Intestinal alkaline phosphatase activity as a molecular marker of enterotoxicity induced by single dose of 5-fluorouracil and protective role of orally administered glutamine

Background. One of the critical limitations for the administration of the chemotherapy is the toxicity affecting normal tissue. The main target organs for 5-fluorouracil (5-FU) toxicity in humans and experimental animals are the gastrointestinal tract, bone marrow, and skin. The cytotoxic effects of antimetabolite chemotherapy are based on their role as substrates for the same transport processes and enzymes involved in anabolism and catabolism as the natural substrates. The main goal of our study was to analyze the dose-dependent antiproliferative effects of 5-FU on intestinal mucosa, enterotoxic potential of 5-FU in experimental animals and to test possible protective role of glutamine. Methods. In our study, we used Sprague Dawley rats. The control group of rats included 50 animals, while the groups where either 5-fluorouracil (5-FU) alone or 5-FU and glutamine were administered included 200 animals. All experimental animals were further stratified according to the experimental model (25 animals in each of 8 experimental subgroups of animals). The 5-FU was administered by intraperitoneal application in single dose of 0, 100, 200, 300, and 400 mg of 5-FU per kg of body weight. Water solution of 1% glutamine was prepared daily and administered orally, in volume of 200 ml, for 7 days continuously, after the 7th day of 5-FU administration. Experimental animals were sacrificed 7 days after the administration of 5-FU. The isolation of enterocytes was performed according to the method of Kralovansky et al. In cell homogenate obtained by described method, we determined the protein content using the Biuret method and the DNA content using the Burton reagent. The activities of enzymes alkaline phosphatase (ALP), glutathione S-transferase (GST), glutathione reductase (GR), and glutathione peroxidase (GPX) were determined by kinetic method. All paraffin samples of the small intestine were stained by haematoxiline and eosine(HE method). All the experiments were done in duplicate and analyzed by standard statistical methods. All the experiments were done in duplicate and analyzed by standard statistical methods. Results: Our results of enterotoxicity induced by intraperitonealy administered 5-FU showed statistically significant decrease of DNA content in small intestine samples of experimental animals, decrease in activity of intestinal alkaline phosphatase enzyme and the increase in glutathione-dependent enzymes. The glutamine supplementation reduced 5-FU intestinal toxicity. Conclusion: Intestinal alkaline phosphatase is a good marker of the dose-dependent enterotoxicity induced by 5-fluorouracil

Miroslav Spalajković:(1869-1951: a biography

Мирослав Спалајковић је рођен у Крагујевцу 1869. године. Студирао је право у Паризу, где је докторирао 1897. Пошто је ступио у српску дипломатску службу, био је секретар Посланства у Петрограду (1900–1904), конзул у Приштини (1904–1906), шеф Конзуларног одељења (1906–1907) и начелник Министарства иностраних послова (1907–1911). Спалајковић се појавио као сведок на Фридјунговом процесу у Бечу (децембра 1909) и доказао да је документ који је коришћен како би се показало да је учествовао у финансирању опозиције у Хрватској невешт фалсификат. Касније је помогао чешком опозиционару Масарику да искористи аферу, што га је довело у сукоб с аустроугарским послаником у Београду Форгачем. Спалајковић је 1911. године постављен за посланика у Софији, где је, као блиски сарадник и повереник председника владе Миловановића и Пашића и штићеник руског посланика у Београду Хартвига, имао значајну улогу у дипломатској историји Балканских ратова. Као импулсивна особа, од одушевљеног присталице савеза са Бугарима постао је њихов огорчени противник. На самом почетку 1914, Спалајковић је преузео свој нови дипломатски положај у Петрограду. Током Јулске кризе те године, телеграми које је слао из руске престонице подизали су самопоуздање у Србији и учврстили њену владу у отпору аустроугарском ултиматуму. После избијања Првог светског рата, уложио је све своје напоре у остваривање српских ратних циљева. Спалајковић је био очевидац руске револуције 1917. године и покушао је да помогне умереним елементима у Привременој влади. Од почетка је био непријатељски расположен према бољшевицима и развио је снажна и непоколебљива антикомунистичка убеђења. Након што је, заједно са другим представницима Антанте, подржао Бели покрет у области Архангелска, напустио је Русију 1919. године. У новообразованој Краљевини Срба, Хрвата и Словенаца, Спалајковић је био вршилац дужности министра иностраних послова (1920) и посланик у Уставотворној скупштини (1920–1922). Као повереник краља Александра, Спалајковић је вршио велики утицај на међуратну спољну политику Београда и био је именован за југословенског посланика у Паризу. Тамо је провео тринаест година (1922–1935), делујући као присталица потпуног политичког ослањања на Француску. После убиства краља Александра Спалајковић је пензионисан, али је сачувао мањи део утицаја захваљујући пријатељским односима с намесником кнезом Павлом, коме је у пролеће 1941. године покушао да помогне да јавности објасни зашто би Југославија требало да приступи Осовини. Након војног удара у Београду и немачке окупације Југославије, Спалајковић је почео да делује као колаборациониста. Вођен својим антикомунизмом и реакционарном идеологијом, подстицао је на борбу против устанка и саветовао генералу Милану Недићу да прихвати немачки захтев за образовање колаборационистичке владе. Изражавајући своје ставове у штампи током три ратне године (1942–1944), стекао је репутацију Недићевог блиског саветника. Спалајковић је у септембру 1944. напустио Београд и придружио се Недићу и остацима његове владе у Аустрији. После завршетка рата, провео је годину дана у кућном притвору у Риму, услед захтева нових југословенских власти за изручење. Француска влада је Мирославу Спалајковићу дала тајно уточиште и он је умро у Севру 1951. године. Тако се завршио живот националисте деветнаестовековног типа који је, бачен у средишњи идеолошки сукоб новог века, изабрао пут контрареволуције.Miroslav Spalajković was born in Kragujevac in 1869. He studied law in Paris, where he defended his doctoral thesis in 1897. Having entered the diplomatic service of Serbia, Spalajković was the Secretary of the Legation in St Peterburg (1900–1904), the consul in Priština (1904–1906), the Chief of the Consular Department (1906–1907) and the Secretary General of the Ministry of Foreign Affairs (1907–1911). Spalajković appeared as a witness in the Friedjung trial in Vienna (December 1909) and proved that the document which had been used to show that he had participated in financing the opposition in Croatia was a poor forgery. He later helped a Czech oppositionist Masaryk to make use of the affair, which led to his conflict with the Austro-Hungarian Minister in Belgrade Forgách. In 1911, Spalajković was appointed the Minister in Sofia, where, as a close assistant and confidant of the Prime Ministers Milovanović and Pašić and a protégé of the Russian Minister in Belgrade Hartwig, he played important roles in the diplomatic history of the Balkan Wars. Being an impulsive person, he altered from an enthusiastic supporter of the Serbo-Bulgarian Alliance to a bitter antagonist of the Bulgarians. At the very beginning of 1914, Spalajković took up his new diplomatic post in St Petersburg. During the July Crisis that year, his dispatches from the Russian capital boosted self-confidence in Serbia and made its leaders firmer in their resistance to the Austro-Hungarian ultimatum. After the outbreak of the First World War, he put all his efforts into achieving Serbia’s war aims. Spalajković witnessed the Russian revolution of 1917 and tried to help moderates in the Provisional Government. From the beginning, he was hostile to the Bolsheviks and he developed strong and unwavering anti-communist sentiments. After supporting the White forces in the Archangel region together with the other representatives of the Entente, he left Russia in 1919. In the newly formed Kingdom of Serbs, Croats and Slovenes, Spalajković was the acting Foreign Minister (1920) and the member of the Constituent Assembly (1920– 1922). As a confidant of King Alexander, Spalajković had a great influence on the Belgrade’s interwar foreign policy and he was appointed the Yugoslav Minister in Paris. He spent there thirteen years (1922–1935), acting as a supporter of the complete political reliance on France. After the King Alexander’s assassination Spalajković was sent into retirement, but he preserved somewhat of his influence due to his friendly relations with the Prince Regent Paul, whom he tried to help to explain to the public why Yugoslavia should join the Axis in the spring of 1941. Following the military coup in Belgrade and the German occupation of Yugoslavia, Spalajković started acting as a collaborationist. Driven by his anticommunism and his reactionary ideology, he encouraged the fight against the uprising and advised General Milan Nedić to accept the German demand for the formation of a collaborationist government. While expressing his opinions in the press during the three war years (1942–1944), he gained a reputation as a close advisor to Nedić. In September 1944, Spalajković left Belgrade and joined Nedić and his ex-government in Austria. After the end of the war, he spent a year in house arrest in Rome, because of the new Yugoslavian authorities’ demand for his extradition. The French government gave Miroslav Spalajković a secret asylum and he died in Sèvres in 1951. Thus ended the life of a nineteenth-century-style nationalist who, having been thrown into the central ideological conflict of the new century, had chosen the path of counter-revolution

Pretposlednje predsedništvo SFRJ (1984–1989)

The article analyzes the activity of the Presidency of the Socialist Federal Republic of Yugoslavia from 1984 to 1989, mainly on the basis of unpublished material from the Archives of Yugoslavia. The accent is on confrontation of the members of the Presidency with the rising crisis of the political system in Yugoslavia. The reactions of the Presidency to the turning events during the last two years of its mandate are presented in more detail

Miroslav Spalajković, the Serbian Minister in Russia in the july crisis of 1914

One of those who played a supporting role in the prologue of the great European tragedy of 1914 was Miroslav Spalajković, the Serbian Minister in St Petersburg. Known as a sworn enemy of Austria-Hungary, he was a close associate of the Serbian Prime Minister Nikola Pašić. The latter was aware of Spalajković’s weaknesses but trusted him nevertheless. Although Spalajković had spent a brief period of time in St Petersburg prior to the July Crisis and could not have exerted considerable influence on the Russian ruling circles, he spared no effort to secure support for Serbia in the face of Vienna’s sabre-rattling. In fact, the Russians did not need a Serbian diplomat to point out what was obvious: that they could not allow the destruction of an independent and pro-Russian Serbia on the southern border of Austria-Hungary. Having sensed the political mood in St Petersburg, he enthusiastically reported to his government that Serbia would not be left in the lurch. His dispatches boosted self-confidence in Serbia and made its leaders firmer in their resistance to Austria-Hungary’s demands

Miroslav Spalajković:(1869-1951: a biography

Мирослав Спалајковић је рођен у Крагујевцу 1869. године. Студирао је право у Паризу, где је докторирао 1897. Пошто је ступио у српску дипломатску службу, био је секретар Посланства у Петрограду (1900–1904), конзул у Приштини (1904–1906), шеф Конзуларног одељења (1906–1907) и начелник Министарства иностраних послова (1907–1911). Спалајковић се појавио као сведок на Фридјунговом процесу у Бечу (децембра 1909) и доказао да је документ који је коришћен како би се показало да је учествовао у финансирању опозиције у Хрватској невешт фалсификат. Касније је помогао чешком опозиционару Масарику да искористи аферу, што га је довело у сукоб с аустроугарским послаником у Београду Форгачем. Спалајковић је 1911. године постављен за посланика у Софији, где је, као блиски сарадник и повереник председника владе Миловановића и Пашића и штићеник руског посланика у Београду Хартвига, имао значајну улогу у дипломатској историји Балканских ратова. Као импулсивна особа, од одушевљеног присталице савеза са Бугарима постао је њихов огорчени противник. На самом почетку 1914, Спалајковић је преузео свој нови дипломатски положај у Петрограду. Током Јулске кризе те године, телеграми које је слао из руске престонице подизали су самопоуздање у Србији и учврстили њену владу у отпору аустроугарском ултиматуму. После избијања Првог светског рата, уложио је све своје напоре у остваривање српских ратних циљева. Спалајковић је био очевидац руске револуције 1917. године и покушао је да помогне умереним елементима у Привременој влади. Од почетка је био непријатељски расположен према бољшевицима и развио је снажна и непоколебљива антикомунистичка убеђења. Након што је, заједно са другим представницима Антанте, подржао Бели покрет у области Архангелска, напустио је Русију 1919. године. У новообразованој Краљевини Срба, Хрвата и Словенаца, Спалајковић је био вршилац дужности министра иностраних послова (1920) и посланик у Уставотворној скупштини (1920–1922). Као повереник краља Александра, Спалајковић је вршио велики утицај на међуратну спољну политику Београда и био је именован за југословенског посланика у Паризу. Тамо је провео тринаест година (1922–1935), делујући као присталица потпуног политичког ослањања на Француску. После убиства краља Александра Спалајковић је пензионисан, али је сачувао мањи део утицаја захваљујући пријатељским односима с намесником кнезом Павлом, коме је у пролеће 1941. године покушао да помогне да јавности објасни зашто би Југославија требало да приступи Осовини. Након војног удара у Београду и немачке окупације Југославије, Спалајковић је почео да делује као колаборациониста. Вођен својим антикомунизмом и реакционарном идеологијом, подстицао је на борбу против устанка и саветовао генералу Милану Недићу да прихвати немачки захтев за образовање колаборационистичке владе. Изражавајући своје ставове у штампи током три ратне године (1942–1944), стекао је репутацију Недићевог блиског саветника. Спалајковић је у септембру 1944. напустио Београд и придружио се Недићу и остацима његове владе у Аустрији. После завршетка рата, провео је годину дана у кућном притвору у Риму, услед захтева нових југословенских власти за изручење. Француска влада је Мирославу Спалајковићу дала тајно уточиште и он је умро у Севру 1951. године. Тако се завршио живот националисте деветнаестовековног типа који је, бачен у средишњи идеолошки сукоб новог века, изабрао пут контрареволуције.Miroslav Spalajković was born in Kragujevac in 1869. He studied law in Paris, where he defended his doctoral thesis in 1897. Having entered the diplomatic service of Serbia, Spalajković was the Secretary of the Legation in St Peterburg (1900–1904), the consul in Priština (1904–1906), the Chief of the Consular Department (1906–1907) and the Secretary General of the Ministry of Foreign Affairs (1907–1911). Spalajković appeared as a witness in the Friedjung trial in Vienna (December 1909) and proved that the document which had been used to show that he had participated in financing the opposition in Croatia was a poor forgery. He later helped a Czech oppositionist Masaryk to make use of the affair, which led to his conflict with the Austro-Hungarian Minister in Belgrade Forgách. In 1911, Spalajković was appointed the Minister in Sofia, where, as a close assistant and confidant of the Prime Ministers Milovanović and Pašić and a protégé of the Russian Minister in Belgrade Hartwig, he played important roles in the diplomatic history of the Balkan Wars. Being an impulsive person, he altered from an enthusiastic supporter of the Serbo-Bulgarian Alliance to a bitter antagonist of the Bulgarians. At the very beginning of 1914, Spalajković took up his new diplomatic post in St Petersburg. During the July Crisis that year, his dispatches from the Russian capital boosted self-confidence in Serbia and made its leaders firmer in their resistance to the Austro-Hungarian ultimatum. After the outbreak of the First World War, he put all his efforts into achieving Serbia’s war aims. Spalajković witnessed the Russian revolution of 1917 and tried to help moderates in the Provisional Government. From the beginning, he was hostile to the Bolsheviks and he developed strong and unwavering anti-communist sentiments. After supporting the White forces in the Archangel region together with the other representatives of the Entente, he left Russia in 1919. In the newly formed Kingdom of Serbs, Croats and Slovenes, Spalajković was the acting Foreign Minister (1920) and the member of the Constituent Assembly (1920– 1922). As a confidant of King Alexander, Spalajković had a great influence on the Belgrade’s interwar foreign policy and he was appointed the Yugoslav Minister in Paris. He spent there thirteen years (1922–1935), acting as a supporter of the complete political reliance on France. After the King Alexander’s assassination Spalajković was sent into retirement, but he preserved somewhat of his influence due to his friendly relations with the Prince Regent Paul, whom he tried to help to explain to the public why Yugoslavia should join the Axis in the spring of 1941. Following the military coup in Belgrade and the German occupation of Yugoslavia, Spalajković started acting as a collaborationist. Driven by his anticommunism and his reactionary ideology, he encouraged the fight against the uprising and advised General Milan Nedić to accept the German demand for the formation of a collaborationist government. While expressing his opinions in the press during the three war years (1942–1944), he gained a reputation as a close advisor to Nedić. In September 1944, Spalajković left Belgrade and joined Nedić and his ex-government in Austria. After the end of the war, he spent a year in house arrest in Rome, because of the new Yugoslavian authorities’ demand for his extradition. The French government gave Miroslav Spalajković a secret asylum and he died in Sèvres in 1951. Thus ended the life of a nineteenth-century-style nationalist who, having been thrown into the central ideological conflict of the new century, had chosen the path of counter-revolution

The mission of Aleksandar Belić and Stanoje Stanojević in Russia 1916-1917

In the spring of 1916, the Serbian Government in exile sent two prominent intellectuals, the philologist Aleksandar Belić and the historian Stanoje Stanojević, on a propaganda mission to Russia, in order to inform the local public about its war aims and its national program. Serbian propaganda activity in Russia became much more organized after their arrival. During 1916, they worked on publishing books and establishing a Serbian institute in St. Petersburg, gave university and public lectures, met with members of the Duma and other influential politicians. Although there were some disagreements between Belić and Stanojević and the representatives of the Yugoslav Committee in Russia (mainly regarding the vision of the future unification), they generally cooperated well, especially in propaganda among Serb, Croat and Slovene volunteers in Odessa. The position of the Serbian representatives in Russia was fundamentally changed by the February Revolution. While liberal politicians were still influential, Belić and Stanojević made use of their acquaintances with them to get promises regarding the Serbian war aims. Their moderate optimism soon turned into bleak pessimism, because chaos and preoccupation with internal issues kept hindering Serbian propaganda in Russia. They tried to organize joint propaganda with Czechoslovak leader Tomáš Masaryk, but without much success. Stanojević left Russia in the summer, and Belić in the fall of 1917. They informed the Serbian Government that further propaganda in Russia was almost impossible. The initially fruitful mission of two Serbian intellectuals ended abruptly due to unpredictable events

Reconstruction of the infected war defects of the tibia: A fragment elongation according to the Ilizarov technique

Introduction/Aim. The treatment of tibia defects complicated with chronic osteomyelitis is difficult, often requiring one or more surgical interventions with prolonged periods of functional incapacity. Methods. We treated 20 patients with tibia defects, who had been wounded during the war operations in the former Yugoslavia, complicated with chronic osteomyelitis by applying the Ilizarov apparatus. In 10 patients with the average defect of 4.7 cm, interfragmentary diastasis of 1.5 cm, and 3.1 cm of shortening we applied the bilocal synchronous compressive - distractive method (BSCD). In the remaining 10 patients with average defect of 6.4 cm, interfragmentary diastasis of 5.5 cm, and 1.6 cm of shortening we applied bilocal alternating distractive - compressive osteosynthesis (BADC). Results. The average followup was 93 months. In the group A, the average distraction index was 10.6, maturation index 39.8, and external fixation index 52.5. In the group B, the average distraction index was 11.7, maturation index 47.1, and external fixation index 60.1. The average time from the application to the apparatus removing was in the group A 6.5 months, and in the group B 11.9 months. There were 27 complications: 11 problems, 8 disturbs, and 8 true complications. Pin-track inflammation of the soft tissue was noted most frequently (6 patients). Conclusions. One stage of repairing inflamation and the restitution of defect in lower leg tissue was the advantage of this type of treatment. All of the patients recovered. There was not any bad result, either in osteal or in functional outcome

Changes of biochemical parameters in rat intestinal mucosa induced by methotrexate and effects of enteral administration of glutamine

BACKGROUND: Rapidly proliferating crypt cells of the intestinal epithelium, the precursors of the mature enterocytes, are extremely sensitive to the effects of cytostatic agents. We investigated the effects of the methotrexate on rat intestinal mucosa in order to get the information on biochemical indicators of intestinal damage. METHODS: Biochemical parameters were investigated in isolated intestinal mucosa of Sprague-Dawley rats, previously treated with methotrexate by intraperitoneal administration. Glutamine was dissolved in water and administered orally. RESULTS: The activity of glutaminase and alkaline phosphatase showed the enzymatic response to different doses of methotrexate. The activity of both enzymes was significantly lower in the mucosa of treated animals, compared to control group. CONCLUSION: Minimal mucosal damage and regeneration time is dose dependent and influenced by the dosage schedule of antitumor therapy