Methods We conducted two prospective phase 2 trials in which patients with atypical hemolytic–uremic syndrome who were 12 years of age or older received eculizumab for 26 weeks and during long-term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infusion (in trial 2) were recruited. The primary end points included a change in the platelet count (in trial 1) and thrombotic microangiopathy event–free status (no decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation of dialysis) (in trial 2).

Results A total of 37 patients (17 in trial 1 and 20 in trial 2) received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count; in trial 1, the mean increase in the count from baseline to week 26 was 73×10 9 per liter (P. Figure 2 End Points. Panel A shows the change in the platelet count (the primary end point) in trial 1.

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Least-squares mean changes are shown. I bars indicate 95% confidence intervals. Panels B and C show the change from baseline in the estimated glomerular filtration rate (GFR) (the secondary end point) in trials 1 and 2, respectively. In Panel B, the mean (±SE) estimated GFR on day 0 was 22.8±3.8 ml per minute per 1.73 m 2 of body-surface area. In Panel C, the mean (±SE) estimated GFR on day 0 was 30.8±4.2.

Baseline data were obtained from 20 patients, and data are for 20 patients at each time point unless otherwise stated. Mean estimated GFR levels on day 0 were 30.8 (±4.24) ml per minute per 1.73 m 2. Data are shown to 64 weeks; there was no 62-week time point. One patient with end-stage renal disease who was receiving long-term dialysis commenced and continued eculizumab treatment before, during, and after kidney transplantation on day 217.

This patient's renal data were censored on day 217 and during continued eculizumab treatment. Panel D shows the inhibition of complement activity (the secondary end point) in trials 1 and 2. Mean hemolytic activity was based on a validated pharmacodynamic assay that quantified the complement activity in serum by measuring the degree of hemolysis; the measure of hemolysis is the amount of hemoglobin release as determined by means of spectrophotometer. Inhibition of complement activity is indicated by 20% or lower hemolysis. Atypical hemolytic–uremic syndrome is a genetic, chronic, and progressive inflammatory disease that affects patients of all ages. This syndrome is caused by defects in regulation of the complement system.

These defects are inherited, acquired, or both, and they result in chronic, uncontrolled activation of the complement system which leads to platelet, leukocyte, and endothelial-cell activation and systemic thrombotic microangiopathy. Affected patients have a lifelong risk of systemic clinical complications of thrombotic microangiopathy, including damage to multiple organ systems (e.g., the central nervous system, kidneys, heart, and gastrointestinal tract). Although plasma exchange or infusion has been used to manage atypical hemolytic–uremic syndrome and may transiently maintain a normal platelet count and lactate dehydrogenase level in some patients, the underlying complement dysregulation and thrombotic microangiopathic processes are likely to persist. Indeed, end-stage renal disease (ESRD) or death occurs in approximately 33 to 40% of patients during the first clinical manifestation of atypical hemolytic–uremic syndrome. Within 1 year after a diagnosis of this syndrome, up to 65% of patients treated with plasma exchange or infusion sustain permanent renal damage, have progression to ESRD, or die. Among patients with atypical hemolytic–uremic syndrome who undergo kidney transplantation, graft failure is reported in 60 to 90% of patients within 1 year. Combined liver and kidney transplantation may normalize complement regulation in patients with certain genetic defects, but it is associated with substantial morbidity and mortality, including a mortality of 14% in the short term.

Eculizumab (Soliris, Alexion Pharmaceuticals), a terminal complement inhibitor, is a humanized monoclonal antibody that binds with high affinity to the human C5 complement protein and blocks the generation of proinflammatory C5a and C5b-9. It is approved for the treatment of paroxysmal nocturnal hemoglobinuria.

Previous case reports have suggested that eculizumab is effective in atypical hemolytic–uremic syndrome. In two separate 26-week, phase 2 studies with long-term extension phases, we evaluated the efficacy and safety of eculizumab in patients with atypical hemolytic–uremic syndrome and clinical evidence of progressing thrombotic microangiopathy (in trial 1) and in patients with disease of long duration, chronic kidney damage, and prolonged treatment with plasma exchange or infusion (in trial 2). The data from these prospective trials, as well as data from a separate retrospective study (unpublished data), were used by regulatory agencies in the United States, Europe, and other countries for the approval of eculizumab in the treatment of atypical hemolytic–uremic syndrome. Patients At 27 European and North American clinical sites, we enrolled patients with a diagnosis of atypical hemolytic–uremic syndrome who were 12 years of age or older and weighed 40 kg or more. Eligibility criteria differed between the studies ( Figure 1 Screening, Treatment, and Follow-up. ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) was measured at a central laboratory.

HUS denotes hemolytic–uremic syndrome, LDH lactate dehydrogenase, LLN lower limit of the normal range, PE/PI plasma exchange or infusion, STEC Shiga toxin–producing Escherichia coli, TMA thrombotic microangiopathy, and ULN upper limit of the normal range. In trial 1, patients were eligible if they had evidence of progressive thrombotic microangiopathy after four or more sessions of plasma exchange or infusion in the prior week. In trial 2, patients were eligible if they had no decrease in the platelet count of more than 25% for at least 8 weeks before they received the first dose of eculizumab and were being treated with plasma exchange or infusion at least once every 2 weeks but no more than three times per week ( ). Both studies required evidence of hemolysis (e.g., lactate dehydrogenase level at or above the upper limit of the normal range, haptoglobin level below the lower limit of the normal range, or the presence of schistocytes) and impaired renal function (creatinine level at or above the upper limit of the normal range). Identification of complement gene mutations or complement factor H autoantibodies was not required.

Key exclusion criteria for both trials were ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity at or below 5% in plasma, evidence of Shiga toxin–producing Escherichia coli infection, or prior eculizumab exposure. Study Design The studies included several periods: screening (a maximum of 3 days in trial 1 and 2 weeks in trial 2), an 8-week observation period (in trial 2 only), eculizumab treatment (26 weeks and a long-term extension period), and an 8-week follow-up period if eculizumab was discontinued. Patients received the first eculizumab dose 1 to 6 hours after their most recent plasma exchange or infusion session. Eculizumab was administered intravenously at a dose of 900 mg per week for 4 weeks, a dose of 1200 mg 1 week later, and a maintenance dose of 1200 mg every 2 weeks. Patients who received plasma exchange or infusion during the eculizumab treatment period received a supplemental dose of 600 mg before plasma infusion or within 1 hour after the completion of each plasma exchange. All patients received meningococcal vaccination at least 14 days before the initiation of eculizumab treatment or they received prophylactic antibiotic therapy until 2 weeks after vaccination. Study Oversight The studies were designed by all the authors in conjunction with the sponsor (Alexion Pharmaceuticals).

Data were collected by the sponsor in association with Parexel International (an independent clinical research organization) and were analyzed by the sponsor and Pharsight, which performed statistical analyses. The authors, the sponsor, and Pharsight vouch for the completeness and accuracy of the data and analyses and for the fidelity of this report to the study, available at NEJM.org. An independent data and safety monitoring committee reviewed the safety data. The decision to submit the manuscript for publication was made by all the authors and the sponsor, which retains the data. All the authors had access to all analyses, wrote the first draft of the manuscript, and approved the final manuscript. Alexion Pharmaceuticals and Infusion Communications provided medical-writing support.

The studies and informed-consent process were approved by the institutional review board at each center or by an independent ethics committee and were conducted in accordance with the Declaration of Helsinki. All patients, their parents or guardians, or both provided written informed consent. Patients Thirty-seven patients with atypical hemolytic–uremic syndrome were enrolled in the trials ( ). For the 17 patients (16 adults and 1 adolescent) with progressive thrombotic microangiopathy who were enrolled in trial 1, the median interval between diagnosis of atypical hemolytic–uremic syndrome and screening was 9.7 months ( Table 1 Baseline Demographic and Clinical Characteristics in the Intention-to-Treat Population. All patients had substantial renal damage (100% had an estimated GFR of.

Primary End Points In trial 1, eculizumab treatment was associated with a significant absolute increase in the platelet count from baseline to week 26 (mean, 73×10 9 per liter; 95% confidence interval [CI], 40×10 9 per liter to 105×10 9 per liter; P. Thrombotic Microangiopathic Outcomes In trial 1, a total of 15 of the 17 patients (88%) had thrombotic microangiopathy event–free status through week 26, as did 13 patients who were treated for 64 weeks ( ). A total of 15 patients (88%) did not receive plasma exchange or infusion for the entire duration of the study. One patient received five sessions of plasma exchange or infusion without an interruption in eculizumab treatment, and 1 received plasma exchange or infusion after discontinuation of eculizumab and withdrawal from the study because of a protocol violation. Renal Outcomes After discontinuation of plasma exchange or infusion and initiation of eculizumab treatment, there were continuous, time-dependent increases in the estimated GFR from baseline to week 26 (mean increase in trial 1, 32 ml per minute per 1.73 m 2; 95% CI, 14 to 49; P=0.001; mean increase in trial 2, 6 ml per minute per 1.73 m 2; 95% CI, 3 to 9; P.

Health-Related Quality of Life Outcomes Eculizumab was associated with a significant improvement in health-related quality of life. The EQ-5D scores range from 0 to 1, with higher scores indicating a better quality of life. In trial 1, the mean increase in the EQ-5D score at week 26 was 0.32 (95% CI, 0.24 to 0.39; P. Safety Adverse events are listed in Table 3 Serious Adverse Events Considered Possibly, Probably, or Definitely Associated with Eculizumab as Identified by the Investigator (throughout the Median Treatment Duration of 64 Weeks in Trial 1 and 62 Weeks in Trial 2). And Section 9 in the. There were no cases of meningococcal infection or infection-related serious adverse events. All patients were alive at the time of data cutoff.

In trial 1, all patients had at least one serious adverse event; four events were reported as being possibly related to eculizumab, one of which was considered severe (hypertension in a patient with a history of this disorder). In trial 2, a total of 10 patients (50%) had serious adverse events, of whom 2 patients had a total of three serious adverse events that were possibly or probably drug-related (peritonitis, influenza, and vein disorder). One patient had one drug-related serious adverse event and the other patient had two such events. All serious adverse events possibly or probably related to eculizumab resolved without interruption of treatment. No new adverse events were reported after the first 26 weeks of treatment.

Adverse events were similar among patient subgroups, including the 15 patients who had undergone kidney transplantation and were receiving concomitant immunosuppressive therapy. Discussion In both prospective, open-label, phase 2 trials — one involving patients with atypical hemolytic–uremic syndrome and clinical evidence of progressive thrombotic microangiopathy (trial 1) and the other involving patients with a long duration of the syndrome, chronic kidney damage, and prolonged plasma exchange or infusion (trial 2) — eculizumab therapy was associated with significant inhibition of complement-mediated thrombotic microangiopathy as measured by a change in the platelet count (trial 1) and an absence of thrombotic microangiopathic events (trial 2).

Plasma exchange or infusion was discontinued in 88% of patients in trial 1 and in 100% of patients in trial 2. Eculizumab therapy was associated with large and sustained improvements in renal function, and four of five patients who were receiving dialysis at the beginning of the study no longer required it (trial 1). These results showed that treatment with a terminal complement inhibitor improved renal function across patient subgroups, including those with long-standing, substantial kidney damage who had undergone plasma exchange or infusion. Earlier intervention with eculizumab (i.e., a shorter interval between the current clinical manifestation of atypical hemolytic–uremic syndrome and initiation of treatment) was associated with significantly greater improvement in the estimated GFR in both trials. These findings suggest that starting eculizumab treatment earlier may lead to improved clinical outcomes and reversal of organ damage. Eculizumab was also associated with significant improvements in health-related quality of life. Historically, the risk of ESRD or death has been similar among patients with and those without identified complement mutations or complement factor H autoantibodies.

In the present trials, the response to eculizumab therapy was also similar, irrespective of status with respect to these two factors, although the studies were not powered to evaluate differences according to mutation status. This finding lends support to the recommendation that treatment with eculizumab in patients with atypical hemolytic–uremic syndrome be considered without requiring results of complement mutation testing. Treatment with eculizumab during a period of 62 to 64 weeks was not associated with major adverse events in these studies. The safety profile of eculizumab reported here, for patients with atypical hemolytic–uremic syndrome, was generally consistent with that in a study involving patients with paroxysmal nocturnal hemoglobinuria who received treatment for up to 8 years. Infection-related serious adverse events were not observed in our trials. Rates of adverse events remained steady or declined between the initial 26-week period and the extension period.

No new adverse events emerged after the initial 26-week study period. Adverse events were similar among patient subgroups, including patients who had undergone kidney transplantation and were receiving concomitant immunosuppressive therapy. No deaths were reported in either trial. Follow-up of patients is ongoing.

Deviations from approved eculizumab dosing are associated with a risk of clinical complications, including rapid progression to ESRD. Such approaches include limiting eculizumab treatment to a single dose, early discontinuation followed by reinitiation of treatment, and administration of doses at intervals longer than those recommended in the eculizumab prescribing information. Five of 18 patients who missed eculizumab doses in our two prospective trials or a retrospective study had severe subsequent complications of thrombotic microangiopathy. These findings highlight the likelihood of ongoing thrombotic microangiopathy in patients with atypical hemolytic–uremic syndrome and underscore the importance of continued monitoring of patients and sustained treatment. Previous studies have suggested that eculizumab is effective in treating atypical hemolytic–uremic syndrome. To confirm an eculizumab treatment effect in these open-label, single-group trials, pretreatment data were used as within-patient controls.

In both trials, the rate of intervention for thrombotic microangiopathy was significantly lower during the period of eculizumab treatment than during the period before treatment. The data highlight the inadequate efficacy of management with plasma exchange or infusion and confirm the clinically relevant treatment effect of eculizumab on thrombotic microangiopathy and organ outcomes. The results of eculizumab therapy appear to represent a substantial advancement in the treatment of patients who have this severe and life-threatening systemic disease. These two clinical studies suggest that long-term eculizumab treatment is effective in patients with atypical hemolytic–uremic syndrome, with earlier intervention associated with a greater clinical benefit. The data indicate that terminal complement inhibition with eculizumab inhibits complement-mediated thrombotic microangiopathy, decreases the need for thrombotic microangiopathy–related intervention, significantly improves the platelet count and renal function across patient groups, and is associated with substantial kidney recovery and improved clinical outcomes in patients with atypical hemolytic–uremic syndrome. References • 1 Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome.

N Engl J Med 2009;361:1676-1687 • 2 Zipfel PF. Thrombotic microangiopathies: new insights and new challenges. Curr Opinion Nephrol Hypertens 2010;4:372-378 • 3 Zipfel PF, Skerka C. Complement regulators and inhibitory proteins. Nat Rev Immunol 2009;9:729-740 • 4 Heinen S, Pluthero FG, van Eimeren VF, Quaggin SE, Licht C. Monitoring and modeling treatment of atypical hemolytic uremic syndrome. Mol Immunol 2013;54:84-88 • 5 Licht C, Pluthero FG, Ling L, et al.

Platelet-associated complement factor H in healthy persons and patients with atypical HUS. Blood 2009;114:4538-4545 • 6 Benz K, Amann K. Thrombotic microangiography: new insights. Curr Opin Nephrol Hypertens 2010;19:242-247 • 7 Caprioli J, Noris M, Brioshi S, et al. Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome.

Blood 2006;108:1267-1279 • 8 Noris M, Caprioli J, Bresin E, et al. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol 2010;5:1844-1859 • 9 Loirat C, Fremeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis 2011;6:60-60 • 10 Loirat C, Garnier A, Sellier-Leclerc AL, Kwon T. Plasmatherapy in atypical hemolytic uremic syndrome. Semin Thromb Hemost 2010;36:673-681.

Contents • • • • • • • • • • • • • • • • • • • • • • • • • Historical and literary background [ ] A number of historical events inspired Voltaire to write Candide, most notably the publication of Leibniz's ', a short metaphysical treatise, the, and the. Both of the latter catastrophes are frequently referred to in Candide and are cited by scholars as reasons for its composition. The 1755 Lisbon earthquake,, and resulting fires of, had a strong influence on theologians of the day and on Voltaire, who was himself disillusioned by them. The earthquake had an especially large effect on the contemporary doctrine of optimism, a philosophical system which implies that such events should not occur. Optimism is founded on the of that says all is for the best because God is a benevolent deity.

This concept is often put into the form, 'all is for the best in the best of all possible worlds' (Fr. Tout est pour le mieux dans le meilleur des mondes possibles). Philosophers had trouble fitting the horrors of this earthquake into the optimist. Voltaire's estate at The conclusion of the novella, in which Candide finally dismisses his tutor's optimism, leaves unresolved what philosophy the protagonist is to accept in its stead. This element of Candide has been written about voluminously, perhaps above all others.

The conclusion is enigmatic and its analysis is contentious. Voltaire develops no formal, systematic philosophy for the characters to adopt. The conclusion of the novel may be thought of not as a philosophical alternative to optimism, but as a prescribed practical outlook (though what it prescribes is in dispute). Many critics have concluded that one minor character or another is portrayed as having the right philosophy.

For instance, a number believe that Martin is treated sympathetically, and that his character holds Voltaire's ideal philosophy—pessimism. Others disagree, citing Voltaire's negative descriptions of Martin's principles and the conclusion of the work in which Martin plays little part. Within debates attempting to decipher the conclusion of Candide lies another primary Candide debate.

This one concerns the degree to which Voltaire was advocating a pessimistic philosophy, by which Candide and his companions give up hope for a better world. Critics argue that the group's reclusion on the farm signifies Candide and his companions' loss of hope for the rest of the human race. This view is to be compared to a reading that presents Voltaire as advocating a philosophy and a precept committing the travellers to improving the world through metaphorical gardening. This debate, and others, focuses on the question of whether or not Voltaire was prescribing passive retreat from society, or active industrious contribution to it. Outside interpretations [ ] Separate from the debate about the text's conclusion is the 'inside/outside' controversy. This argument centers on the matter of whether or not Voltaire was actually prescribing anything. Roy Wolper, professor emeritus of English, argues in a revolutionary 1969 paper that Candide does not necessarily speak for its author; that the work should be viewed as a narrative independent of Voltaire's history; and that its message is entirely (or mostly) inside it.

This point of view, the 'inside', specifically rejects attempts to find Voltaire's 'voice' in the many characters of Candide and his other works. Indeed, writers have seen Voltaire as speaking through at least Candide, Martin, and the Turk. Wolper argues that Candide should be read with a minimum of speculation as to its meaning in Voltaire's personal life. His article ushered in a new era of Voltaire studies, causing many scholars to look at the novel differently. Critics such as Lester Crocker, Henry Stavan, and Vivienne Mylne find too many similarities between Candide's point of view and that of Voltaire to accept the 'inside' view; they support the 'outside' interpretation.

They believe that Candide's final decision is the same as Voltaire's, and see a strong connection between the development of the protagonist and his author. Some scholars who support the 'outside' view also believe that the isolationist philosophy of the Old Turk closely mirrors that of Voltaire. Others see a strong parallel between Candide's gardening at the conclusion and the gardening of the author. Martine Darmon Meyer argues that the 'inside' view fails to see the satirical work in context, and that denying that Candide is primarily a mockery of optimism (a matter of historical context) is a 'very basic betrayal of the text'. Reception [ ].

• Will Durant in The Age of Voltaire: It was published early in 1759 as Candide, ou l'optimisme, purportedly 'translated from the German of Dr. Ralph, with additions found in the pocket of the Doctor when he died at Minden.' The Great Council of Geneva almost at once (March 5) ordered it to be burned.

Of course Voltaire denied his authorship: 'people must have lost their senses,' he wrote to a friendly pastor in Geneva, 'to attribute to me that pack of nonsense. I have, thank God, better occupations.' But France was unanimous: no other man could have written Candide. Here was that deceptively simple, smoothly flowing, lightly prancing, impishly ironic prose that only he could write; here and there a little obscenity, a little scatology; everywhere a playful, darting, lethal irreverence; if the style is the man, this had to be Voltaire.

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54 • ^ Aldridge (1975), p. 260 • Waldinger (1987), p. Ix • Wade (1959b), p. 88 • ^ Radner & Radner (1998), pp. 669–686 • Mason (1992), p. 4 • Wade (1959b), p. 93 • Wade (1959b), pp.

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1 • Aldridge (1975), pp. 251–254, 361 • Leister (1985), p. 29 • Bottiglia (1951), pp. 723–724 • Bottiglia (1951), p. 726 • Leister (1985), p.

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Xiii • ^ Mason (1992), pp. 13–15 • Will Durant (1965). The Story of Civilization Volume 9:The Age of Voltaire.

• Mason (1992), ch. 3 • ^ Haight (1970), p. 33 • Hobbs (1930), p. 190 • Bowerman (1931), p. 20 • Boyer (2002), p.

209 • ^ Bottiglia (1959), p. 247 • Mason (1992), ch. 2 • Britannica (2008) • Readings on Candide (2001), pp. 112–113 • Kamrath (1991), pp. 5–14 • Monty (2006), p.

5 • Mason (1992), pp. 33, 37 • Mason (1992), p. 98 • Monty (2006), p. 151 • ^ Astbury (2005), p. 503 • Clark (1993), pp.

VIII, IX • Peyser (1987), p. 247 • ^ Peyser (1987), p. 248 • Peyser (1987), pp. 249–251 • Morrison (2002), p. 59 • Burns (2000), p.

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