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(2/28) Remainder Theorem
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MYTH The British helped the Jews displace the native Arab population of Palestine. FACT Herbert Samuel, a British Jew who served as the first High Commissioner of Palestine, placed restrictions on Jewish immigration âin the âinterests of the present populationâ and the âabsorptive capacityâ of the country.â1 The influx of Jewish settlers was said to force the Arab fellahin (native peasants) from their land. This was when less than a million people lived in an area that now supports more than nine million. The British limited the absorptive capacity of Palestine when, in 1921, Colonial Secretary Winston Churchill severed nearly four-fifths of Palestineâsome thirty-five thousand square milesâto create a new Arab entity, Transjordan. As a consolation prize for the Hejaz and Arabia (which are both now Saudi Arabia) going to the Saud family, Churchill rewarded Sharif Husseinâs son Abdullah for his contribution to the war against Turkey by installing him as Transjordanâs emir. The British went further and placed restrictions on Jewish land purchases in what remained of Palestine. By 1949, the British had allotted 87,500 acres of the 187,500 acres of cultivable land to Arabs and only 4,250 acres to Jews. This contradicted Article 6 of the Mandate which stated that âthe Administration of PalestineâŠshall encourage, in cooperation with the Jewish AgencyâŠclose settlement by Jews on the land, including State lands and waste lands not acquired for public purposes.â2 Ultimately, the British admitted that the argument about the countryâs absorptive capacity was specious. The Peel Commission said, âThe heavy immigration in the years 1933â36 would seem to show that the Jews have been able to enlarge the absorptive capacity of the country for Jews.â3 MYTH The British allowed Jews to flood Palestine while Arab immigration was tightly controlled. FACT The British response to Jewish immigration set a precedent of appeasing the Arabs, which was followed for the duration of the Mandate. The British restricted Jewish immigration while allowing Arabs to enter the country freely. Apparently, London did not feel that a flood of Arab immigrants would affect the countryâs âabsorptive capacity.â During World War I, the Jewish population in Palestine declined because of the war, famine, disease, and expulsion by the Turks. In 1915, approximately 83,000 Jews lived in Palestine among 590,000 Muslim and Christian Arabs. According to the 1922 census, the Jewish population was 83,000, while the Arabs numbered 643,000.4 Thus, the Arab population grew exponentially while that of the Jews stagnated. In the mid-1920s, Jewish immigration to Palestine increased primarily because of anti-Jewish economic legislation in Poland and Washingtonâs imposition of restrictive quotas.5 The record number of immigrants in 1935 (see table) was a response to the growing persecution of Jews in Nazi Germany. The British administration considered this number too large, however, so the Jewish Agency was informed that less than one-third of the quota it asked for would be approved in 1936.6 The British gave in further to Arab demands by announcing in the 1939 White Paper that an independent Arab state would be created within ten years and that Jewish immigration was to be limited to 75,000 for the next five years, after which it was to cease altogether. It also forbade land sales to Jews in 95% of the territory of Palestine. The Arabs, nevertheless, rejected the proposal. Jewish Immigration to Palestine7 1919 1,806 1931 4,075 1920 8,223 1932 12,533 1921 8,294 1933 37,337 1922 8,685 1934 45,267 1923 8,175 1935 66,472 1924 13,892 1936 29,595 1925 34,386 1937 10,629 1926 13,855 1938 14,675 1927 3,034 1939 31,195 1928 2,178 1940 10,643 1929 5,249 1941 4,592 1930 4,944 By contrast, throughout the Mandatory period, Arab immigration was unrestricted. In 1930, the Hope Simpson Commission, sent from London to investigate the 1929 Arab riots, said the British practice of ignoring the uncontrolled illegal Arab immigration from Egypt, Transjordan, and Syria had the effect of displacing the prospective Jewish immigrants.8 The British governor of the Sinai from 1922 to 1936 observed, âThis illegal immigration was not only going on from the Sinai, but also from Transjordan and Syria, and it is very difficult to make a case out for the misery of the Arabs if at the same time their compatriots from adjoining states could not be kept from going in to share that misery.â9 The Peel Commission reported in 1937 that the âshortfall of land isâŠdue less to the amount of land acquired by Jews than to the increase in the Arab population.â10 MYTH The British changed their policy to allow Holocaust survivors to settle in Palestine. FACT The gates of Palestine remained closed for the duration of the war, stranding hundreds of thousands of Jews in Europe, many of whom became victims of Hitlerâs âFinal Solution.â After the war, the British refused to allow the survivors of the Nazi nightmare to find sanctuary in Palestine. On June 6, 1946, President Truman urged the British government to relieve the suffering of the Jews confined to displaced persons camps in Europe by immediately accepting 100,000 Jewish immigrants. Britainâs foreign minister Ernest Bevin replied sarcastically that the United States wanted displaced Jews to immigrate to Palestine âbecause they did not want too many of them in New York.â11 Some Jews reached Palestine, many smuggled in on dilapidated ships organized by the Haganah. Between August 1945 and the establishment of the State of Israel in May 1948, sixty-five âillegalâ immigrant ships, carrying 69,878 people, arrived from European shores. In August 1946, however, the British began to intern those they caught in camps on Cyprus. Approximately 50,000 people were detained in the camps, and 28,000 remained imprisoned when Israel declared independence.12 MYTH As the Jewish population grew, the plight of the Palestinian Arabs worsened. FACT In July 1921, Hasan Shukri, the mayor of Haifa and president of the Muslim National Associations, sent a telegram to the British government in reaction to a delegation of Palestinians that went to London to try to stop the implementation of the Balfour Declaration. Shukri wrote: We are certain that without Jewish immigration and financial assistance there will be no future development of our country as may be judged from the fact that the towns inhabited in part by Jews such as Jerusalem, Jaffa, Haifa, and Tiberias are making steady progress while Nablus, Acre, and Nazareth where no Jews reside are steadily declining.13 The Jewish population increased by 470,000 between World War I and World War II, while the non-Jewish population rose by 588,000.14 The permanent Arab population increased by 120% between 1922 and 1947.15 This rapid growth of the Arab population was a result of several factors. One was immigration from neighboring statesâconstituting 37% of the total immigration to pre-state Israelâby Arabs who wanted to take advantage of the higher standard of living the Jews had made possible.16 The Arab population also grew because of the improved living conditions created by the Jews as they drained malarial swamps and brought improved sanitation and health care to the region. Thus, for example, the Muslim infant mortality rate fell from 201 per thousand in 1925 to 94 per thousand in 1945, and life expectancy rose from 37 years in 1926 to 49 in 1943.17 The Arab population increased the most in cities where large Jewish populations had created new economic opportunities. From 1922â1947, the non-Jewish population increased by 290% in Haifa, 131% in Jerusalem, and 158% in Jaffa. The growth in Arab towns was more modest: 42% in Nablus, 78% in Jenin, and 37% in Bethlehem.18 MYTH Jews stole Arab land. FACT Despite the growth in their population, the Arabs continued to assert they were being displaced. From the beginning of World War I, however, part of Palestineâs land was owned by absentee landlords who lived in Cairo, Damascus, and Beirut. About 80% of the Palestinian Arabs were debt-ridden peasants, semi-nomads, and Bedouins.19 Jews went out of their way to avoid purchasing land in areas where Arabs might be displaced. They sought land that was largely uncultivated, swampy, cheap, andâmost importantâwithout tenants. In 1920, Labor Zionist leader David Ben-Gurion expressed his concern about the Arab fellahin, whom he viewed as âthe most important asset of the native population.â He insisted that âunder no circumstances must we touch land belonging to fellahs or worked by them.â Instead, he advocated helping liberate them from their oppressors. âOnly if a fellah leaves his place of settlement,â Ben-Gurion added, âshould we offer to buy his land, at an appropriate price.â20 Jews only began to purchase cultivated land after buying all the uncultivated territory. Many Arabs were willing to sell because of the migration to coastal towns and because they needed money to invest in the citrus industry.21 When John Hope Simpson arrived in Palestine in May 1930, he observed, âThey [the Jews] paid high prices for the land and, in addition, they paid to certain of the occupants of those lands a considerable amount of money which they were not legally bound to pay.â22 In 1931, Lewis French conducted a survey of landlessness for the British government and offered new plots to any Arabs who had been âdispossessed.â British officials received more than 3,000 applications, of which 80% were ruled invalid by the governmentâs legal adviser because the applicants were not landless Arabs. This left only about 600 landless Arabs, 100 of whom accepted the government land offer.23 In April 1936, a new outbreak of Arab attacks on Jews was instigated by local Palestinian leaders who were later joined by Arab volunteers led by a Syrian guerrilla named Fawzi al-Qawuqji, the commander of the Arab Liberation Army. By November, when the British finally sent a new commission headed by Lord Peel to investigate, 89 Jews had been killed and more than 300 wounded.24 The Peel Commissionâs report found that Arab complaints about Jewish land acquisition were baseless. It pointed out that âmuch of the land now carrying orange groves was sand dunes or swamp and uncultivated when it was purchasedâŠThere was at the time of the earlier sales little evidence that the owners possessed either the resources or training needed to develop the land.â25 Moreover, the Commission found the shortage was âdue less to the amount of land acquired by Jews than to the increase in the Arab population.â The report concluded that the presence of Jews in Palestine, along with the work of the British administration, had resulted in higher wages, an improved standard of living, and ample employment opportunities.26 It is made quite clear to all, both by the map drawn up by the Simpson Commission and by another compiled by the Peel Commission, that the Arabs are as prodigal in selling their land as they are in useless wailing and weeping (emphasis in the original). âTransjordanâs king Abdullah27 Even at the height of the Arab revolt in 1938 (which began in April 1936 with the murder of two Jews by Arabs and the subsequent murder of two Arab workers by members of the Jewish underground28), the British high commissioner to Palestine believed the Arab landowners were complaining about sales to Jews to drive up prices for lands they wished to sell. Many Arab landowners had been so terrorized by Arab rebels they decided to leave Palestine and sell their property to the Jews.29 The Jews paid exorbitant prices to wealthy landowners for small tracts of arid land. âIn 1944, Jews paid between $1,000 and $1,100 per acre in Palestine, mostly for arid or semiarid land; in the same year, rich black soil in Iowa was selling for about $110 per acre.â30 By 1947, Jewish holdings in Palestine amounted to about 463,000 acres. Approximately 45,000 were acquired from the mandatory government, 30,000 were bought from various churches, and 387,500 were purchased from Arabs. Analyses of land purchases from 1880 to 1948 show that 73% of Jewish plots were purchased from large landowners, not poor fellahin.31 Many leaders of the Arab nationalist movement, including members of the Muslim Supreme Council, and the mayors of Gaza, Jerusalem, and s sold land to the Jews. Asâad el-Shuqeiri, a Muslim religious scholar and father of Palestine Liberation Organization chairman Ahmed Shuqeiri, took Jewish money for his land. Even King Abdullah leased land to the Jews.32 MYTH The British helped the Palestinians to live peacefully with the Jews. FACT In 1921, Haj Amin el-Husseini first began to organize fedayeen (âone who sacrifices himselfâ) to terrorize Jews. El-Husseini hoped to duplicate the success of Kemal AtatĂŒrk in Turkey by driving the Jews out of Palestine just as Kemal had driven the invading Greeks from his country.33 Arab radicals gained influence because the British administration was unwilling to take effective action against them until they began a revolt against British rule. Colonel Richard Meinertzhagen, former head of British military intelligence in Cairo, and later chief political officer for Palestine and Syria, wrote in his diary that British officials âincline towards the exclusion of Zionism in Palestine.â The British encouraged the Palestinians to attack the Jews. According to Meinertzhagen, Col. Bertie Harry Waters-Taylor (financial adviser to the military administration in Palestine 1919â23) met with el-Husseini in 1920, a few days before Easter, and told him that âhe had a great opportunity at Easter to show the worldâŠthat Zionism was unpopular not only with the Palestine administration but in Whitehall.â He added that âif disturbances of sufficient violence occurred in Jerusalem at Easter, both General [Louis] Bols [chief administrator in Palestine, 1919â20] and General [Edmund] Allenby [commander of the Egyptian force, 1917â19, then high commissioner of Egypt] would advocate the abandonment of the Jewish Home. Waters-Taylor explained that freedom could only be attained through violence.â34 El-Husseini took the colonelâs advice and instigated a riot. The British withdrew their troops and the Jewish police from Jerusalem, allowing the Arab mob to attack Jews and loot their shops. Because of el-Husseiniâs overt role in instigating the pogrom, the British decided to arrest him. He escaped, however, and was sentenced to ten years in absentia. A year later, some British Arabists convinced High Commissioner Herbert Samuel to pardon el-Husseini and to appoint him Mufti (a cleric in charge of Jerusalemâs Islamic holy places). By contrast, Vladimir Jabotinsky and several followers, who had formed a Jewish defense organization during the unrest, were sentenced to 15 years. They were released a few months later.35 Samuel met with el-Husseini on April 11, 1921, and was assured âthat the influences of his family and himself would be devoted to tranquility.â Three weeks later, riots in Jaffa and elsewhere left forty-three Jews dead.36 El-Husseini consolidated his power and took control of all Muslim religious funds in Palestine. He used his authority to gain control over the mosques, the schools, and the courts. No Arab could reach an influential position without being loyal to the Mufti. His power was so absolute that âno Muslim in Palestine could be born or die without being beholden to Haj Amin.â37 The Muftiâs henchmen also ensured he would have no opposition by systematically killing Palestinians who discussed cooperation with the Jews from rival clans. As the spokesman for Palestinian Arabs, el-Husseini did not ask that Britain grant them independence. On the contrary, in a letter to Churchill in 1921, he demanded that Palestine be reunited with Syria and Transjordan.38 The Arabs found rioting an effective political tool because of the lax British response toward violence against Jews. In handling each riot, the British prevented Jews from protecting themselves but made little effort to prevent the Arabs from attacking them. After each outbreak, a British commission of inquiry would try to establish the cause of the violence. The conclusion was always the same: The Arabs feared being displaced by the Jews. To stop the rioting, the commissions would recommend that restrictions be placed on Jewish immigration. Thus, the Arabs learned they could always stop the influx of Jews by staging riots. This cycle began after a series of riots in May 1921. After failing to protect the Jewish community from Arab mobs, the British appointed the Haycraft Commission to investigate the cause of the violence. Although the panel concluded the Arabs had been the aggressors, it rationalized the cause of the attack: âThe fundamental cause of the riots was a feeling among the Arabs of discontent with, and hostility to, the Jews, due to political and economic causes, and connected with Jewish immigration, and with their conception of Zionist policy.â39 One consequence of the violence was the institution of a temporary ban on Jewish immigration. The Arab fear of being âdisplacedâ or âdominatedâ was an excuse for their attacks on Jewish settlers. Note, too, that these riots were not inspired by nationalistic fervorânationalists would have rebelled against their British overlordsâthey were motivated by economics, the radical Islamic views of the Mufti, and misunderstanding. In 1929, Arab provocateurs convinced the masses that the Jews had designs on the Temple Mount (a tactic still used today to incite violence). A Jewish religious observance at the Western Wall, which forms a part of the Temple Mount, served as a pretext for rioting by Arabs against Jews, which spilled out of Jerusalem into other villages and towns, including Safed and Hebron. Again, the British administration made no effort to prevent the violence, and, after it began, the British did nothing to protect the Jewish population. After six days of mayhem, the British finally brought troops in to quell the disturbance. By this time, most of Hebronâs Jews had fled or been killed. In all, 133 Jews were killed and 399 wounded in the pogroms.40 After the riots, the British ordered an investigation, resulting in the Passfield White Paper. It said the âimmigration, land purchase and settlement policies of the Zionist Organization were already or were likely to become, prejudicial to Arab interests. It understood the mandatory governmentâs obligation to the non-Jewish community to mean that Palestineâs resources must be primarily reserved for the growing Arab economy.â41 This meant it was necessary to restrict Jewish immigration and land purchases. MYTH The Mufti was not a Nazi collaborator. FACT In 1941, Haj Amin al-Husseini, the Mufti of Jerusalem, fled to Germany and met with Adolf Hitler, Heinrich Himmler, Joachim Von Ribbentrop, and other Nazi leaders. He wanted to persuade them to extend the Nazisâ anti-Jewish program to the Arab world. The Mufti sent Hitler fifteen drafts of declarations he wanted Germany and Italy to make concerning the Middle East. One called on the two countries to declare the illegality of the Jewish home in Palestine. He also asked the Axis powers to âaccord to Palestine and to other Arab countries the right to solve the problem of the Jewish elements in Palestine and other Arab countries in accordance with the interest of the Arabs, and by the same method that the question is now being settled in the Axis countries.â42 In November 1941, the Mufti met with Hitler, who told him the Jews were his foremost enemy. The Nazi dictator rebuffed the Muftiâs requests for a declaration in support of the Arabs, however, telling him the time was not right. The Mufti offered Hitler his âthanks for the sympathy which he had always shown for the Arab and especially Palestinian cause, and to which he had given clear expression in his public speeches.â He added, âThe Arabs were Germanyâs natural friends because they had the same enemies as had Germany, namelyâŠthe Jews.â Hitler told the Mufti he opposed the creation of a Jewish state and that Germanyâs objective was destroying the Jewish element in the Arab sphere.43 In 1945, Yugoslavia sought to indict the Mufti as a war criminal for his role in recruiting twenty thousand Muslim volunteers for the SS, who participated in the killing of Jews in Croatia and Hungary. He escaped French detention in 1946, however, and continued his fight against the Jews from Cairo and later Beirut where he died in 1974. MYTH The bombing of the King David Hotel was part of a deliberate terror campaign against civilians. FACT British troops seized the Jewish Agency compound on June 29, 1946, and confiscated large quantities of documents. At about the same time, more than 2,500 Jews from all over Palestine were arrested. A week later, news of a massacre of 40 Jews in a pogrom in Poland reminded the Jews of Palestine how Britainâs restrictive immigration policy had condemned thousands to death. In response to the British provocations, and a desire to demonstrate that the Jewsâ spirit could not be broken, the United Resistance Movement planned to bomb the King David Hotel, which housed the British military command and the Criminal Investigation Division in addition to hotel guests. The Haganah pulled out of the plot and left it up to the Irgun. Irgun leader Menachem Begin stressed his desire to avoid civilian casualties and the plan was to warn the British so they would evacuate the building before it was blown up. Three telephone calls were placed on July 22, 1946, one to the hotel, another to the French Consulate, and a third to the Palestine Post warning that explosives in the King David Hotel would soon be detonated. The call to the hotel was received and ignored. Begin quotes one British official who supposedly refused to evacuate the building, saying, âWe donât take orders from the Jews.â44 As a result, when the bombs exploded, the casualty toll was high: 91 killed and 45 injured. Among the casualties were 15 Jews. Few people in the main part of the hotel were injured.45 For decades, the British denied they had been warned. In 1979, however, a member of the British Parliament provided the testimony of a British officer who heard other officers in the King David Hotel bar joking about a Zionist threat to the headquarters. The officer who overheard the conversation immediately left the hotel and survived.46 In contrast to Arab attacks against Jews, which Arab leaders hailed as heroic actions, the Jewish National Council denounced the bombing of the King David.47 1 Aharon Cohen, Israel and the Arab World, (NY: Funk and Wagnalls, 1970), p. 172 Received: 26 November 2019 Revised: 10 January 2020 Accepted: 19 January 2020 DOI: 10.1111/obr.13005 PEDIATRICS/PHYSIOLOGY Adipokines: A gear shift in puberty DesirĂ©e Nieuwenhuis | NatĂ lia Pujol-Gualdo Amanda J. Kiliaan Department of Anatomy, Radboud university medical center, Donders Institute for Brain, Cognition and Behaviour, Preclinical Imaging Center PRIME, Nijmegen, The Netherlands Correspondence Amanda J. Kiliaan, PhD, Associate Professor, Department of Anatomy, Donders Institute for Brain, Cognition, and Behaviour, Preclinical Imaging Center PRIME, Radboud university medical center, 6500 HB Nijmegen, Geert Grooteplein 21N 6525 EZ Nijmegen, The Netherlands. Email: amanda.kiliaan@radboudumc.nl Funding information Europees Fonds voor Regionale Ontwikkeling (EFRO), Grant/Award Number: BriteN 2016 1 | INTRODUCTION The prevalence of obesity in adolescents and children is increasing in | Ilse A.C. Arnoldussen | Summary In this review, we discuss the role of adipokines in the onset of puberty in children with obesity during adrenarche and gonadarche and provide a clear and detailed overview of the biological processes of two major players, leptin and adiponectin. Adipokines, especially leptin and adiponectin, seem to induce an early onset of puberty in girls and boys with obesity by affecting the hypothalamic-pituitary- gonadal (HPG) axis. Moreover, adipokines and their receptors are expressed in the gonads, suggesting a role in sexual maturation and reproduction. All in all, adipokines may be a clue in understanding mechanisms underlying the onset of puberty in child- hood obesity and puberty onset variability. KEYWORDS adipokines, obesity, puberty 1,2 the age of 5 years were overweight or were with obesity in 2016, and 3 Obesity is defined by an excessive accumulation of white adipose tissue (WAT), and it is often indicated by a body mass index (BMI) 4 above 30. Two main types of adipose tissue were described: WAT and brown adipose tissue (BAT), which differ in morphology and func- 5-7 Ilse A.C. Arnoldussen and Amanda J. Kiliaan contributed equally to this work. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2020 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity Federation Obesity Reviews. 2020;21:e13005. wileyonlinelibrary.com/journal/obr 1 of 10 https://doi.org/10.1111/obr.13005 alarming rates. Specifically, worldwide, 41 million children below this number is expected to increase to 70 million in 2025. obesity is associated with various severe health complications, includ- ing increased risk of diabetes mellitus type 2, hypertension, heart dis- eases, and disturbances in sex hormone levels. 5,6 and mitochondria and plays a role in thermogenesis. Adipocytes in tion. BAT consists of adipocytes containing multiple lipid droplets WAT contain only a few mitochondria and a single lipid droplet. Adipose tissue has several functions including the storage of energy, thermogenesis, and the production and secretion of adipokines Generally, two physiological processes, adrenarche and gonadarche, 11,24 Childhood 5,7,8 a key role in puberty onset. Puberty is known as a period through which the body changes physically, being a physiological process resulting in the maturation of children, i.e. they develop sexual characteristics and obtain reproduc- 9,11 Adipokines are involved in a number of physiological processes including blood pressure, metabo- lism, glucose, and vascular homeostasis and may play amongst others 8-10 (hormones, cytokines, and peptides). tive functions. between obesity and puberty,2,12-23 the biological mechanisms under- lying obesity and puberty onset remain unclear. Hereafter, we review in detail the role of adipokines in the onset of puberty in childhood obesity. Although many studies have shown associations 2 | INITIATION OF PUBERTY PHYSIOLOGICAL PROCESSES IN THE interact to regulate the onset of puberty. During adrenarche, the adrenal cortex secretes steroid hormones (including 2 of 10 NIEUWENHUIS ET AL. androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate (DHEAS), androstenedione, and cortisol), insulin-like growth factor, and growth hormone, which contribute to the pubertal insights on new genetic loci (e.g. melanocortin-4 receptor, mitochon- drial carrier 2, and mitogen-activated protein kinase 13) and on sev- eral pathways that regulate the timing of puberty; however, it partly 34 9,24,25 Both adrenarche and gonadarche are involved in the development growth spurt, body odor, skin oiliness, and skeletal maturation. explains puberty timing variation. Thereby, defining the role of 25 adipokines is of importance in elucidating the variability in puberty as the expression of adipokines is sex-specific and is altered with body composition, adiposity, and during growth spurts. Moreover, adipokines and their receptors are expressed in gonads and several brain regions suggesting involvement in the onset of puberty and sex- ual maturation. Lastly, adipokines interfere in processes regulating timing and duration of puberty, for instance in the HPA and HPG axes which are both key players during adrenarche and gonadarche. Involvement of adipokines in the onset of puberty and specifically in individuals with obesity will be further reviewed in the next 2,24 3 | Puberty onset in girls is assessed using different markers, such as thelarche (breast development), menarche (the start of of pubic hair. pituitary-gonadal (HPG) axis is activated,2,26 and several hormones have been identified to participate in the activation of the HPG axis During gonadarche (Figure 1), the hypothalamic- 2,27 Kisspeptin, neurokinin B, and dynorphin are released by specialized including kisspeptin, neurokinin B, dynorphin, leptin, and ghrelin. 28 key regulator of the pulsatile secretion of gonadotropin releasing neurons, the KNDy neurons in the hypothalamus. Kisspeptin is a 29,30 B stimulates, and dynorphin inhibits the release of kisspeptin, which hormone (GnRH) from the hypothalamus. In addition, neurokinin implies that both coordinate a pulsatile release of kisspeptin. 31 Sub- sections. sequently, the activated HPG axis induces the pituitary gland to secrete luteinising hormone (LH) and follicle stimulating hormone (FSH). As a result, gametogenesis occurs, and the gonads will release sex hormones. Consequently, secondary sex characteristics develop including breast development in girls and an increased testicular vol- 2,26,32 is possibly due to differences in levels of body fat, hypothalamic-pitui- THE ONSET OF PUBERTY IN GIRLS ume in boys. The age at puberty onset varies greatly among individuals, which 19 35 menstruation), and pubic hair development. 33 genome-wide association studies have provided important new tary-adrenal (HPA) axis activity, and genetic background. Recent The average age of However, this age differs between cultures and ethnicities, and since 1980, age at menarche is girls at start of menarche is 12.4 years. 36 significantly decreasing. 36-39 F I G U R E 1 Hormonal regulation in the initiation of puberty in boys and girls. The secretion of kisspeptin, neurokinin B, and dynorphin from KNDy neurons initiate the release of gonadotropin releasing hormone (GnRH) from the hypothalamus. This activates the pituitary gland to produce and secrete luteinising hormone (LH) and follicle stimulating hormone (FSH), which in turn stimulate the gonads to produce estrogen and testosterone in girls and boys, respectively 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 3 of 10 T A B L E 1 Summary of included studies Authors Year Country Study Design Primary Outcome Sex Sample Size (n) Age (y) Data Collection Lian et al21 2019 China Cross-sectional Puberty starts earlier in Chinese Han girls with obesity compared with Chinese Han girls with normal weight. Girls 2996 9-19 2012 and 2013 Biro et al12 Lazzeri et al20 2018 USA 2018 Italy Longitudinal Cross-sectional Body mass index had a greater effect on age at menarche than did race and ethnicity. Girls 946 6-16 2004-2014 Li et al23 2018 China Longitudinal For both, boys and girls, a higher BMI (ie, overweight and obese) is associated with earlier onset of puberty Girls Girls Boys Girls 542 Deng et al22 Flom et al15 2017 China Cross-sectional Increased BMI is associated with early timing spermarche and menarche. Boys Girls Girls 1278258 9-15 2005-2012 He et al24 Holmgren et al17 2017 China 2017 Sweden Cross-sectional Longitudinal Onset of puberty is not related to obesity in boys. Boys Boys Girls Girls 782 7-17 972 929 5839 Kelly et al19 2017 UK 2016 Brazil 2016 USA Longitudinal prospective cohort Higher BMI in girls is associated with the onset of menstruation at an earlier age. 11 10-18 11-17 Barcellos Gemelli et al25 Cross-sectional Longitudinal Excess weight is associated with early age of menarche. Girls 727 2014 2003-2009 Glass et al16 Lee et al26 In girls, but not in boys, greater adiposity is associated with the earlier onset of puberty. Boys Girls 135 Cabrera et al27 Leonibus et al14 2014 USA 2013 Italy Cross-sectional Longitudinal Thelarche occurred earlier than recently reported, while age of menarche remained unchanged. Girls 610 3-17.9 2007 2005-2012 Currie et al13 2012 Europe, USA, Canada Cross-sectional Overweight/obesity during childhood predicts the early onset of puberty in girls. Girls 20410 11, 13, 15 2005-2006 2017 USA Prospective birth cohort Overweight/obese status at the age of 7 ye was associated with increased risk of early menarche 788 From birth to menarche occurred Pregnancies 1959-1966 2016 USA Cross-sectional Boys with overweight enter puberty earlier compared with boys with normal weight or obesity, while puberty starts later in boys with obesity compared with boys with normal weight and overweight. Boys 3872 6-16 2005-2010 Overweight during childhood shows a relation with the early onset of puberty in girls. 6535 4259 695 11 15 5.8-12.2 2009/2010 2013/2014 2014-2017 Higher BMI during childhood is associated with early puberty. 2008 and 2009 2000-2002 Obesity during childhood is related to the earlier onset of puberty. Boys Girls 84 123 71 (Continues) 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 4 of 10 NIEUWENHUIS ET AL. 3.1 | Fat storage For the initiation of puberty, the timing of stimulation and/or inhibi- tion of different hormones is important, and additionally, a certain amount and distribution of body fat is needed in order to start menar- che, which emphasizes the importance of body fat. From an evolution- ary point of view, body fat increases in mammalian females during puberty onset, and it highlights the need to guarantee a healthy preg- 40 women with anorexia nervosa. particularly body fat localized predominantly on the gluteofemoral fat depots, is profoundly associated with start of menarche, more than nancy, offspring, and maternal survival. fat, sex-hormones, and neuroendocrine alterations can evolve in men- strual dysfunction, for instance, in women with severe obesity or in 41-43 44-46 to gluteofemoral fat depots suggesting that leptin may convey infor- amount of total body fat. mation on body fat distribution to the hypothalamus during puberty. An improper level of body Importantly, body fat distribution, Blood leptin levels are strongly related 45 3.2 | HPG axis The HPG axis is activated by the release of kisspeptin resulting in the release of GnRH from the hypothalamus, and LH and FSH from the pituitary gland. In girls, FSH is involved in the development of the folli- cles in the ovaries, and it promotes the secretion of estrogen. LH stim- ulates the production of androgen hormones and induces ovulation 48 9,47 the release of kisspeptin and neurokinin B, and kisspeptin thereby (Figure 1). The secretion of estrogen has an inhibitory effect on inhibits the GnRH release from the hypothalamus. pattern of GnRH is important for the regulation of the menstrual cycle. This roughly 28-day-cycle comprises several phases, including the follicular phase and luteal phase. During the follicular phase, increasing levels of FSH stimulate the maturation of follicles and the production of estrogen from the ovaries. This in turn inhibits the release of FSH from the pituitary gland. A high level of estrogen will induce the production of LH by the pituitary gland, resulting in ovula- tion. The matured follicle secretes progesterone thereby inhibiting the release of GnRH. When the corpus luteum is demolished, there is less 48 3.3 | Adipokines According to results from studies reported in Table 1, girls with obe- sity enter puberty earlier compared with girls with normal higher leptin concentrations inhibit the intake of food and increases inhibition of GnRH. As a consequence, the cycle will start again. whole process, starting from the activated HPG axis, results in the development of the secondary sex characteristics in girls including 9,47 thelarche and menarche. 13,14,16-23,49-51 weight. these girls might be found in the secretion of adipokines. For instance, leptin is positively associated with the amount of body fat. Generally, energy expenditure. 9,52-54 An explanation for the early onset of puberty in The expression This TABLE 1 (Continued) Authors Year Country Study Design Primary Outcome Sample Sex Size (n) Age (y) Data Collection Herman-Giddens et al28 2012 USA Cross-sectional Observed mean ages of beginning genital and pubic hair growth and early testicular volumes were earlier than in past studies, depending on the characteristic and race/ethnicity. Boys 4131 6-16 2005-2010 Sorensen et al29 Aksglaede et al30 2010 2009 Denmark Denmark Cross-sectional/longitudinal Longitudinal Puberty onset at earlier ages was associated with an increased BMI in boys. Boys 1528 5.8-19.9 1991-1993/2006-2008 1930-1969 Juul et al31 Ribeiro et al32 2007 2006 Denmark Portugal Retrospective cohort Cross-sectional Higher BMI is associated with early voice break. 11-15 10-15 1990-1999 Kaplowitz et al18 Abbreviation: BMI, body mass USA Cross-sectional The early onset of puberty in Caucasian girls is likely related to an increased BMI. 5-12 1992-1993 2001 index. The higher BMI in boys and girls at 7 y of age, the earlier they enter puberty. Boys 21 612 Girls 135 223 Boys 463 Boys 382 Girls 437 Girls 10 750 Early sexual maturation in boys and girls is associated with overweight. 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 5 of 10 Leptin may possibly play a role in adrenarche as its plasma level increases with higher levels of body fat and as it can modulate both girls. 33 ing adrenarche. In coherence, in children with obesity, the androgen These findings suggested that lower reproductive status was associated with higher total adiponectin concentrations and that a higher reproductive status was related to higher HMW adiponectin the HPA and HPG axes. These axes are functionally integrated dur- DHEAS was positively associated with leptin levels. Nevertheless, concentrations in girls. In addition, individuals with obesity often another study showed that enhanced adrenal androgen secretion in girls with premature adrenarche was not explained by leptin or BMI 55 ated with androgen levels in girls ; however, it was not related to levels. and IL-6. TNF-α alters, and IL-6 inhibits the expression of 56 8 In addition, the adipokine adiponectin was negatively associ- 57 differences of adiponectin seem to develop during the progression of 56 adiponectin (Figure 2). Thereby, a low level of total adiponectin and/or high levels of inflammatory cytokines in individuals with obe- sity can promote the onset of puberty. Many more adipokines are secreted by WAT including omentin, 52,65-67 9,36,62,68 adrenarche in girls with Prader-Willi syndrome. Interestingly, sex puberty. adrenarche; however, both are not required factors. Thus, leptin and adiponectin might be able to influence In gonadarche, leptin can stimulate the secretion of kisspeptin, and subsequently activation of the HPG axis, which eventually increases the expression of estrogen and androstenedione in the ova- 58 2,60 65-67 The expression of these ries (Figure 2). Ob gene in WAT, resulting in the synthesis and secretion of leptin. Thus, high levels of leptin promote onset of puberty in girls via secre- tion of kisspeptin, and estrogen stimulates leptin secretion addition- ally. Moreover, adiponectin can affect the HPG axis due to the expression of adiponectin receptors in the hypothalamus, pituitary In return, estrogen stimulates the expression of the 59 gland, and gonads. onset as it inhibits the secretion of kisspeptin and GnRH in the hypo- thalamus and the release of GH and LH in the pituitary gland, and 2,60-62 52,60 63 girls with central precocious puberty (CPP). Moreover, total adiponectin had negative correlations with progression of puberty in girls (defined by Tanner stages), whereas HMW adiponectin had FIGURE 2 Adipokinesaffectingthe initiation of puberty in girls. Leptin stimulates the release of kisspeptin in KNDy neurons, which activates the hypothalamus to produce gonadotropin releasing hormone (GnRH). In response to the release of GnRH, the pituitary gland secretes follicle stimulating hormone (FSH) and luteinising hormone (LH), which stimulates the ovaries to release estrogen resulting in the formation of secondary sex characteristics in girls. Estrogen stimulates the production of leptin. Adiponectin inhibits GnRH release resulting in reduced levels of GnRH and thereby a delayed onset of puberty. TNF- α and IL-6 inhibit the production of adiponectin and therefore stimulate the onset of puberty In detail, adiponectin is a regulator of puberty thereby inhibiting the onset of puberty (Figure 2). with obesity often have low levels of adiponectin. et al. showed that total adiponectin was significantly lower, whereas high molecular weight (HMW) adiponectin was significantly higher in ment. 55 63 develop a chronic low-grade inflammatory state, which can be indi- cated by a high level of circulating inflammatory cytokines like TNF-α 64 Individuals Sitticharoon positive associations with LH levels and the progression of puberty in 63 visfatin, resistin, and chemerin. and visfatin are expressed in the ovaries. adipokines in the ovaries suggests a role within the reproductive sys- tem; however, the exact biological processes have to be examined. Thus, specifically leptin, adiponectin, and inflammatory cytokines pro- duced by WAT could be permissive key players during an early onset of puberty in girls with obesity. As an exception, HMW adiponectin seems to have a stimulatory effect on peripheral repro- ductive function as HMW is not able to cross the blood brain 63 barrier. 4 | Markers that are used to assess puberty onset in boys are THE ONSET OF PUBERTY IN BOYS spermarche, voice break, testicular volume, and pubic hair develop- 35 spermarche develop in the early stages of puberty onset, voice In women, omentin, chemerin, While pubic hair development, larger testicular volume, and 69 testicular volume increases, which occurs at an average age of break usually appears in later stages of puberty. Generally, first 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 6 of 10 NIEUWENHUIS ET AL. 11.9 years, followed by the development of pubic hair at 12.2 years of average, and lastly, boys experience spermarche around an aver- 55 related with leptin levels. Thereby, leptin plausibly has a minor impact in adrenarche in boys. Since leptin receptors are found in the hypothalamus, pituitary gland, and testes, they might be involved in the onset of puberty by affecting the HPG axis during gonadarche. Leptin stimulates the release of kisspeptin and GnRH, and as a consequence, it accelerates the onset of puberty (Table 1, Figure 3). In contrast, adiponectin inhibits the secretion of GnRH, GH, LH, and FSH therewith delaying the onset of puberty. However, adiponectin levels are generally lower in men compared with women and even lower in men with obe- age age of 13.4 years. 70 4.1 | Fat storage Many aspects of the reproductive physiology are energetically demanding,71 and therefore, an adequate energy level is necessary. In boys, a dynamic change in body composition occurs around the age of 10 to 13 years, in which they gain approximately 40% of sity. culating inflammatory cytokines. levels can stimulate the HPG axis and therewith an early onset of puberty in boys. Nevertheless, leptin can inhibit the production of tes- 72 mostly consisting of lean mass, which causes exhaustion of most of fat. Subsequently, a growth spurt follows in which they gain tissue 72 in boys, an adequate amount of body fat is important in the onset of their body fat. These alterations in amount of body fat indicate that 4.2 | Puberty in boys is initiated by the release of kisspeptin. As mentioned before, this activates the HPG axis, resulting in the release of GnRH from the hypothalamus, and consequently the release of LH and FSH 9,74 puberty. tosterone from the testes, to estrogen (Figure 3). of the development of secondary sex characteristics in boys. Additionally, leptin can affect fertility in men as it can modulate the nutritional support of spermatogenesis, and moreover, dysfunction of spermatogenesis is associated with an increased leptin level and 73 58 2,60-62 HPG axis from the pituitary gland (Figure 1). and LH stimulates the secretion of testosterone from the testes, which inhibits the release of kisspeptin from the KNDy neurons and 9,48 in men, the release of kisspeptin is more consistent, causing a con- 29,48 subsequently GnRH from the hypothalamus. receptors expressed on KNDy neurons. In humans, KNDy neurons Contrarily to women, LH-induced testosterone levels lead to the stant release of LH. development of secondary sex characteristics in boys. differences between sexes in kisspeptin release are related to a sex- specific and sex steroid-dependent kisspeptin system as estrogen and progesterone modulate kisspeptin activity through the sex-steroid 48 in the infundibular nucleus are involved in negative and positive sex- 48 tal exposure to sex steroids and result in sex-specific differences in steroid feedbacks. kisspeptin release. These sexual dimorphisms are induced by perina- 75,76 4.3 | Adipokines The association between obesity and puberty onset in boys is rather controversial compared with findings in girls. Most studies reported an early onset of puberty in boys associated with increased ate adipose tissue from actual breast tissue. stages are more difficult to assess than female stages as boys lack a more determined marker such as menarche. Thirdly, puberty onset can be indicated by the activation of the HPG axis, and the presence of these secondary sex characteristics is the result of hormonal 2 14,17,22,23,50,51,77,78 BMI, 20,49 all while others reported no associations at Current markers used 79 16,80 or a delayed onset of puberty (Table 1). The presence of excessive adipose tissue can be involved in puberty onset in boys as the secretion of adipokines can modulate both adrenarche and gonadarche. Leptin can affect adrenarche by modulating both the HPG and HPA axes,33 and moreover, androgen levels were positively 55 nal androgen secretion in boys with premature adrenarche was not associated with plasma leptin levels. Nevertheless, enhanced adre- 9 In more detail, 61,62 adiponectin, and individuals with obesity often have high levels of cir- Moreover, inflammatory cytokines, TNF-α, and IL-6, inhibit expression of the leptin receptor in the testis. FSH induces spermatogenesis, too. function and role still have to be examined. 64 High leptin and low adiponectin and fat tissue can convert testosterone Both processes might result in the delay 29,61,79 81,82 In men, other adipokines like chemerin are found in the gonads 65 Thus, particularly high leptin and low adiponectin levels stimulate the HPG axis and thereby accelerate the onset of puberty in boys. Additionally, leptin can dysregulate the development of secondary sex characteristics and spermatogenesis by affecting testosterone levels and nutritional sup- port of spermatogenesis. 5 | LIMITATIONS AND FUTURE RESEARCH DIRECTIONS Even though multiple epidemiological studies have shown the link between puberty onset and obesity, there are some important limita- tions. Firstly, determining both the onset and stage of puberty is rather difficult. For instance, assessing the stage of breast develop- ment in girls with obesity is complicated as clinicians should differenti- 2 changes in response to the activated HPG axis. to determine the onset of puberty refer to secondary sex characteris- tics, such as testicular volume in boys and breast development in girls. A more accurate measurement of puberty onset would be to combine secondary sex characteristics with plasma or serum hormone level measurements such as LH, FSH, adipokines, e.g. leptin. Thereby, differences in puberty measurements could explain variations in the age of puberty onset between boys and girls within different Thereby, resistin is expressed in the testes of rats, but its exact 83 Secondly, male pubertal 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License NIEUWENHUIS ET AL. 7 of 10 FIGURE 3 Adipokines affecting the initiation of puberty in boys. Leptin activates kisspeptin secretion in KNDy neurons, this activates the production of gonadotropin releasing hormone (GnRH) from the hypothalamus. GnRH stimulates the pituitary gland to secrete follicle stimulating hormone (FSH) and luteinising hormone (LH), activating the production of testosterone from the testes allowing the development of secondary sex characteristics. Leptin also inhibits the production of testosterone, which may cause a delayed onset of puberty. Adiponectin inhibits GnRH release. Low levels of adiponectin, as a result of TNF-α and IL-6 expression, lead to a reduced inhibition of GnRH. In response to GnRH release, the pituitary gland will secrete FSH and LH, and the testes will produce testosterone resulting in the development of secondary sex characteristics in boys countries, and In addition, the inclusion of a of puberty. ferent time points is complicated, as subjects examined several decades ago presented pronounced differences concerning lifestyle patterns such as nutrition and exercise habits. Lastly, obesity or over- weight is often determined by BMI, a classification based on weight and height measurements. Additionally, it is important that all studies studies or across continents, ethnicities proper age range (8-16 years) is important when assessing the onset (Figure 4). 12-15,17,20-23,49,77-79,84,85 30,47 Furthermore, comparison between studies from dif- 86 Specifically in children, BMI is often dependent on age and growth use the same anthropometric standards and sex-specific cut-offs. 13,14,16-23,49-51,77-80 fat and would represent a more accurate measurement in its regard. Based on this review, several suggestions can be made for further research. Firstly, the roles of adipokines like resistin, chemerin, visfatin, and omentin in puberty onset, fertility, and sexual maturation should be examined in detail. Secondly, future research examining the onset of puberty should combine indicators of puberty onset (e.g. breast development or testicular volume) with plasma or serum hor- mone measurements such as LH, FSH, sex-steroids, adipokines (e.g. spurts. ment in case of growth spurts. distribution of body fat should be taken into account in determining puberty and obesity in children. For instance, the body adiposity index (BAI), which was introduced in 2011 by Bergman et al.,87 uses hip cir- cumference and height in order to estimate the percentage of body 87 Thereby, BMI is a less accurate measure- F I G U R E 4 87,88 Therefore, both percentage and Average age of puberty onset in Europe, China, and the United States according to several studies from Table 1. Age of puberty onset ranges from 8.47 to 13.33 years in girls and from 8.63 leptin), and body fat distribution (e.g. BAI,87 waist-hip ratio's and/or dual-energy X-ray absorptiometry (DXA)2). Additionally, defining con- sistent and general measurements of puberty in both boys and girls, combined with a proper age range (8-16 years), would facilitate the comparisons between different studies and their results. 12-15, 17, 20-23, 25-29, 31 to 13.7 years in boys. included if average age of markers used to assess puberty was not reported. Pink: girls. Blue: boys Studies (Table 1) were not 39, 56 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 8 of 10 NIEUWENHUIS ET AL. 6 | CONCLUSION In conclusion, epidemiological data regarding obesity and puberty onset in girls show similar outcomes as adiposity results in the early onset of puberty in girls. The majority of the studies examining boys with obesity indicate an early onset of puberty, while not all reported an earlier onset of puberty. In detail, high leptin, TNF-α, and IL-6 levels combined with low adiponectin levels stimulate the activation of the HPG axis in girls and boys with obesity, and 5, 45, 50, 51 REFERENCES 1. Kumar S, Kelly AS. Review of childhood obesity: from epidemiology, etiology, and comorbidities to clinical assessment and treatment. May- o Clin Proc. 2017;92(2):251-265. 2. Reinehr T, Roth CL. Is there a causal relationship between obesity and puberty? The Lancet Child & adolescent health. 2019;3(1):44-54. 3. WorldHealthOrganization. Facts and figures on childhood obesity. 2017. 4. Guglielmi V, Sbraccia P. Obesity phenotypes: depot-differences in adipose tissue and their clinical implications. Eat Weight Disord. 2018; 23(1):3-14. 5. Gomez-Hernandez A, Beneit N, Diaz-Castroverde S. Escribano O. 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FUNDING INFORMATION This research was funded by Europees Fonds voor Regionale Ontwikkeling (EFRO), project BriteN 2016. ORCID Ilse A.C. Arnoldussen Amanda J. Kiliaan https://orcid.org/0000-0002-7395-5284 https://orcid.org/0000-0002-2158-6210 13, 14, 16-26, 29-32 Furthermore, several receptors Nevertheless, We conclude Search strategy We searched PubMed for articles published before Novem- ber 15th, 2019 using relevant keywords, including âonset of puberty and adiposity/obesityâ, âonset of pubertyâ, âchildren with obesityâ, âadipose tissueâ, âchildhood obesityâ, âadiposityâ, âobesityâ, âadipokine(s)â, âHPG axisâ, âadipokines ovary/ova- riesâ, or âadipokines testesâ, either alone or in combination. 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Obesity Reviews. 2020;21:e13005. https://doi.org/ 10.1111/obr.13005 1467789x, 2020, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/obr.13005, Wiley Online Library on [10/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are gover2-28 (story vocabulary / celia cruz)2/28/252/28 Game2/28/23 SS The Middle Passage Ship Ride for West Africans to the Americans 2/28/19 SS Chapter 3: Eleanor Roosevelt Post-Test2-28 (La casa #3)