Les aldose-cétose isomérases sont des enzymes catalysant l’isomérisation réversible entre un aldose et un cétose. Nous avons étudiés trois d’entre-elles : les phosphoribose isomérases (RPI), les phosphomannose isomérases (PMI) et les phosphoglucose isomérases (PGI). Ces enzymes interviennent dans différentes voies métaboliques comme la glycolyse, la néoglucogenèse, la voie des pentoses phosphates ou le métabolisme du mannose. Il a été montré qu’elles jouent un rôle important pour assurer la survie et le développement de plusieurs parasites responsables de maladies comme la leishmaniose, la mucoviscidose, la tuberculose, le paludisme ou la maladie du sommeil. Ces enzymes sont donc des cibles thérapeutiques potentielles. Ainsi, les puissants inhibiteurs de ces enzymes peuvent donc être des agents thérapeutiques efficaces pour combattre ces maladies. Les réactions catalysées par ces enzymes impliquent des intermédiaires de haute énergie (IHE) de type 1,2-cis-ènediol(ate). La synthèse d’analogues de ces intermédiaires a permis d’obtenir au laboratoire, les meilleurs inhibiteurs connus de ces enzymes, l’acide 5-phospho-D-arabononohydroxamique (5PAH, meilleur inhibiteur des PMI et PGI) et le 5-phospho-D-ribonate (5PRA, meilleur inhibiteur des RPI). Cependant, ces inhibiteurs possèdent une fonction phosphate facilement hydrolysable en milieu physiologique. Ce qui les rend inactifs in vivo. Au cours de ce travail de thèse, des phosphoanalogues du 5PAH, du 5-phospho-D-ribose (R5P, le substrat des RPI) et du 5PRA possédant une fonction malonate, phosphonate, phosphorothiate, sulfate et sulfonate à la place de la fonction phosphate ont été obtenus par des voies de synthèse multi-étapes faisant intervenir le D-arabinose ou le D-ribose comme produit de départ. Les propriétés inhibitrices de ces composés ont ensuite été déterminées et leur stabilité en milieu physiologique évaluée. Le phosphoanalogue du 5PAH de type malonate, l’acide 5-désoxy-5-dicarboxyméthyl-D-arabinonohydroxamique (5DCAH) est un inhibiteur moyen et stable de la PMI d’Escherichia Coli. Parmi les phosphoanalogues du R5P, les composés de type sulfate et sulfonate, respectivement, le 5-sulfate-D-ribose (5SR) et 5-désoxy-5-sulfonométhyl-D-ribose (5SMR) sont de bons inhibiteurs de trois RPI (la RPI d’épinard, la RPI d’Escherichia Coli et la RPI de Micobacterium tuberculosis). Seul le composé de type sulfonate est stable en milieu physiologique. Le phosphoanalogue de type malonate, le 5-désoxy-5-dicarboxyméthyl-D-ribose (5DCR) est un inhibiteur moyen de ces trois RPI. En revanche, les phosphoanalogues de type phosphorothioate et phosphonate, respectivement, le 5-désoxy-5-phosphorothioate-D-ribose (5PTR) et 5-désoxy-5-phosphonométhyl-D-ribose (5PMR) sont de mauvais inhibiteurs. Le phosphoanalogue de type phosphonate du 5PRA, le 5-désoxy-5-phosphonométhyl-D-ribonate (5PMRA) est un bon inhibiteur de la RPI de Micobacterium tuberculosis. De plus, ce composé est stable en milieu physiologique. Il est en revanche un mauvais inhibiteur de la RPI d’épinard et d’Escherichia Coli. Ces résultats sont particulièrement prometteurs puisque le 5PMRA est à ce jour le meilleur inhibiteur stable et spécifique de la RPI de Micobacterium tuberculosis. / Aldose-ketose isomerases are enzymes which catalyze the interconversion of an aldose and a ketose. We have studied three of them: phosphoribose isomerase (RPI), phosphomannose isomerase (PMI) and phosphoglucose isomerase (PGI). These enzymes play a major role in various metabolic pathways as glycolysis, neoglucogenesis, the pentoses phosphates pathways or the mannose metabolism. It has been shown to have a crucial role for the survival and development of several microorganisms responsible for diseases as the leishmaniose, the cystic fibrosis, the tuberculosis, the malaria or the insomnia. These enzymes are thus potential therapeutic targets. Consequently, strong inhibitors of these enzymes could provide efficient therapeutic tools against these deseases. The reactions catalyzed by these enzymes involve intermediaries of high energy (IHE) of 1,2-cis-enediol(ate) type. The synthesis of analogues of these intermediaries allowed to obtain in the laboratory, the best inhibitors known for these enzymes, the acid 5-phospho-D-arabononohydroxamique (5PAH, the best inhibitor of the PMI and PGI) and the 5-phospho-D-ribonate (5PRA, the best inhibitor of the RPI). However, these inhibitors possess a phosphate group which is easily hydrolysable in physiological environment, what makes them inactive in vivo. During this work of thesis, phosphoanalogues of the 5PAH, the 5-phospho-D-ribose (R5P, the substrate of the RPI) and of the 5PRA possessing a malonate, phosphonate, phosphorothiate, sulphate and sulfonate were obtained by multi-steps synthesis bringing in D-arabinose or D-ribose as starting product. The inhibitive properties of these compounds were then determined and their stability in physiological environment evaluated. The phosphoanalogue of the 5PAH of malonate type, the acid 5-desoxy-5-dicarboxyméthyl-D-arabinonohydroxamique (5DCAH) is a modest and stable inhibitor of the PMI of Escherichia Coli. Among the phosphoanalogues of the R5P, the compounds of sulphate and sulfonate types, respectively, the 5-sulfate-D-ribose (5SR) and 5-desoxy-sulfonomethyl-D-ribose (5SMR), are good inhibitors of three RPI (the RPI of spinach, the RPI of Escherichia Coli and the RPI of Micobacterium tuberculosis). Only the compound of sulfonate type is stable in physiological environment. The phosphoanalogue of malonate type, the 5-desoxy-5-dicarboxymethyl-D-ribose (5DCR) is a modest inhibitor of this three RPI. On the other hand, the phosphoanalogues of phosphorothioate and phosphonate types, respectively, the 5-desoxy-5-phosphorothioate-D-ribose (5PTR) and the 5-desoxy-5-phosphonomethyl-D-ribose (5PMR), are bad inhibitors. The phosphoanalogue of phosphonate type of the 5PRA, the 5-desoxy-5-phosphonomethyl-D-ribonate (5PMRA), is a good inhibitor of the RPI of Micobacterium tuberculosis. Furthermore, this compound is stable in physiological environment. It is on the other hand a bad inhibitor of the RPI of spinach and Escherichia Coli. These results are particularly promising because the 5PMRA is this day the best stable and specific inhibitor of the RPI of Micobacterium tuberculosis.

En el gen de la proteïna priònica, o PRNP, hem observat que el particular patró de variació que hem trobat basant-nos en dades de seqüenciació en humans es deu a selecció positiva, i que el mètode utilitzat per detectar selecció és crític. Utilitzant dades basades en SNPs es pot introduir un biaix al aplicar tests de neutralitat basats en diversitat de seqüències, i això pot portar a conclusions errònies. A més, hem vist que els polimorfismes en els codons 129 i 219 presenten gran diferències de freqüència en diferents poblacions humanes i també hem vist que aquestes posicions estan fixades en ximpanzés. La variació trobada en controls ha estat comparada amb el patró de variació existent en pacients per la mateixa regió. La reseqüenciació del gen PRNP en un gran nombre de mostres humanes i de ximpanzés ens ha permès obtenir un gran nombre d´informació d´aquest gen. / In the prion gene or PRNP, we have observed that the particular pattern of variation that we have found in this gene based on sequencing data in humans is due to positive selection, and that the method and the approach used to detect this selection critical. Ascertainment bias can be introduced by using SNP data and applying neutrality tests based on sequence diversity, therefore leading to anomalous conclusions being drawn. Moreover, we have seen that polymorphisms in codon 129 and 219 have big differences in frequency in different human populations and we have also seen that these positions are fixed in chimpanzees. The normal variation that we found in controls have been then compared with patients for the same region. The resequencing of PRNP in a very large sample of humans and chimpanzees has provided a great deal of information on this gene.

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研究目的：在現今高壓力與忙碌的社會中，失眠是很常見的問題。在國外的失眠的相關調查結果顯示，失眠的盛行率會受對於失眠定義之嚴謹程度影響，而有大範圍的變異，其範圍約落在6~48%。當定義符合臨床上之診斷標準時，失眠盛行率約降至6~15%。因此，受失眠之苦的個體中，有一大部分可能未達診斷標準，而為暫時性或急性失眠之患者。然而過去的研究大多將重點聚焦在符合失眠疾患診斷的失眠族群上，針對剩下雖未符合失眠疾患診斷標準，但又飽受失眠症狀困擾之群體，卻是缺乏探討。此外，失眠的縱貫研究中也發現，暫時性失眠個體到最後會有一部份會發展成為慢性失眠。因此，針對這群為數不少，且容易經歷暫時性失眠之個體，若能更加了解其暫時性失眠發生的成因與相關機制，便能及早介入，協助個體不落入慢性失眠的惡性循環中。過去研究發現，暫時性失眠的發生，最常見的促發因素為壓力事件。Drake、Richardson、Roehrs、Scofield與Roth（2004）便發展出福特壓力失眠反應量表（Ford Insomnia Response to Stress Test, FIRST）來測量個體特質上遭遇壓力情境的睡眠脆弱程度；且研究結果也發現個體身心激發程度是和睡眠脆弱特質息息相關的因素之一。由於過去在失眠的相關研究中，少有研究探討暫時性失眠的相關機制，因此，本研究從和暫時性失眠相關的壓力下睡眠脆弱特質出發，探討此脆弱特質與過度激發的關聯性，並欲探討其他會提升激發程度的相關認知與情緒因子，如：失功能信念、情緒反應性、反芻特質、情緒遲惰特質和此特質間的關係。本研究假設個體對於睡眠的失功能信念與對負向事件的情緒反應性可能會透過提高睡前身心的激發程度，而使個體容易經歷壓力下的急性失眠，增加睡眠的脆弱性；即睡前身心激發程度在睡眠的失功能信念與情緒反應性對睡眠脆弱性的關係間扮演一中介作用之角色。另外，也假設睡眠的失功能信念與情緒反應性與睡前身心激發程度間的關係，會分別受反芻特質與情緒遲惰特質調節，即具有高反芻特質與高情緒遲惰特質者，其睡眠的失功能信念與情緒反應性與睡前身心激發程度間的關係更強烈，因此在壓力下，其有較高的睡眠脆弱性，容易經歷暫時性失眠。 研究方法：本研究於大學中招募60位20~35歲之受試者（男：22位；女：38位），經晤談以確認受試者符合收案標準後，將請受試者填寫研究相關問卷（包含：壓力下失眠反應量表、反芻型反應風格短版量表、睡前激發程度量表、睡眠失功能信念及態度簡式量表、情緒反應量表、失眠嚴重度量表、貝克憂鬱量表第二版與貝克焦慮量表）；並在詳細解釋情緒經驗取樣流程後，請受試者回到日常生活環境中進行連續三天的情緒遲惰經驗取樣紀錄。 研究結果：根據執行檢驗中介效果步驟的階層迴歸與Sobel test的分析結果，睡前認知激發程度對擔憂的失功能信念與情緒持續性和睡眠脆弱性間的關係具中介的作用；即對睡眠有過度擔憂的失功能信念、情緒持續性較久皆可能會提高睡前認知激發程度而增加壓力下的睡眠脆弱性。其他失功能信念之向度，如：知覺失眠造成的影響、對睡眠的期待、藥物使用，以及情緒反應性之其他向度，如：情緒敏感度與情緒激發度對睡前認知過度激發狀態無顯著的預測力。另外，根據執行檢驗調節效果步驟的階層迴歸分析結果，反芻特質與情緒遲惰特質分別在失功能信念與情緒反應性對認知激發程度的關係上，皆未有顯著的調節效果。 研究結論：研究結果部分支持身心激發程度為對睡眠的失功能信念與情緒反應性影響壓力下睡眠脆弱性的中介因子之假設。本研究發現過度擔憂睡眠的信念以及情緒持續度較久這兩個因子會分別獨立地提高睡前認知激發程度，顯示睡前認知激發程度分別受認知與情緒因素影響；且相較與睡前的生理激發狀態，睡前的認知激發對於壓力下的失眠反應之影響具有顯著的預測力，顯示認知激發在失眠的前置因子中可能扮演較重要的角色。另外，反芻特質與情緒遲惰特質分別在失功能信念與情緒反應性對認知激發程度的關係上，皆未有顯著的調節效果，此部份不符合研究預期。基於本研究結果，在臨床上對於容易經歷失眠之個體，若能及早調整對於睡眠的擔憂相關的信念，並學習有效調節情緒的方式，皆可有效降低個體睡前的認知激發活動，減少失眠的發生率與改善失眠症狀，避免使其落入失眠慢性化的惡性循環中。

Endocrine and Metabolic Aspects of Various Sleep Disorders MUDr. Zuzana Vimmerová Lattová Abstract: Recent epidemiological and experimental data suggest a negative influence of shortened or disturbed night sleep on glucose tolerance. However, no comparative studies of glucose metabolism have been conducted in clinical sleep disorders. Dysfunction of the HPA axis may play a causative role in some sleep disorders and in other sleep disorders it may be secondary to the sleep disorder. Moreover, dysfunction of the HPA axis is regarded as a possible causative factor for the impaired glucose sensitivity associated with disturbed sleep. However, data on HPA system activity in sleep disorders are sparse and conflicting. We studied 25 obstructive sleep apnea (OSA) patients, 18 restless legs syndrome (RLS) patients, 21 patients with primary insomnia and compared them to 33 healthy controls. We performed oral glucose tolerance test and assessed additional parameters of glucose metabolism. The dynamic response of the HPA system was assessed by the DEX-CRH-test which combines suppression (dexamethasone) and stimulation (CRH) of the stress hormone system. Compared to controls, increased rates of impaired glucose tolerance were found in OSA (OR: 4.9) and RLS (OR: 4.7), but not in primary insomnia. In addition, HbA1c...

Sammanfattning Syftet med studien var att skapa en deskriptiv bild över de tre utvalda sårbarhetsfaktorer (tävlingsoro, sömnsvårigheter och fysiska skador) samt undersöka eventuella samband och skillnader mellan dessa gällande elever som läser specialidrott på Riksidrottsgymnasium (RIG). Studiens frågeställningar var: 1) Vilken fysisk skadefrekvens (överbelastning respektive traumatisk skada) har RIG-elever haft under det senaste året? 2) I vilken grad upplever RIG-elever tävlingsoro inför och under tävling/match? 3) I vilken grad upplever RIG-elever sömnsvårigheter? 4) Vilka samband eller skillnader finns mellan de tre valda sårbarhetsfaktorerna? 5) Vilka skillnader i skadefrekvens, skadetyp, sömnsvårigheter och tävlingsoro finns mellan årskurserna? Metod Elektronisk enkätundersökning användes som verktyg för mätbara data genom slutna enkätfrågor. De formulär som använts för den elektroniska enkätundersökningen var CSAI-2 (tävlingsoro), ISI (Sömnsvårigheter) samt fysisk skadefrånvaro enligt definition av Tranæus (2013). Inbjudan till att delta i studien skickades ut till samtliga RIG i Sverige, totalt 40 skolor. Av dessa tackade 18 skolor ja till deltagande, 8 tackade nej och 14 svarade inte på inbjudan. Av den totala populationen deltog 336 riksidrottsgymnasieelever från 24 olika idrotter. Svaren från enkäten presenteras dels i deskriptiv kvantitativ karaktär och dels i en analytisk del. Resultat Inom populationen hade 70 procent varit frånvarande på grund av fysiska skador under året (48 procent på grund av en överbelastnings- och 22 procent på grund av en traumatisk skada), varav 41 procent var frånvarande från träning, tävling eller match längre än en vecka.  Markanta sömnbesvär rapporterades hos 15 procent av eleverna. På CSAI-2 skalan hade självförtroende ett medelvärde på 22,3 ± 5,9 poäng, somatisk oro 18,6 ± 5,6 poäng, kognitiv oro 17,6 ± 4,8 poäng. Statistiska analysen visade signifikanta samband mellan skadefrånvaro, ISI och CSAI-2, förutom mellan somatisk oro och skadefrånvaro. Inga signifikanta skillnader i någon aspekt fanns mellan årskurserna. Slutsats Studiens slutsats är att fysiska skador har ett samband med sömnstörningar och att tävlingsoro korrelerar med både fysiska skador och sömnen negativt. Resultatet kan hjälpa lärare och tränare att få förståelse för dessa faktorer kan behöva uppmärksammas i starten av unga elitidrottares uppväxt. / Abstract The aim of this study was to get a descriptive view of the area and to investigate possible relationships/differences between the three selected vulnerability factors for students who study sports at a Riksidrottsgymnasium (RIG). The study aimed to answer the following questions: 1) To what physical injury rate (overload or traumatic injury) have RIG students had in the past year? 2) To what extent do RIG students experience anxiety before and during competition / match? 3) To what extent do RIG students experience sleep difficulties? 4) What are the relationships or differences between the three selected vulnerabilities? 5) What differences in rate of injury, type of injury, insomnia and anxiety are between grades? Method Electronic survey was used as a tool for measurable data through closed questionnaires. The form that the study used for the electronic survey was CSAI-2 (Anxiety), ISI (Injury) and physical injury severity according to the same definition as Tranæus (2013). The invitation to participate in the study was sent to all RIGs in Sweden, a total of 40 schools. Out of these 40 schools 18 schools accepted to participate in the study, 8 schools voted to not participate and 14 did not respond. Of the total population, 336 high school athletics students participated in 24 different sports. The answers from the questionnaire are presented in a descriptive quantitative character and an analytical part. Results In the population, 70 percent were absent due to physical injuries, of which 41 percent were absent from training, competition or match longer than one week. 48 percent of all students had an overload injury and 22 percent traumatic injury in the past year. 15 percent showed significant sleep disorders. Self-confidence had an average of 22.3 ± 5.9 points, somatic concern, 18.6 ± 5.6 points, cognitive concern, 17.6 ± 4.8 points. Statistical analysis showed significant results between injury absence, ISI and CSAI-2 aside from somatic concern and injuries. Regarding differences between grades, the results showed no diferences in any aspects. Conclusion The conclusion of this study is that physical injuries are associated with sleep disorders and that anxiety is correlated negatively with both physical injuries and sleep. The result can help teachers and coaches to understand these factors may need to be noted at the start of young elite athletes.

1. Unterschiedliche Definitionen der Gesundheit mit verschiedenen Betrachtungsweisen (WHO: Der Mensch eine biopsychosoziale Einheit. Schulmedizin: ohne klinischen und paraklinischen Befund mit Orientierung an kritikbedürftigen Referenzmittelwerten) führt bei Fachleuten, Behörden und Laien zu Verwirrungen, wenn es um die Beurteilung gesundheitlicher Schäden geht. 2. Es wurde die Aufgabe gestellt zu prüfen, welche der beiden Definitionen der Realität näher kommt. 3. Mittels der chronopsychobiologischen Regulationsdiagnostik, des Dreiphasenentspannungstests (Hecht und Balzer 2001), wurden unter dem Aspekt der beiden Gesundheitsdefinitionen drei Gruppen untersucht (je 40 Probanden). - klinisch Gesunde (klinisch Gesunde nach Schulmedizin ) - Gesunde nach Definition der WHO - Probanden mit nichtorganische Insomnie (ohne pathologische klinische und paraklinische Befunde) 4. Die mit den verwendeten Methoden gewonnenen Daten wiesen aus, dass zwischen den klinisch Gesunden und den Probanden mit nichtorganischer Insomnie weitgehend größere Ähnlichkeiten bestehen. Beide Gruppen zeigten aber zu der Gruppe der Gesunden nach WHO-Definition, welche die biopsychosoziale Einheit des Menschen berücksichtigt, noch hochsignifikante Unterschiede. Die Gruppe der klinisch Gesunden kann daher auf Grund unserer Ergebnisse nicht den Anspruch erheben, real gesund zu sein. 5. Mit der Bezugnahme auf die Internationale Klassifikation der Krankheiten (ICD 10F) haben die von uns untersuchten klinisch Gesunden und die nichtorganischen Insomniker eine mehr oder weniger stark ausgeprägte Symptomatik von psychischen Störungen. Dies müsste bei der Beurteilung von Schadstoff-, Lärm-, und EMF-Wirkungen auf den Menschen, wie auch bei den klinisch-pharmakoloischen Untersuchungen beachtet werden. Die in der Arbeit erzielten Ergebnisse bedürfen durch weitere Untersuchungen eine Fundierung. Sie signalisieren aber sowohl unter praktischen als auch unter theoretischen Aspekten einen dringenden Forschungsbedarf. / 1. Differing definitions of health using different criterea (WHO: The human being as a bio- psycho-social unit versus classical medicine: without clinical and paraclinical results based on suspect reference values) bring confusion to experts, authorities and laymen when assessing health damages. 2. The given task was to check which of the two definitions is closer to reality. 3. Using the chrono-psycho-biological diagnostic of regulation, the three-phase-relaxation test (Hecht and Balzer 2001), three groups were examined considering the aspects of the two health definitions (40 test subjects in the study group). - clinically healthy (clinically healthy per classical medicine definition) - healthy per definition of the WHO - test persons with non organic insomnia (i.e. no pathological or paraclinical findings) 4. The data gained from the employed methods revealed bigger similarities between clinically healthy persons and those with non organic insomnia. Both groups still showed highly significant differences to the group which fulfils the definition of the WHO regarding a human as a bio-psycho-social unit. As a result of this study, persons, though classified as "clinically healthy" might nevertheless not absolutely be healthy in reality. 5. In reference to the international classification of illnesses (ICD 10 F) the groups examined, both of clinically healthy and those with non organic insomnia, have more or less severe psychological symptoms. This should be taken into account when assessing the effects of pollution, noise, and EMF as well as clinical pharmacological studies. These present findings still need broader confirmation by further investigations. However, they clearly indicate, for practical and theoretical considerations, an urgent need for further research.