg fast delivery, malice and everything else characteristic of all those who are diseased and sick antimicrobial jewelry discount zyvox 600 mg on-line, all of which smoulders in the herd itself antibiotic injections discount 600mg zyvox free shipping, he carries out a clever antibiotic medication list buy zyvox 600 mg lowest price, hard and secret struggle against anarchy and the ever-present threat of the inner disintegration of the herd, where that most dangerous of blasting and explosive materials, ressentiment, continually piles up. His particular trick, and his prime use, is to detonate this explosive material without blowing up either the herd or the shepherd; if we wanted to sum up the value of the priestly existence in the shortest formula, we would immediately say: the priest is the direction-changer of ressentiment. For every sufferer instinctively looks for a cause of his distress; more exactly, for a culprit, even more precisely for a guilty culprit who is receptive to distress, in short, for a living being upon whom he can release his emotions, actually or in effigy, on some pretext or other: because the release of emotions is the greatest attempt at relief, or should I say, at anaesthetizing on the part of the sufferer, his involuntarily longedfor narcotic against pain of any kind. But the difference is fundamental: in the one case, the attempt is made to prevent further harm being done, in the other case, the attempt is made to anaesthetize a tormenting, secret pain that is becoming unbearable with a more violent emotion of any sort, and at least rid the consciousness of it for the moment, for this, one needs an emotion, the wildest possible emotion and, in order to arouse it, the first available pretext. The sufferers, one and all, are frighteningly willing and inventive in their pretexts for painful emotions; they even enjoy being mistrustful and dwelling on wrongs and imagined slights: they rummage through the bowels of their past and present for obscure, questionable stories that will allow them to wallow in tortured suspicion, and intoxicate themselves with their own poisonous wickedness they rip open the oldest wounds and make themselves bleed to death from scars long-since healed, they make evil-doers out of friend, wife, child and anyone else near to them. That is bold enough, wrong enough: but at least one thing has been achieved by it, the direction of ressentiment is, as I said changed. Just remember the notorious witch-trials: at the time, the most perspicacious and humane judges did not doubt that they were dealing with guilt; the witches themselves did not doubt it, and yet there was no guilt. A strong and well-formed man digests his experiences (including deeds and misdeeds) as he digests his meals, even when he has hard lumps to swallow. It is only suffering itself, the discomfort of the sufferer, that he combats, not its cause, not the actual state of being ill, this must constitute our most fundamental objection to priestly medication. But if we just put ourselves into the only perspective known to the priests for a moment, it is 95 On the Genealogy of Morality hard to stop admiring how much he has seen, sought and found within this perspective. We have every right to call Christianity in particular a large treasure-trove of the most ingenious means of consolation, so much to refresh, soothe and narcotize is piled up inside it, so many of the most dangerous and most daring risks are taken for the purpose, it has been so especially subtle, so refined, so southerly refined in guessing which emotions to stimulate in order to conquer the deep depression, the leaden fatigue and the black melancholy of the physiologically obstructed, at least temporarily. For, to speak generally: with all great religions, the main concern is the fight against a certain weariness and heaviness that has become epidemic. In such a case, an attempt is made every time to fight against the feeling of lethargy on a grand scale; let us briefly 93 Nietzsche read Shakespeare in the Schlegel/Tieck translation. To this end, an amazing amount of human energy has been expended perhaps in vain? The use of various ascetic techniques was thought to culminate in a vision of the divine light. The interpretation placed on these states by those subject to them has always been as fanatically incorrect as possible, this goes without saying: but we should not overlook the tone of the most convinced gratitude resounding in the mere will to such a kind of interpretation. To have remained true in this may perhaps be regarded as the best piece of realism in the three greatest religions otherwise so thoroughly steeped in moralizing. This bridge is not crossed by day or night, age, death, suffering, good work nor evil work. The alleviation consists of completely diverting the interest of the sufferer from the pain, so that constantly an action and yet another action enters consciousness and consequently little room is left for suffering: because this chamber of human consciousness is small! If we look for the beginnings of Christianity in the Roman world, we find associations for mutual support, associations for the poor, the sick, for burials, which have sprouted on the lowest level of that society, where the chief means to counter depression, that of the small pleasure, of mutual do-gooding, was deliberately nurtured, perhaps this was something new then, an actual discovery? Behind every oligarchy the whole of history informs us the lust for tyranny always lurks; every oligarchy constantly quakes at the tension that each individual has to exert in order to remain in control of this desire. They are all concerned with one thing: some kind of excess of feeling, which is used as the most effective anaesthetic for dull, crippling, long-drawn-out pain; that is why the ingenuity of the priests has been practically inexhaustible in thinking out the implications of this one question: `how can one achieve excess of feeling? Why, for our part, should we give in, even by an inch, to their verbal tartuffery? For us psychologists, this would constitute a tartuffery of deed; apart from the fact that it would nauseate us. Actually, a psychologist today shows his good taste, if he shows any at all (others might say: his integrity), by resisting the scandalously overmoralistic language with which practically all modern judgments about men and things are smeared. For we must make no mistake about it: the 101 On the Genealogy of Morality most characteristic feature of modern souls, modern books, is not their lies but the deep-rooted innocence in their moralistic mendaciousness. Let us, think of the comical horror which the Catholic priest Janssen101 aroused with his incredibly down-to-earth and innocuous picture of the German Reformation; what would people do next if someone told the story differently for once, if a real psychologist told us about the real Luther, no longer with the moralistic simplicity of a country pastor, no longer with the sugary, deferential modesty of Protestant historians, but instead with the intrepidity of a Taine, from strength of soul and not from a shrewd indulgence toward strength. The ascetic ideal utilized to produce excess of feelings: if you can remember the last essay, you will be able to extrapolate the essentials of what follows from the meaning compressed in these nine words. To throw the human soul out of joint, plunging it into terror, frosts, fires and raptures to such an extent that it rids itself of all small and petty forms of lethargy, apathy and depression, as though hit by lightning: what paths lead to this goal? Basically, all strong emotions have this capacity, providing they are released suddenly: anger, fear, voluptuousness, revenge, hope, triumph, despair, cruelty; in fact, the ascetic priest has insouciantly taken into his service the whole Johannes Janssen, Geschichte des deutschen Volkes seit dem Mittelalter (Freiburg/Br. However, we have to insist all the more firmly, as fairness demands, that this remedy was applied with a good conscience, that the ascetic priest prescribed it with the utmost faith in its efficacy, indeed its indispensability, often enough nearly collapsing himself at the distress he caused; similarly that the vehement physiological revenge taken by such excesses, perhaps even mental disturbance, is fundamentally not actually inconsistent with the general idea of this type of medication: which did not, as I have already shown, set out to heal diseases but rather to fight the lethargy of depression, to alleviate and anaesthetize it. The main contrivance which the ascetic priest allowed himself to use in order to make the human soul resound with every kind of heartrending and ecstatic music was as everyone knows his utilization of the feeling of guilt. The previous essay indicated the descent of this feeling briefly as a piece of animal-psychology, no more: there we encountered the feeling of guilt in its raw state, as it were. Only in the hands of the priest, this real artist in feelings of guilt, did it take shape and what a shape! Man, suffering from himself in some way, at all events physiologically, rather like an animal imprisoned in a cage, unclear as to why? The unhappy man has heard, has understood; he is like a hen around which a line has been drawn. That great old magician fighting lethargy, the ascetic priest had obviously won, his kingdom had come: already people were no longer making complaints against pain, they thirsted for it; `more pain! Goethe claimed there were only thirty-six tragic situations:105 from this we gather, if we did not know already, that Goethe was not an ascetic priest. That such an excess of feeling as prescribed by the ascetic priest to his patient (under the holiest of names, as goes without saying, and likewise impregnated with the sanctity of his purpose) should in any way have been really of use to any patient, who 104 105 Gospel according to John 18. Likewise, study history: everywhere where the ascetic priest has prevailed with this treatment of the sick, the sickness has increased in depth and breadth at a terrific speed. A shattered nervous system added on to the sickness; and that applied on the largest and smallest scale, with individuals and with masses. Broadly speaking, the ascetic ideal and its sublimely moral cult, this most ingenious, unscrupulous and dangerous systematization of all the methods of emotional excess under the protection of holy intentions, has inscribed itself, in a terrible and unforgettable way, into the whole history of man, and unfortunately not just into his history. The only thing that can be compared with its influence is the specifically Germanic influence: I mean the alcoholic-poisoning of Europe, which has strictly kept pace so far with the political and racial predominance of the Germans ( where they injected their blood, they injected their vice as well). I do not like the New Testament, you have worked that out by now; it almost disturbs me to be so very isolated in my taste regarding this most valued, over-valued work (the taste of two millenia is against me): but it is no use! The Old Testament well, that is something quite different: every respect for the Old Testament! I find in it great men, heroic landscape and something of utmost rarity on earth, the incomparable naпvety of the strong heart; even more, I find a people. Humility and pomposity right next to each other; a garrulousness of feeling that almost stupefies; ostensibly passionate but lacking passion; embarrassing gesticulation; obviously breeding is lacking here. What right have people to make such a fuss about their little failings, like these pious little men do? They have an ambition which makes you laugh: people like that regurgitating their most personal affairs, stupidities, sorrows and lingering worries, as if the in-itself of things were duty-bound to concern itself with all that, people like that never tire of involving God in the most trivial trouble they are in. I do not want to bring to light what the ideal did; rather simply what it means, what it indicates, what lies hidden behind, beneath and within it and what it expresses in a provisional, indistinct way, laden with question marks and misunderstandings. And only in regard to this purpose could I not spare my readers a glimpse of the monstrosity of its effects, and of how calamitous those effects are: to prepare them, as a matter of fact, for the final, terrible aspect that the question of the meaning of this ideal has for me. The ascetic ideal expresses a will: where is the opposing will, in which an opposing ideal might express itself? The ascetic ideal has a goal, this being so general that all the interests of human existence appear petty and narrow when measured against it; it inexorably interprets epochs, peoples, man, all with reference to this one goal, it permits of no other interpretation, no other goal, and rejects, denies, affirms, confirms only with reference to its interpretation ( and was there ever a system of interpretation more fully thought through? But I am told it is not lacking, not only has it fought a long, successful fight with that ideal, but it has already mastered that ideal in all essentials: all our modern science is witness to that, modern science which, as a genuine philosophy of reality, obviously believes only in itself, obviously possesses the courage to be itself, the will to be itself, and has hitherto got by well enough without God, the beyond and the virtues of denial. There are enough worthy and modest workers even amongst the scholars of today, who like their little corner and therefore, because they like being there, are occasionally somewhat presumptuous in making their demand heard that people today ought to be content in general, especially with science there being so much useful work to be done. I do not deny it: I am the last to want to spoil the pleasure of these honest workers in their craft: for I delight in their work. But the fact that nowadays people are working hard in science, and that they are contented workmen, does not at all prove that today, science as a whole has a goal, a will, an ideal, a passion of great faith. The opposite, as I said, is the case: where it is not the most recent manifestation of the ascetic ideal there are too few noble, exceptional cases for the general judgment to be deflected then science today is a hiding place for all kinds of ill-humour, unbelief, gnawing worms, despectio sui,113 bad conscience it is the disquiet of the lack of ideals itself, the suffering from a lack of great love, the discontent over enforced contentedness. The industry of our best scholars, their unreflective diligence, heads smoking night and day, their very mastery of their craft how often does all that mean trying to conceal something from themselves? Everyone in contact with scholars has the experience that they are sometimes wounded to the marrow by a harmless word, we anger our scholarly friends at the very moment when we want to honour them, we make them lose their temper and control simply because we were too coarse to guess who we were actually dealing with, with sufferers who do not want to admit what they are to themselves, with people drugged and dazed who fear only one thing: coming to consciousness. Certainly that was freedom of the mind [des Geistes], with that the termination of the belief in truth was announced. Has a European or a Christian free-thinker [Freigeist] ever strayed into this proposition and 114 115 Gospel according to Luke 1. However, the compulsion towards it, that unconditional will to truth, is faith in the ascetic ideal itself, even if, as an unconscious imperative, make no mistake about it, it is the faith in a metaphysical value, a value as such of truth as vouched for and confirmed by that ideal alone (it stands and falls by that ideal). Science itself now needs a justification (which is not at all to say that there is one for it). On this question, turn to the most ancient and most modern philosophies: all of them lack a consciousness of the extent to which the will to truth itself needs a justification, here is a gap in every philosophy how does it come about? Because the ascetic ideal has so far been master over all philosophy, because truth was set as being, as God, as the highest authority itself, because truth was not allowed to be a problem. Do not come to me with science when I am looking for the natural antagonist to the ascetic ideal, when I ask: `Where is the opposing will in which its opposing ideal expresses itself? Its relationship to the ascetic ideal is certainly not yet inherently antagonistic; indeed, it is much more the case, in general, that it still represents the driving force in the inner evolution of that ideal. Its repugnance and pugnacity are, on closer inspection, directed not at the ideal itself but at its outworks, its apparel and disguise, at the way the ideal temporarily hardens, solidifies, becomes dogmatic science liberates what life is in it by denying what is exoteric in this ideal. Both of them, science and the ascetic ideal, are still on the same foundation I have already explained ; that is to say, both overestimate truth (more correctly: they share the same faith that truth cannot be assessed or criticized), and this makes them both necessarily allies, so that, if they 118 See below, Supplementary material, pp. Artistic servitude in the service of the ascetic ideal is thus the specific form of artistic corruption, unfortunately one of the most common: for nothing is more corruptible than an artist. Look at the epochs in the life of a people where scholars predominated: they are times of exhaustion, often of twilight, of decline, gone are the overflowing energy, the certainty of life, the certainty as to the future. The preponderance of the mandarins never indicates anything good: any more than the rise of democracy, international courts of arbitration instead of wars, equal rights for women, the religion of compassion and everything else that is a symptom of life in decline. These famous victories of the latter: undoubtedly they are victories but over what? Do you really think that, for example, the defeat of theological astronomy meant a defeat of that ideal? Has man perhaps become less in need of a transcendent solution to the riddle of his existence because this existence has since come to look still more arbitrary, loiterer-like, and dispensable in the visible order of things? Since Copernicus, man seems to have been on a downward path, now he seems to be rolling faster and faster away from the centre where to? What is certain is that every sort of transcendentalist since Kant has had a winning hand, they are emancipated from the theologians: what good luck! Likewise: who would blame the agnostics if, as worshippers of the unknown and the secret, they worship the question mark itself as God. All this is ascetic to a high degree; but to an even higher degree it is nihilistic, make no mistake about it! You see a sad, hard but determined gaze, an eye peers out, like a lone explorer at the North Pole (perhaps so as not to peer in? Here there is snow, here life is silenced; the last crows heard here are called `what for? I would vastly prefer to wander through the most sombre, grey, cold mists with those historic nihilists! But why am I talking about courage: one thing only is needful, a hand, an uninhibited, very uninhibited hand. Let us leave these curiosities and complexities of the most modern spirit, which have as many ridiculous as irritating aspects: our problem, indeed, can do without them, the problem of the meaning of the ascetic ideal, what has that to do with yesterday and today! The only reason I have alluded to this is that the ascetic ideal has, for the present, even in the most spiritual sphere, only one type of real enemy and injurer: these are the comedians of this ideal because they arouse mistrust. But this will, this remnant of an ideal, if you believe me, is that ideal itself in its strictest, most spiritual formulation, completely esoteric, totally stripped of externals, and thus not so much its remnant as its kernel. Unconditional, honest atheism ( its air alone is what we breathe, we more spiritual men of the age! The answer is in my Gay Science (section 357):128 `Christian morality itself, the concept of truthfulness which was taken more and more seriously, the confessional punctiliousness of Christian conscience, translated and sublimated into scientific conscience, into intellectual rigour at any price. After Christian truthfulness has drawn one conclusion after another, it will finally draw the strongest conclusion, that against itself; this will, however, happen when it asks itself, `What does all will to truth mean? Other things made him suffer too, in the main he was a sickly animal: but suffering itself was not his problem, instead, the fact that there was no answer to the question he screamed, `Suffering for what? The meaninglessness of suffering, not the suffering, was the curse that has so far blanketed mankind, and the ascetic ideal offered man a meaning! Within it, suffering was interpreted; the enormous emptiness seemed filled; the door was shut on all suicidal nihilism. The interpretation without a doubt brought new suffering with it, deeper, more internal, more poisonous suffering, suffering that gnawed away more intensely at life: it brought all suffering within the perspective of guilt. It is absolutely impossible for us to conceal what was actually expressed by that whole willing that derives its direction from the ascetic ideal: this hatred of the human, and even more of the animalistic, even more of the material, this horror of the senses, of reason itself, this fear of happiness and beauty, this longing to get away from appearance, transience, growth, death, wishing, longing itself all that means, let us dare to grasp it, a will to nothingness, an aversion to life, a rebellion against the most fundamental prerequisites of life, but it is and remains a will! And, to conclude by saying what I said at the beginning: man still prefers to will nothingness, than not will. He who has the power to requite, good with good, evil with evil, and also actually practises requital is, that is to say, grateful and revengeful is called good; he who is powerless and cannot requite counts as bad. Good and bad is for a long time the same thing as noble and base, master and slave. In the community of the good goodness is inherited; it is impossible that a bad man could grow up out of such good soil. If, however, one of the good should do something unworthy of the good, one looks for excuses; one ascribes the guilt to a god, for example, by saying he struck the good man with madness and rendered him blind. Here every other man, whether he be noble or base, counts as inimical, ruthless, cruel, cunning, ready to take advantage. Evil is the characterizing expression for man, indeed for every living being one supposes to exist, for a god, for example; human, divine mean the same thing as diabolical, evil. Signs of goodness, benevolence, sympathy are 123 Supplementary material received fearfully as a trick, a prelude with a dreadful termination, a means of confusing and outwitting, in short as refined wickedness. When this disposition exists in the individual a community can hardly arise, at best the most rudimentary form of community: so that wherever this conception of good and evil reigns the downfall of such individuals, of their tribes and races, is near. Each satisfies the other, inasmuch as each acquires what he values more than the other does. One gives to the other what he wants to have, to be henceforth his own, and in return receives what one oneself desires. Justice is thus requital and exchange under the presupposition of an approximately equal power position: revenge therefore belongs originally within the domain of justice, it is an exchange. Since, in accordance with their intellectual habit, men have forgotten the original purpose of so-called just and fair actions, and especially because children have for millennia been trained to admire and imitate such actions, it has gradually come to appear that a just action is an unegoistic one: but it is on this appearance that the high value accorded it depends; and this high value is, moreover, continually increasing, as all valuations do: for something highly valued is striven for, imitated, multiplied through sacrifice, and grows as the worth of the toil and zeal expended by each individual is added to the worth of the valued thing How little moral would the world appear without forgetfulness! A poet could say that God has placed forgetfulness as a doorkeeper on the threshold of the temple of human dignity. Whether one subjects oneself with effort or gladly and willingly makes no difference, it is enough that one does it. How the tradition has arisen is here a matter of indifference, and has in any event nothing to do with good and evil or with any kind of immanent categorical imperative; it is above all directed at the preservation of a community, a people; every superstitious usage which has arisen on the basis of some chance event mistakenly interpreted enforces a tradition which it is in accordance with custom to follow; for to sever oneself from it is dangerous, and even more injurious to the community than to the individual (because the gods punish the community for misdeeds and for every violation of their privileges and only to that extent punish the individual). Every tradition now continually grows more venerable the farther away its origin lies and the more this origin is forgotten; the respect paid to it increases from generation to generation, the tradition at last becomes holy and evokes awe and reverence; and thus the morality of piety is in any event a much older morality than that which demands unegoistic actions. In conditions obtaining before the existence of the state we kill the creature, be it ape or man, that seeks to deprive us of a fruit of the tree if we happen to be hungry and are making for the tree ourself: as we would still do to the animals even now if we were travelling in inhospitable regions. It is this belief in choice that engenders hatred, revengefulness, deceitfulness, all the degrading our imagination undergoes, while we are far less censorious towards an animal because we regard it as unaccountable. To do injury not from the drive to preservation but as requital is the consequence of a mistaken judgment and therefore likewise innocent. In conditions obtaining before the existence of the state the individual can act harshly and cruelly for the purpose of frightening other creatures: to secure his existence through such fear-inspiring tests of his power. Thus does the man of violence, of power, the original founder of states, act when he subjugates the weaker. His right to do so is the same as the state now relegates to itself; or rather, there exists no right that can prevent this from happening. The ground for any kind of morality can then be prepared only when a greater individual or a collective individuality, for example society, the state, subjugates all other individuals, that is to say draws them out of their isolation and orders them within a collective. Morality is preceded by compulsion, indeed it is for a time itself still compulsion, to which one accommodates oneself for the avoidance of what one regards as unpleasurable. Later it becomes custom, later still voluntary obedience, finally almost instinct: then, like all that has for a long time been habitual and natural, it is associated with pleasure and is now called virtue. A mighty drive of nature has at all times prompted a protest against these phenomena as such; science, insofar as it is, as aforesaid, an imitation of nature, permits itself at least to register a protest against the alleged inexplicability, indeed inapproachability, of the said phenomena. So far, to be sure, it has done so in vain: they are still unexplained, a fact that gives great satisfaction to the above-mentioned votaries of the morally miraculous. Let us therefore venture first to isolate individual drives in the soul of the saint and ascetic and then conclude by thinking of them entwined together. Even if the individual suffers from an arrangement which benefits the whole, even if he languishes under it, perishes by it the custom must be maintained the sacrifice offered up. Such an attitude originates, however, only in those who are not the sacrifice for the latter urges that, in his own case, the individual could be worth more than the many, likewise that present enjoyment, the moment in paradise, is perhaps to be rated higher than an insipid living-on in a painless condition of comfort. The philosophy of the sacrificial beast, however, is always noised abroad too late: and so we continue on with custom and morality [Sittlichkeit]: which latter is nothing other than simply a feeling for the whole content 127 Supplementary material of those customs under which we live and have been raised and raised, indeed, not as an individual, but as a member of the whole, as a cipher in a majority. For they must either combine together to produce an equivalent power or subject themselves to one already possessing this equivalent power (perform services for him in exchange for his protection). The latter proceeding is easily the preferred one, because at bottom it holds two dangerous beings in check: the former through the latter, the latter through considerations of advantage; for the latter derives benefit from treating the subject community with kindness or restraint so that they may feed not only themselves but their master too.
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