Johan Schioldann’s clarification of his comment in relationship to Samuel Gershon’s comment on Edward Shorter’s comment
Johan Schioldann: History of the Introduction of Lithium into Medicine and Psychiatry: Birth of Modern Psychopharmacology 1949
Barry Blackwell’s Review
Receive spleen, make a bed for it when you go to sleep, give it room next to you when you sit down to eat and offer it your arm on your promenades. …Do not confuse sorrow with spleen! The depressed would rejoice if only he could grieve. …At times you are seized by such loathing of and disgust with life that you fervently wish to bring an end to it all. (D. G. Monrad, Prædikener,Aforismer[Sermons, Aphorisms], 1841, 1866 (translated from Danish by J. Schioldann).
There is something unexplainable in depression (Tungsind). A person overcome by grief or full of worry knows why he is grieving or worrying. If a depressed is asked what the reason is, what it is that weighs on him, he will answer: I do notknow, I cannot explain it. Therein lies the depression’s endlessness. …You hardly assume as do many physicians that depression is rooted in the physical, and what is strange to say, nevertheless, physicians are unable to eliminate (hæve) it. (Søren Kierkegaard, Enten-Eller [Either/Or], 1843 (retranslated from Danish by J. Schioldann).
In his comment on Edward Shorter’s comment Sam Gershon wrote that Kraepelin took a very negative view of the Langes’ concept of Recurrent Depression and that his presentations against this work also carried with it a generally negative view of the Langesand because of Kraepelin’s influence on European psychiatry this was a major blow for them.
I wish to make the followings comments:
The Langes were the two brothers Carl and Frederik (Fritz) Lange, Carl Professor of Neuropathology and General Pathology at Copenhagen University, and in private neurology practice, and Fritz Superintendent Psychiatrist at Middelfart Mental Asylum, Funen.
It was in 1886 that Carl Langedelivered to the Danish Medical Society his speech: On periodical depressions and their pathogenesis (Schioldann 2001, 2009, 2011), i.e., the uric acid diathesis, published the same year. He issued a reprint with a postscript in 1895, noting that his observation material had now grown from 7-800 cases in 1886, to about2,000. The work was translated into German by Kurella the following year (1896)and reviewed in Journal of Medical Science in 1897(Anon.).Kurella had already reviewed Fritz Lange’s 1894textbook of psychiatry in the German medical press (1895).He drewspecial attention to Fritz’s description of uric acid diathesis and periodical depression to the effect that his thorough description of “the psychoses in uric acid diathesis, especially the periodical depressions that occur due to this, would be of special interest to the German reader.” Unfortunately, though, he “could not go into further details in the review about these very interesting accounts.” Kurella did not refer to Fritz’s use of “treatment with Carbonaslithicus.” However, Kurella’s enthusiasm was short-lived. Thus, in 1899 Kraepelin in the sixth edition of his seminal psychiatric textbook took Kurella up on thisand with reference to his translationof Carl’s treatise (Lange 1896),strongly questioned if not dismissed his theory outright:
“Lange has described peculiar periodical states of depression with psychic inhibition whose cause he presumes to be of a gouty nature. Going by his description, I cannot like Hecker  doubt that he had milder forms of manic-depressive insanity in mind whose manic episodes he missed. That gout really should play an essential role has been neither demonstrated nor is probable at this time, yet metabolic investigations might perhaps someday bring some clarification of this matter” (translated from German).
Carl Lange considered “periodical depression” to be a clinical entity sui generis, first described by him, and being unrelated to melancholy. He argued that
“…not in a single one of the hundreds of patients I have had the opportunity to monitor is any closer to melancholia now than when his illness first afflicted him, perhaps thirty or forty years before, and not a single one has developed either delusions or hallucinations.”
Delusions and/or hallucinations were main constituents of the classic concept of melancholy.In Lange’s view, “periodical depression is purely and simply an anomaly of mood,” consistent with the redefining in the 1820s of melancholy being a primary disorder of emotions (Berrios 1995).1
According to Lange, states of mania never develop between the periods of depression, which “could place the whole illness under the sphere of the cyclical forms of insanity.”2Hewas well-acquainted with the symptomatology not only of depression,but also of mania.In his famous work on the theory of emotions (Lange 1885), a forerunner of his periodical depression concept (1886), he had even come close to formulating alternating periods of “melankoli” and “mani” as a nosological entity (Falret 1851;Baillarger 1854;Lange 1885;Schioldann 2009,2011):
“Every psychiatrist knows the strongly developed forms which occur as ‘melankoli’ or ‘mani.’ Every doctor, who occupies himself with nervous illnesses, has abundant opportunity to observe the even more instructive mild cases which lie on the border between the insanities proper and such ‘despondencies’ that could be subsumed under concepts such as oddity, morosity, melancholy and so on and so forth. Most frequently depression (‘Nedtrykthed’) is encountered, the picture of sorrow, at times even despair, which often enough results in suicide despite of the clear awareness that there is a complete lack of any psychic motive for the sorrow. Almost as common is the morbid anxiety which is often linked with its close relative, sorrow, but often it also occurs alone. It is a more rare occurrence, of course, that joy is manifested in a morbid way as such; the mere fact that joy appears in an unmotivated way, without cause, as can be easily understood, will usually not be sufficient, not for the layman at any rate, to characterize it as something morbid, and even less to seek the condition changed by medical treatment [sic]; this would usually demand either the happy mood to vent itself in an absolutely careless and uncontrollable manner in the form of a more or less pronounced mania, or that in a striking manner it alternates with periods of depression (‘Nedtrykthed’) and thus leaps to the eye as something abnormal.”
Lange’s emotion treatise had been translated into German by Kurellain 1887 and Kraepelin could well have become acquainted with thisedition as well. It was in 1899 that he formulated hisrevolutionizing concept:Das manisch-depressive Irresein.
Carl believed there to be some kind of connection, direct or indirect, between periodical depression and uric acid diathesis, uric acid in excess having a toxic effect on the brain cells, but
“…although the constant tendency of the urine to deposit uric acid sediment can be considered proof that there is an ample production of it in the organism or its metabolism insufficient – and there is hardly any reason to doubt this – in no way is it certain that uric acid diathesis is the cause of periodical depression, and although there is no doubt that there is in one way or another a relationship between the two phenomena, a priori, this can be assumed to have been of a very different nature.”
His clinical description is masterly:
“As is suggested by the name that I have chosen for it, the illness manifests itself in distinct periods of very varying duration and intensity… In reality, there is no other difference between the condition described here and what is usually described as sorrow other than the latter has a psychological basis which… the depression lacks, or at least does not to a degree adequate fully to account for it… One cannot help getting the impression from these patients that the protoplasm in their brain cells has really congealed so that their molecular transformations, which are basic to mental activity, require an unaccustomed, at times impossible, impulse to occur. This feeling that ‘all has stiffened’ in them results, of course, in the lack of spirits and joie de vivre which is their constant complaint… Sleep is often disturbed, broken by anxious dreams, and at times insomnia becomes a very tormenting symptom…Awakening is then all the more painful as the early morning hours in the predominant number of cases are the most tormenting part of the day. The feeling of misery and anxiety… at these hours reach their highest degree, gradually abating during the day, in particular towards evening to the extent that the condition can be almost completely normalized later in the evening. This morning exacerbation and evening remission are extremely characteristic and very pronounced in well over half of the cases…Appetite is in many cases only moderate.”
Regarding treatment measures, Carl wrote:
“…if we dare only rely on the assumption that states of depression, when they occur in the form and with the course, that I have described here, bear testimony to the presence of uric acid diathesis, and that they must be understood as effects of this diathesis of which the predisposition, as a rule, is inborn, this provides the basis for a rational treatment of the depression, a treatment thatextends somewhat further than the exclusively symptomatic treatment or expectant or restrictive regime with which the mental illnesses usually have to make do. It is certainly true, however, that the rules for the rational treatment so far can only be given in the crudest outline. It is not yet possible to get closer to the matter than to the establishment of this general direction: to counteract the underlying diathesis. This is what we are limited to as long as we do not know anything about the way in which the diathesis affects or harms the nervous system.”
Although not knowing the exact underlying cause of periodical depression, “the treatment,” he added, that “I have already been using for a considerable number of years… has primarily consisted in the battle against the uric acid diathesis.” He did not make explicit mention of lithium, but the alkaline treatment method was implied:“It would be needless to give a special account of the remedies that I have applied in this regard, for I would not be able to communicate anything to you that is not well known to all of you.”
Undeniably, Kraepelin’s negative criticism of Carl Lange’s and thus his brother’s depression theory, and by implication lithium treatment, would certainly have thrown a spanner in their works in German-speaking psychiatry, whereas it received a warmer reception in English and French psychiatry(Haig 1891, 1900; Kahn 1909). The strongest, direct oppositionwas mounted by the Langes’ countrymen, psychiatrists and physicians alike, especially from the physician F. Levison (1894), the psychiatrist Viggo Christiansen (1904) and the rheumatologist E. Faber (1911). The stumbling block, of course, was the erroneous concept of uric acid diathesis.
In 1904 Fritz,in his book Degeneration in Families: Observations in a lunatic Asylum, English edition 1907, expanded on his and Carl’s views on the etiological theories regarding uric acid diathesis and so-called auto-intoxication.
Fritz described four forms of mental degeneracy, among them uratic degeneracy, which he assumed was caused by uric acid diathesis: “I have attempted to pursue this phenomenon in all directions across the realm of insanity, where for a long time, in the form of periodical depressions (Carl Lange), it has had a recognized and indisputable place.” It was on the basis of the doctrine of degeneracy that Fritz explained mental decline in a number of great or famous families that he had encountered, some of whom ending up as patient aristocracies in mental asylums. Some of them, he wrote, had a family history of milder forms of mental illness, characterized by “melancholia,” “exaltation” and “eccentric behavior.” Suicide had been a rather frequent occurrence. Many of their relatives had held high, academic positions, and they enjoyed high social status – Fritz had close contact with many artists and intellectuals in Denmark, of whom some would seek his treatment when in “nervous crises.” Among 28great families he had found 24 cases – uratic degenerates – where with certainty he had been able “to demonstrate” the phenomenon of uric acid diathesis causing auto-intoxication. In this instance he made no mention of treatment aspects, alkaline or otherwise.
This book was gefundenes Fressen for Fritz’s colleague, the much younger Viggo Christiansen, who the same year, 1904, mounted a scathing attack on his and thus Carl’s views. Christiansen was in a prime position to do so in that in 1896 he had completed his doctorate,On the Toxicity of Urine, especially in Insane Patients: an experimental Study.3Christiansen wrote in his review:
“The author [Fritz Lange] has adapted Carl Lange’s postulate of a supposed causal relation between periodical depression and uric acid diathesis, a phenomenon, he claims ‘for a long time has had a recognized and indisputable place.’ However, the real situation is that, apart from a couple of authors, the majority both at home and abroad, who have been studying this question, either deny the connection outright, or although they admit to the possibility of such, state that this is quite unproven.”
Christiansen would have been au fait with Kraepelin’s dismissal (1899, 1904). He did not shy away from deridingFritz for not having provided any information about his investigation method because
“…has it, as all points towards, been restricted to his purely macroscopic finding of uric acid crystals or tile-colored sediment in the urine, then it is quite an unscientific method which means nothing at all. It must really, to put it mildly, be characterized as a much too primitive investigation method, this walking around (in the asylum) peering into the patients’ chamber pots for in this manner to draw conclusions about what harmful substances are circulating in their blood. And this is inreality what the author has done. The excretion of uric acid in the urine in no way is proof of the presence of uric acid diathesis.”
Christiansen found the book “remarkable” from “the medical point of view,” since
“it is very strange indeed when a doctor thinks he has found the cause of an illness, and this is but one of the forms of manifestation of a whole range of other illnesses for which there exists a rational treatment that the author not with onewordtouches on this for the patients so extremely important point… Also here, a lunatic asylum would be one of the places where a dietary and medicinal treatment could be carried out as consequently as in few other places. It would have been of extremely great interest to learn something about how the results of such a treatment would have turned out.”
Finally, concerning the great families Christiansen could not accept the view that “giftedness of whatever kind, high culture and rare intelligence, or for that matter any high spiritual achievement could be caused by chronic auto-intoxication.” Therefore, with barely veiled irony, he could not help comparing Fritz’s book with a “similar more comprehensive book by the renowned physician Havelock Ellis: A Study of British Genius, 1904, thus published as Christiansen wrote his attack. Also Ellis, he wrote: “has been struck by the relative frequency… with which gout occurs in outstanding people.”
It was not till three years later, in 1907, that Fritz riposted with a 30-page article, Uratic Insanity, published posthumously in the Danish medical press in 1908, three weeks after he had died. Gentlemanly, he had refrained from making any mention of Christiansen though, but the address was clear. He also took the opportunity to address the criticism that had been leveled at Carl, who had died seven years before, in 1900.This article was probably ignored by Lange’s contemporaries, only to fall into oblivion until retrieved by this author (Schioldann 2014).
Fritz Lange opened the article with the announcement that it was rare that new disease entities were included in the Annual Reports from Danish Mental Asylums. However,
“Over the last decade, the Middelfart Asylums in the etiological section of its Annual Report has included uratic insanity as a constant number, although it is not particularly great. However, it has not escaped my attention that the same doubt that in so many ways is being raised concerning this illness is also being raised towards out specifications, and I have, therefore, found it proper with a small casuistic material to substantiate the Asylum’s information and explain its diagnosis.”
Fritz also emphasized that his view of the matter “essentially confirms the previously by the late Carl Lange presented teachings of the periodical depressions”:
“If here and there concerning details exists some divergence between his (Carl’s) and my view and presentation, then this is probably caused by a difference between our areas of work. He based his teaching on a very rich material of more outpatient character, generally milder cases such as they occur in life in general, whereas I have worked with a much more limited material that virtually consisted of patients whose sufferings were of a more intense character. They understandably sought the Mental Asylum (Middelfart) because it was overwhelming for them to carry their sufferings on their own shoulders. It is only a matter of difference in degree, therefore, but not in essence that exists between Carl Lange’s and my material.”
Hewent on to give an account of his observations on patients admitted to Middelfart, “where as a rule only people with a certain social position and importance come,” in accordance with what he wrote in 1904. In these families, he reiterated, there was generally “a rather significant” prevalence of “melancholic and irritable natures” and suicide among them was not rare. The patientswere prone to mood swings: melancholy, exaltation, and phases of normal equilibrium, but with a predominance of melancholy, attacks of depression. The patients themselves, he emphasized, neither understand nor can explain “the occurrence of constantly recurring mood swings.” When not depressed they would often be sanguine and optimistic; when depressed, some of them would become seized by doubt and lose their self-confidence. “The same kind of thoughts, doubts, keeps occurring during the constantly recurrent periods of depressions,” at times accompanied by suicidal thoughts. Fritz included a casuistry of 10patients, seven of whom had been treated with lithium carbonate, to demonstrate “the way that it has appeared to me over time, which I thought I could not disregard.”
Fritz emphasized that he was referring to severe cases with a prolonged course. It was a “striking” experience for him to see the feeling of “relief and liberation” in some of these patients when their depression remitted. He recounted the case of a young woman from his private practice, who shortly after the treatment, not specified by him, had been established, exclaimed: “Oh, it is like coming out from a dark cellar back into daylight again.” In another patient he observed that “an abrupt transition” had affected the man’s brain function particularly strongly and thrown him “into a transitory switch to exaltation, this being much more noticeable than the euphoric lift of mood one usually encounters when the depression remits.”
“As criterion for periodical depression,” Fritz wrote with implicit address to Christiansen: “I shall limit myself exclusively to the excretion of unquestionable uric acid crystals in the urine.” He wished to refrain from making further theoretical considerations of the matter.
The critical moot point was that the Langes used “uroscopic” inspection of the patients’ urine. Thune Jacobsen, Strömgren’s predecessor at Risskov, wrote to him in 1955 how
“In my younger days at Middelfart, Lange used lithium mixture with plenty of water in the treatment of depression caused by uric acid diathesis… As soon as macroscopic investigations revealed sedimentation of uric acid crystals, Lange said to the patient that now the cause of the depression had been found… and that now the patient would recover as long as he drank water and lithium mixture.”
Jacobsen added that “in fact, the patients recovered in many cases.” He had had to examine the crystals microscopically. In many instance, they turned out to be of another kind than uric acid crystals, or it was simply an “amorphous sedimentation” he observed. Intriguingly, he wrote, Lange had
“…especially based his treatment method on self-observations. At times he could feel in a low mood without knowing why – and then suddenly he discovered uric acid crystals in his urine – “hoho” – he told himself – now it was eliminated and then he was relieved and felt happy again, meaning that his hypothesis had proven correct.”4
Still, in his 1908 work Fritz did notfail to exhort his colleagues to prescribe lithium:
“Here in (Middelfart Asylum) lithium salts…are very generally used… In such patients (with periodical depression)it could perhaps be useful to send them out into the world with an explanation of their illness and a prescription for the medicament (‘carbonaslithicus’) which has shown fit and beneficial for them. In fact, I have attempted to do this several times, and I am still trying, but the result has not matched the good intents. In their free and good intervals between the depressions the patients never think of their past illness, and when it hits them again, they are quite constrained and helpless and are not at all able to reason over their own condition. Their faculties are inhibited and paralyzed. For a long time they suffer in silence, and then they seek the help where they have found it before.”
Carl had also emphasized a similar view (to the psychiatrist Steenberg, 1886) that “the treatment ought not be limited to the sick periods, but that also as prophylaxis it is just as important in the healthy periods.”
In retrospect, Fritz’s description of his patients’ psychopathology can leave no doubt they were suffering from manic-depressive illness. As Ib Ostenfeld (1966) was to point out, from the viewpoint of heredity Fritz Lange was on the right track: in these patients, uratic degenerates, there was a confluence of manic-depressive predisposition.
The case files concerning patients treated with lithium in the Middelfart Asylum should be compared with those files which during and after the Lange superintendency carried a diagnosis of melancholy and/or mania, these labels being diagnostic categories, periodical and circularinsanity,that he had described in his psychiatric textbook (1894). Such a study should also address the question whether “uroscopic” screenings were carried out in all patients. Or were only depressed patients with presumed uric acid concrements and gravel treated with lithium, thus paradoxically withholding lithium treatment from manic and depressed patients. In cases of mania, Lange prescribed opium, digitalis, sulphonal and hyoscine, and in melancholy opium.
As mentioned above, Carl did not mention lithium in his depression treatise. However, firm evidence that he did prescribe lithium (carbonate) can be found in an article he published in 1891 on idiopathic pruritus, which he assumed was caused by uric acid diathesis. He prescribed Bicarb. Natr. c. Carb. Lith.In his work from 1897, Contributions to the clinic of uric acid diathesis, which contains 25 case vignettes with a variety of symptoms, including a couple of cases with periodical depression, Carl had included the following lithium prescription:
Bicarb. natrici. 20 Gram.
aa 2 Gram.
1 tablespoon q.i.d.
A similar formula, MixturaGentianaeLithica, was included in the Copenhagen Hospital Formulary, 1913. It would yield a daily dose of 11.86mmol of lithium (equaling 81.83mg; 460mg of lithium carbonate), estimating one tablespoon at 15ml in accordance with the Danish Pharmacopoea.
Final proof that Carlhad made reference to lithium in his 1886 treatise is found in an anonymous letter from an “old medical practitioner” in Ugeskrift for Lægerin 1901. He had been present when Carl presented his treatise: “…Prof. Lange presented his view of the matter as an explanation of his treatment of many people with lithion,etc.….”
C. Flach, one-time Superintendent Psychiatrist at Middelfart, in the 1980s established that Fritz used “dose powders,” the lithium content of which it was not possible to determine. However, some guidance may be found in the Danish Pharmacopoea of 1907, which included carbonas lithicus to be dispensed in doses of 50-300mg several times daily, either as powder or mixture.
Garrod recommended dose ranges of lithium carbonate from one to four grains dissolved in water and repeated two to three times a day (3-12 grains of lithium carbonate daily, i.e., 9-18mmol of lithium) in the 1859edition; in the 1863 and 1876 editions it was broadened to 1-4grains, two to three times daily (3.5 to 26 mmol of lithium daily) -one gram equals ca. 15 grains.Based on Garrod and contemporaneous German pharmacopoeas, Felber (1987, 1996), estimated that Carl’s lithium regime ranged from 8 to 40mmol daily. In the estimate of Amdisen (Johnson, 1984;Amdisen1987), based on Carl’s 1897 prescription it ranged from 5 to 25 mmol daily.As Mogens Schou commented in his preface to Felber (1996), the Lange brothers used lithium carbonate in high enough doses to achieve serum concentrations comparable to those of today.
Carl and Fritz Lange must be considered founding fathers of lithium therapy,the old Danish lithium treatment, a term coined by Strömgren (Johnson 1984). Consecutively from approximately 1874 to 1907, when Fritz died, not only did they prescribe and recommend systematic lithium (carbonate) in the acute treatment of “periodical depression” (“uratic depression”), they were also possibly the first to raise the possibility that continuation therapy may prevent recurrence of a psychiatric condition (Soares and Gershon, 2000). Furthermore, Fritz was possibly also the first who systematically treated hospitalized patients in states of exaltation, some of them undoubtedly,retrospectively, in manic phases, with lithium (at times “a rather vigorous lithium treatment”), although the treatment was paradoxically used for the right reason, as we know now, but back then it was for “the wrong reason”: the association with the die-hard erroneous uric acid diathesis. But recommendations for further investigations into this controversial issue, not only from Carl Lange himself, but Viggo Christiansen and even Kraepelin, were not heeded. Alas.
It was in a meeting in the Medical Society of Copenhagen in 1911, where Carl Lange 25 years before had presented his today classic theory of periodical depression, that the rheumatologist E. Faber ex cathedra with direct reference to the Langes saw fit to deal it its death-blow in Danish medicine:“…the dilapidated ruins of uric acid diathesis should be removed, partly because it is a hindrance to newer and more correct understandings, partly because it also results in useless or even harmful therapy.”
The uric acid diathesis declared dead, the Langes in disrepute, discredited, “the old Danish lithium treatment”fell into complete oblivion – a sad chapter in the history of medicine. Had the Lange brothers’ ingenious observations and treatment recommendation, lithium carbonate, been heeded and further explored, it might have resulted in its introduction into psychiatry about 50years before the Australian, John Cade, made his revolutionizing discovery of lithium’s specific anti-manic effect, which in 1949 ushered in the modern era of psychopharmacology.
1. For comprehensive scholarly accounts of the history and varying conceptual “transformations” and “transvaluations” of melancholy/melancholiaand later depression and their cognates, see the works by Lewis (1934a, 1934b), Starobinski (1960), Klibansky, Saxl and Panopsky (1964) and Jackson (1986). Griesinger introduced the term “psychic depression” (Die psychischenDepressionszustände) in the 1850s as a synonym for melancholy (Jackson 1986) and by 1860 it appeared in medical dictionaries (Berrios 1988, 1995). The term “depressive insanity” (depressiverWahnsinn) was used by Kraepelin in the 1880s (Jackson 1986). “Periodicity” of mental illness was a prevalent concept in contemporary psychiatry. Under the term “periodischePsychosen” Kirn (1878) included “periodical mania,” “periodical melancholy” and “circular insanity” (Lewis 1979). To denote mild forms of “circular insanity,” Kahlbaum (1882) coined the term “Cyclothymie,” a forerunner of Kraepelin’s concept of manic-depressive insanity (1899), which also encompasses, among others, the concept of “foliecirculaire” and “folie à double,”a form coined by, respectively, J.P. Falret (1851) and Baillarger (1854).
2. One of Carl Lange’s patients with “stuporous depression” alternating with “maniacal exaltation,” concurrently with a “considerable amount of uratic sediment,” had made him wonder whether to draw “uratic periodical mania, non-circular forms” to the attention of the “psychiatrist” (Lange 1897). Similarly, he made reference to a colleague, Kragelund (1896), who had published a paper on atypical forms of uric acid diathesis. It contained a case vignette of a womanwho had manifested “unmotivated exaltation with incessant talking and laughter, jumping from theme to the other…At one moment she is incessantly talking, the next lamenting and tearful, unreasonable… to the highest degree…Such a state can last weeks and months and is replaced by an apparently completely normal period.”
3. Christiansen conducted more than 500experiments, injecting rabbits with urine from psychotic patients. He observed that the urotoxicity, that is the convulsant coefficient of urine, was independent of both the patients’ mental state (exaltation, depression, confusion) and their physical state, and that it was due rather to the individuality of the test animals. Not only did he find it to be independent of etiological factors, but also that “the amount of toxins, which are excreted in the urine, is less than under normal conditions”: approximately 50per cent less (Schioldann 2009).
4. A tendency to mood swings was “not rare” in the Lange family. Therefore, raising the intriguing but unanswerable question whether the Langes treated themselves with lithium carbonate.
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May 31, 2018