L’élimination des cellules sénescentes met en jeu le SASP et les cellules immunitaires de l’immunité innée et adaptative tels que les macrophages (Mφ). Dans le cadre de ce projet, nous rapportons que le SASP a un effet pléiotropique sur l’activité des cellules immunitaires incluant leur recrutement, leur activation et leur différenciation. Nos données montrent que les Mφ humains mis en culture avec le SASP de fibroblastes humains développement un profil inflammatoire spécifique au SASP caractérisé par une sécrétion pro-inflammatoire (M1) (ex : IL- 1β, GM-CSF) et des marqueurs de surface anti-inflammatoires (M2) (cellules CD23+CD206+). Le SASP est aussi capable d’augmenter les capacités d’invasion des Mφ, tel que montré via des essais d’invasion, mais n’a pas d’effet sur la différentiation des monocytes. Nos modèles de co- culture montrent que, quoique les cellules NK sont probablement responsables de l’élimination directe et spécifique des cellules sénescentes, leur activité peut être modulée par d’autres cellules immunitaires tels que les Mφ qui réduisent l’élimination faite par les cellules NK, suggérant un profil M2. Les lymphocytes T CD8+ sont aussi essentiels pour l’élimination des cellules sénescentes puisque leur retrait retarde le processus. De plus, nous démontrons que les cellules T CD4+ mises en culture pendant 48h dans le SASP sécrètent de hauts niveaux d’IL-4, indiquant une polarisation Th2. Somme toute, ces données montrent que le SASP peut moduler l’activité des Mφ tout comme celle d’autres cellules immunitaires impliquées dans l’élimination des cellules sénescentes et peut promouvoir, étonnamment, une réponse immunosuppressive pouvant être importante pendant la réparation tissulaire. / Senescent cell clearance brings into play the senescence-associated secretory phenotype (SASP) and immune cells from the innate and adaptive immunity including macrophages (Mφ). In this study, we report that the SASP has a pleiotropic effect on immune cell activity including recruitment, activation and differentiation. We show that human Mφ exposed to the SASP of human fibroblasts develop a SASP-specific inflammatory profile characterized by pro- inflammatory (M1) secretion (e.g. IL-1β, GM-CSF) and anti-inflammatory (M2) surface markers (CD23 and CD206). The SASP also increases Mφ invasion but has no effect on monocyte differentiation. Co-culture models show that while NK cells are likely the direct effectors of senescent cell specific killing, their activity is modulated by other immune cells including Mφ, which reduced NK-mediated killing, suggesting a M2 profile. Alternatively, CD8+ T lymphocytes are essential for senescent cell killing by NK cells. Finally, CD4+ T cells cultured for 48h in the SASP secrete high-levels of IL-4, indicating a Th2 polarization. Overall, our data reveal that the SASP can modulate Mφ and other immune cells involved in senescent cell clearance and surprisingly promote an immunosuppressive response that could be important in tissue repair.

OBJECTIF: La mauvaise clairance des lipoprotéines riches en triglycérides par le tissu adipeux blanc (TAB) entraîne l’hypertriglycéridémie, la résistance à l’insuline et la sécrétion hépatique d’apolipoprotéine B (apoB). Ce mémoire tente de déterminer si le LDL entraîne une clairance réduite des lipoprotéines riches en triglycérides par le TAB. MÉTHODES/RÉSULTATS: Suivant l’ingestion d’un repas riche en gras marqué à la trioléine-13C, des femmes obèses postménopausées avec apoB plasmatique élevé (> médiane 0.93 g/L, N=22, 98% sous forme de IDL/LDL) avaient une clairance réduite de triglycérides-13C et acides gras non-estérifiés-13C (AGNE), comparées à celles avec un apoB plus bas. L'aire sous la courbe à 6 heures des triglycérides-13C et AGNE-13C plasmatiques corrélait avec l'apoB, suggérant une moindre captation dans les tissus périphériques chez les femmes avec apoB élevé. Ex vivo, suivant une incubation de 4 heures de biopsies de TAB avec de la trioléine-3H, l’apoB des patientes corrélait négativement avec les lipides-3H intracellulaires. Le traitement des biopsies de TAB des participantes avec leur propre LDL menait à une réduction de l’hydrolyse et de la captation de la trioléine-3H et à l’accumulation d’AGNE-3H dans le médium. In vitro, le LDL inhibait l’activité de la LPL. De plus, les adipocytes 3T3-L1 différenciés en présence de LDL avaient une hydrolyse et une captation réduite des lipoprotéines riches en trioléine-3H. CONCLUSION: Ce mémoire suggère que le LDL diminue la clairance des lipoprotéines riches en triglycérides par le TAB humain, ce qui pourrait expliquer la résistance à l’insuline observée chez des sujets avec apoB élevé. / OBJECTIVE: Delayed plasma clearance of postprandial triglyceride-rich lipoproteins (TRL) by white adipose tissue (WAT) promotes hypertriglyceridemia, insulin resistance and hepatic secretion of apoB-lipoproteins. The aim of this memoir was to examine whether low-density lipoproteins (LDL) induced delayed clearance of TRL by WAT. METHOD/RESULTS: Six hours following the ingestion of a high-fat meal, 22 postmenopausal obese women were separated based on plasma apoB levels (above/below median of 0.93 g/L). The high apoB group had delayed plasma clearance of postprandial triglyceride and non-esterified fatty acids (NEFA) compared to women with low apoB. There was no group difference in triolein oxidation rate, suggesting a lower NEFA uptake and storage in peripheral tissue in women with high apoB. Ex vivo, following a 4 hour incubation of participant’s WAT with synthetic 3H-triolein-TRL, plasma apoB correlated negatively with incorporated 3H-lipids. Incubation of women’s WAT with their own LDL (90% of apoB-lipoproteins in plasma) decreased 3H-TRL hydrolysis and increased medium 3H-NEFA accumulation. In vitro, LDL directly inhibited LPL activity. Finally, LDL-differentiated 3T3-L1 adipocytes had lower 3H-TRL hydrolysis and 3H-NEFA storage. CONCLUSION: This thesis suggests that LDL delay clearance and storage of TRL in human WAT, possibly explaining the increased insulin resistance observed in subjects with high apoB.

Luffa operculata é uma planta medicinal popularmente usada para tratamento de rinites e rinossinusites. A infusão de seu fruto seco é usada no nariz, liberando secreção mucosa profusa, mas pode causar irritação, epistaxe ou anosmia. Avaliamos os efeitos de diferentes concentrações da infusão do fruto seco da Luffa operculata na velocidade de transporte mucociliar (VTM), freqüência de batimento ciliar (FBC), diferença de potencial transepitelial (DPT) e morfologia do epitélio (microscopia de luz e eletrônica de transmissão), no modelo do palato isolado de rã. Os resultados apontam para dano epitelial dose-dependente no epitélio mucociliar, sugerindo que ela seja potencialmente nociva à mucosa nasal humana / Luffa operculata is a medicinal plant popularly used for treatment of rhinitis and rhinosinusitis. Its dry fruit infusion is used into the nose, delivering profuse mucous secretion, but may cause nasal mucosa irritation, epistaxis or anosmia. We evaluated the effects of different concentrations of Luffa operculata dry fruit infusion on mucociliary transport velocity (MTV), ciliary beat frequency (CBF), transepithelial potential difference (TPD) and epithelial morphology (light and electron transmission microscopy) of the isolated frog palate preparation. Results pointed to dose-dependent epithelial damage on mucociliary epithelium, suggesting that it is potentially noxious to the human nasal mucosa

Complicações renais e urológicas incluindo nefrolitíase, cristalúria, cólica renal e lombalgia, são eventos adversos bem conhecidos do indinavir (IDV), um inibidor de protease (IP) largamente utilizado no tratamento de pacientes infectados com o vírus da imunodeficiência humana (HIV). Prévios estudos em ratos demonstraram que o IDV, um potente IP capaz de provocar uma sustentada supressão da carga viral do HIV, induz vasoconstricção renal, diminui a filtração glomerular (RFG) e reduz a excreção urinária de nitrito (NO2-), sugerindo que a vasoconstricção causada pelo IDV deve ser mediada pelo óxido nítrico (NO). Os objetivos deste estudo foram investigar a ocorrência de insuficiência renal (clearance de creatinina < 80ml/min) em pacientes com infecção pelo HIV tratados com terapia anti-retroviral altamente potente incluindo o inibidor de protease IDV, e mensurar a excreção urinária de nitrato (NO3-) nestes pacientes, comparando-os com outro grupo de pacientes tratados com efavirenz (EFV), um inibidor de transcriptase reversa não-análogo de nucleosídeo (NNRTI). No período compreendido entre março de 2000 e outubro de 2003, estudamos 36 pacientes infectados pelo HIV que estavam em terapia com IDV na dose de 800 mg de 8/8 horas por pelo menos 12 meses. Os pacientes foram avaliados para uma variedade de parâmetros clínicos e laboratoriais: idade, peso, tempo de infecção, tempo de uso de IDV, uso de sulfametoxazol-trimetoprim (SMX-TMP) ou sulfadiazina, exames bioquímicos (colesterol total, triglicérides, magnésio, sódio, potássio e creatinina), exame do sedimento urinário, clearance de creatinina, osmolaridade urinária, volume urinário de 24 h, fração de excreção de sódio (FENa), fração de excreção de potássio (FEK) e fração de excreção de água (FEH2O). NO3 urinário foi mensurado em 18 pacientes recebendo terapia anti-retroviral com IDV e 8 pacientes recebendo terapia com EFV. Leucocitúria ocorreu em 78.8% dos pacientes tratados com IDV. Clearance de creatinina diminuído foi observado em 21 pacientes e foi associado com menor peso e uso de derivados de sulfa. Nestes pacientes com diminuição da função renal, também detectamos menor osmolaridade urinária e uma FEH2O mais alta. A excreção urinária de NO3- foi significativamente menor nos pacientes tratados com IDV (908 ± 181) quando comparados aos pacientes do grupo EFV (2247 ± 648, p<0.01). Nossos resultados mostram que insuficiência renal ocorreu em 58% dos pacientes tratados com IDV e foi associada com menor peso corpóreo e uso de derivados de sulfa. A menor excreção urinária de NO3- e as alterações na osmolaridade e FEH2O sugerem que o IDV diminui a produção de óxido nítrico e causa dano tubular, respectivamente. Sugerimos então que os pacientes em uso de IDV sejam monitorados routineiramente para função renal através do clearance de creatinina. / Renal and urological complications including nephrolithiasis, crystalluria, renal colic and flank pain are significant side effects of the HIV protease inhibitor indinavir (IDV), and IDV has been widely used in the treatment of human immunodeficiency virus (HIV) infection. Previous studies in rats demonstrated that IDV, a potent protease inhibitor that causes profound and sustained supression of HIV replication, also induces renal vasoconstriction, decreases glomerular filtration rate (GFR) and reduces urinary excretion of nitrite (NO2-), suggesting that IDV-vasoconstriction may be mediated by nitric oxide (NO). The objectives of this study were to investigate the occurrence of renal failure (creatinine clearance <80ml/min) in human HIV patients treated with highy active antiretroviral therapy (HAART), including IDV, and to measure urinary excretion of nitrate (NO3-) in those patients, comparing it with that of another group of patients treated with the non-nucleoside reverse-transcriptase inhibitor efavirenz (EFV). From March 2000 through October 2003, we evaluated 36 patients infected with HIV who was receiving IDV 800 mg q8h for at least 12 months. The patients were assessed for a variety of clinical and laboratory parameters including age, body weight, duration of infection, time of IDV treatment, trimethoprim/sulfamethoxazole (TMP/SMX) or sulfadiazine use, biochemistry (total cholesterol, triglycerides, magnesium, sodium, potassium and creatinine), urinalysis, creatinine clearance, urine osmolality, 24-hour urine volume, fractional excretion of sodium (FENa), potassium (FEK) and water (FEH2O). Urinary NO3 was measured in 18 IDV-treated patients and compared with that of 8 EFV-treated patients. Leukocyturia occurred in 78.8% of the IDV-treated patients. Reduced creatinine clearance was observed in 21 patients and was associated with lower body weight and sulfa-derivated use. In these renal failure patients, we also detected a lower osmolality and a higher FEH2O. Excretion of NO3- was significantly lower in IDV-treated patients (908 ± 181) than in EFV-treated patients (2247 ± 648, p<0.01). Our data show that renal failure occurred in 58% of IDV-treated patients and was associated with lower body weight and sulfa administration. The lower NO3- excretion suggests that this drug decreases nitric oxide production, and the alterations in osmolality and FEH2O indicate that it also causes tubular damage. Based on our findings, we suggest that the renal function of patients under IDV treatment should be closely monitored with creatinine clearance.

INTRODUÇÃO: A toxina botulínica tipo A (TXB-A) tem sido testada no tratamento da rinite, principalmente nos casos de rinite idiopática. Sugere-se que um estado de hiper-reatividade do nervo trigêmeo esteja envolvido na fisiopatologia da rinite idiopática. O nervo trigêmeo possui fibras sensitivas não mielinizadas tipo C (FSNMT-C) que contém os neuropeptídeos substância P (SP) e peptídeo relacionado ao gene da calcitonina (CGRP). O óxido nítrico (NO) produzido pelas enzimas óxido nítrico sintase (NOS) também está envolvido nesse processo de neurorregulação nasal. O transporte mucociliar, mecanismo primário de defesa do sistema respiratório, é formado pelo batimento ciliar e muco nasal, e esses componentes podem ser influenciados por diferentes neuropeptídeos e neurotransmissores presentes na mucosa nasal. OBJETIVO: O objetivo deste estudo foi avaliar o efeito da TXB-A sobre a expressão da SP, CGRP e óxido nítrico sintase neural (nNOS), além de sua influência sobre o transporte mucociliar nasal em coelhos. MÉTODOS: Coelhos machos saudáveis da linhagem Nova Zelândia foram divididos em dois grupos: o grupo tratamento recebeu TXB-A (25UI) na concha nasomaxilar (CNM) do lado direito e soro fisiológico a 0,9% (SF0,9%) na CNM esquerda. O grupo controle recebeu SF0,9% na CNM direita e nenhuma intervenção na CNM esquerda. Foram investigados os efeitos da TXB-A sobre a expressão da SP, CGRP e nNOS no tecido de CNM por meio da imuno-histoquímica. Para esta análise, dividiu-se o tecido em camada externa (CE, acima da membrana basal) e camada interna (CI, abaixo da membrana basal). Avaliou-se também a presença de apoptose celular, a frequência de batimento ciliar (FBC), o perfil histoquímico do muco nasal (glicoproteínas ácidas e neutras) e a espessura do epitélio (ESP-CE). RESULTADOS: Foi observado um aumento significativo na quantidade de células apoptóticas na CNM do grupo tratamento que recebeu TXB-A em comparação aos controles (p <= 0,001). A CNM do grupo tratamento que recebeu SF0,9% exibiu um aumento na quantidade de células apoptóticas na CI ao comparar com os controles (CNM SF0,9%, p=0,035) (CNM sem intervenção, p=0,022), e também um aumento da expressão de SP na CE em comparação aos controles (CNM SF0,9%, p=0,021) (CNM sem intervenção, p=0,040). A expressão de CGRP apresentou um aumento na CNM do grupo tratamento que recebeu TXB-A em comparação à CNM sem intervenção (p=0,008). A FBC, expressão de nNOS, perfil histoquímico do muco nasal e ESP-CE não apresentaram diferenças significativas. DISCUSSÃO: O aumento da expressão de CGRP e SP pode ter sido causado por inibição de sua exocitose vesicular pela TXB-A, levando ao seu acúmulo intracelular. Não foram observadas diferenças significativas na FBC ou perfil histoquímico do muco nasal, indicando que o aumento da expressão de CGRP e SP não foi associado à inflamação. O aumento da quantidade de células apoptóticas e da expressão de SP na CNM SF0,9% do grupo tratamento pode ter sido causado por um efeito central da TXB-A. CONCLUSÃO: A administração nasal de TXB-A aumentou a expressão de CGRP e SP, possivelmente por acúmulo intracelular por causa da inibição da sua exocitose, mas sem alterar a FBC e o perfil histoquímico do muco nasal / INTRODUCTION: Botulinum toxin type A (BoNT-A) has been assessed in the treatment of rhinitis, especially in cases of idiopathic rhinitis. Trigeminal hyper-responsiveness appears to be involved in the pathological process of idiopathic rhinitis. Trigeminal nociceptive type C unmyelinated sensory fibers contain the neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP). Nitric oxide (NO) produced by the enzyme nitric oxide synthase (NOS) are also involved in this nasal neurorregulation process. The mucociliary clearance, primary defense system of the respiratory system, is composed by the ciliary beat and nasal mucus. These components can be influenced by different nasal neuropeptides and neurotransmitters. OBJECTIVE: The aim of this study was to evaluate the effect of BoNT-A on the expression of SP, CGRP and neural nitric oxide synthase (nNOS), and its influence on nasal mucociliary clearance in rabbits. METHODS: Healthy New Zealand male rabbits were divided into two groups: the treatment group was challenged with BoNT-A (25UI) in the right nasomaxillary turbinate (NMT) and saline (SF0.9%) in the left NMT. The control group received SF0.9% in the right NMT and no-intervention in the left NMT. We investigated the effects of BoNT-A on SP, CGRP and nNOS expression in the NMT tissue by immunohistochemistry. Each area of interest was subdivided into an internal layer (IL: below the basement membrane) and outer layer (OL: above the basement membrane) for analysis. It was also assessed signs of cellular apoptosis, ciliary beat frequency (CBF), mucus histochemical profile (acidic and neutral glycoproteins) and epithelial thickness (EP-TH). RESULTS: It was observed a significant increase in the amount of apoptotic cells in the BoNT-A-challanged NMT compared with controls (p <= 0.001). The NMT of treatment group which received only SF0.9% showed an increase in the amount of apoptotic cells in the IL compared with controls (NMT SF0.9%, p = 0.035) (NMT no-intervention, p = 0.022), and also an increase in the SP expression in the OL compared with controls (NMT SF0.9%, p = 0.021) (NMT no-intervention, p = 0.040). CGRP expression showed higher expression in the BoNT-A-challanged NMT compared with no-intervention NMT (p=0.008). The CBF, nNOS expression, mucus histochemical profile and EP-TH did not show significant differences. DISCUSSION: The increased CGRP and SP expression could be due to inhibition of vesicular exocytosis by BoNT-A, leading to CGRP and SP intracellular accumulation. No significant differences in CBF or mucus histochemical profile were observed, indicating that the increased CGRP and SP expression was not associated with inflammation. The increase in the amount of apoptotic cells and SP expression in the SF0.9% NMT of treatment group may be due to a central effect of BoNT-A. CONCLUSION: Nasal administration of BoNT-A increased SP and CGRP expression, possibly via inhibition of their release, but did not change the CBF or mucus profile

<p>I dagens konfliktområden är förekomsten av minor och oexploderad ammunition(OXA) ett vanligt förekommande problem för civilbefolkning samt de militära enheter som arbetar i området för att skapa stabilitet och säkerhet. Den här uppsatsen avhandlar möjligheten att lösa eventuella problem som har att göra med förekomsten av minor och OXA i ett missionsområde utan tillgång till stödresurser i form av min- och ammunitionsröjningsteam. Uppsatsens syfte är att undersöka om det är möjligt att tillföra minröjningskompetens på gruppnivå utan att tappa ursprunglig kompetens och fokus från huvudtjänsten. Uppsatsen tar även upp vilken lägsta nivå av utbildning som krävs för att kunna röja mineringar och OXA, samt hur man når upp till det målet. Uppsatsens frågeställning har varit: Går det att inom ramen för Jägarbataljon 09 utbilda en soldat som besitter kompetensen att kunna identifiera och röja mineringar samt OXA? Om ja, vilken utrustning bör tillföras? Mina slutsatser är att det är praktiskt möjligt genom att tillföra en min- och amröjledare på bataljons nivå. Min- och amröjledaren kan i sin tur utbilda och ge soldaterna den reella kompetens som behövs på enbart fyra veckor, ca 130h stimmar. Utbildningen som krävs är grundkursen Minröjning Manuella Metoder(MMM). För att fullt ut kunna nyttja förmågan krävs det att gruppen tillförs viss ammunitionsröjningsutrustning, bland annat extra tänd- och sprängmedel. Effekten man vinner på tillförsel av minröjningskompetensen är kopplat mot förbandets förmåga till okonventionellt uppträdande samt möjligheterna att ta ytterligare steg innanför motståndarens beslutscykel.</p> / <p>In today’s conflict areas the remnants of war, mines and unexploded ordnance (UXO) is a common problem for the civilian population. These remnants also pose a great threat for the military units who work in the area to create peace, stability and security for the people. The purpose of this essay is to discover if and how it is possible to solve eventual problems associated with remnants of war in conflict areas, without the support of Explosive Ordnance Disposal (EOD) teams. My research has explored if it is possible to implement mine clearance and ammunition disposal on a squad without loosing additional competence and focus from the squad’s main field of service. Additional research has been carried out to ascertain the lowest level of competence necessary to work within the field of mine clearance and ammunition disposal, and what education is needed. My thesis aims to answer, if it is possible within the frame of the Army Ranger Battalion 09, to educate a soldier on a squad to have the ability and competence to do work within the field of mine clearance and ammunition disposal? If yes, what additional equipment should be added to the squad, to be able to perform that task? My conclusion is that it is possible to achieve by adding a mine clearance and ammunition disposal leader to the Battalion staff who can educate, train and give the soldiers the proper education in four weeks (approximately 130h). The education required to achieve this goal is the course, Mine clearance Manuel Methods (MMM). To use this ability it is necessary to equip the group with some additional and specific disposal-equipment (i.e. extra explosives.) The main effort gained from implementing this ability on a ranger squad is the Ranger Battalion’s overall ability to operate and appear in unexpected areas, and to get inside the enemy’s OODA-LOOP.</p>

I dagens konfliktområden är förekomsten av minor och oexploderad ammunition(OXA) ett vanligt förekommande problem för civilbefolkning samt de militära enheter som arbetar i området för att skapa stabilitet och säkerhet. Den här uppsatsen avhandlar möjligheten att lösa eventuella problem som har att göra med förekomsten av minor och OXA i ett missionsområde utan tillgång till stödresurser i form av min- och ammunitionsröjningsteam. Uppsatsens syfte är att undersöka om det är möjligt att tillföra minröjningskompetens på gruppnivå utan att tappa ursprunglig kompetens och fokus från huvudtjänsten. Uppsatsen tar även upp vilken lägsta nivå av utbildning som krävs för att kunna röja mineringar och OXA, samt hur man når upp till det målet. Uppsatsens frågeställning har varit: Går det att inom ramen för Jägarbataljon 09 utbilda en soldat som besitter kompetensen att kunna identifiera och röja mineringar samt OXA? Om ja, vilken utrustning bör tillföras? Mina slutsatser är att det är praktiskt möjligt genom att tillföra en min- och amröjledare på bataljons nivå. Min- och amröjledaren kan i sin tur utbilda och ge soldaterna den reella kompetens som behövs på enbart fyra veckor, ca 130h stimmar. Utbildningen som krävs är grundkursen Minröjning Manuella Metoder(MMM). För att fullt ut kunna nyttja förmågan krävs det att gruppen tillförs viss ammunitionsröjningsutrustning, bland annat extra tänd- och sprängmedel. Effekten man vinner på tillförsel av minröjningskompetensen är kopplat mot förbandets förmåga till okonventionellt uppträdande samt möjligheterna att ta ytterligare steg innanför motståndarens beslutscykel. / In today’s conflict areas the remnants of war, mines and unexploded ordnance (UXO) is a common problem for the civilian population. These remnants also pose a great threat for the military units who work in the area to create peace, stability and security for the people. The purpose of this essay is to discover if and how it is possible to solve eventual problems associated with remnants of war in conflict areas, without the support of Explosive Ordnance Disposal (EOD) teams. My research has explored if it is possible to implement mine clearance and ammunition disposal on a squad without loosing additional competence and focus from the squad’s main field of service. Additional research has been carried out to ascertain the lowest level of competence necessary to work within the field of mine clearance and ammunition disposal, and what education is needed. My thesis aims to answer, if it is possible within the frame of the Army Ranger Battalion 09, to educate a soldier on a squad to have the ability and competence to do work within the field of mine clearance and ammunition disposal? If yes, what additional equipment should be added to the squad, to be able to perform that task? My conclusion is that it is possible to achieve by adding a mine clearance and ammunition disposal leader to the Battalion staff who can educate, train and give the soldiers the proper education in four weeks (approximately 130h). The education required to achieve this goal is the course, Mine clearance Manuel Methods (MMM). To use this ability it is necessary to equip the group with some additional and specific disposal-equipment (i.e. extra explosives.) The main effort gained from implementing this ability on a ranger squad is the Ranger Battalion’s overall ability to operate and appear in unexpected areas, and to get inside the enemy’s OODA-LOOP.

L’extensa implantació del control digital als entorns industrials, científics, comercials, professionals i domèstics ha revelat, d’ençà dues dècades, la gran sensibilitat d’aquests dispositius davant sobtats i breus descensos de tensió al subministrament elèctric de xarxa: aturades de plantes a processos productius, re – arrancades a processadors i sistemes de telecomunicació, etc.; i la causa sol esdevenir aparentment inexplicable pels usuaris. La normalització de les conseqüències, però, pot equivaler a un dia sencer de producció nul•la. L’ínfima correlació mostrada pels fenòmens esmentats amb anomalies al sistema elèctric proper (un client pot patir sèries conseqüències, per bé que el client veí només ha percebut una oscil•lació a l’enlluernat, i tots dos comparteixen la mateixa escomesa) sumada amb l’absència contrastada d’interrupció elèctrica suposà, al començament, un major grau d’incertesa, no només pels consumidors; també per a les empreses elèctriques. Fou necessari analitzar el problema en les seves vessants “microscòpica” i “macroscòpica” per a determinar la causa eficient: registrar la forma d’ona al punt de subministrament afectat i fer l’inventari de tots els incidents al Sistema Elèctric del mateix moment. La causa: els sots de tensió produïts per incidents elèctrics a xarxes remotes respecte el subministrament. Davallades sobtades (entre el 80 i el 10% del valor nominal) i ràpides (entre 10 ms i 1 s) al valor eficaç de la tensió subministrada, sense pas per “Zero”, produïdes, principalment, per curt - circuits perfectament detectats i eliminats a xarxes d’Alta Tensió (AT), molt allunyats de la conseqüència observada. A Catalunya, hom comptabilitzen afectacions davant curt - circuits a les interconnexions amb l’Aragó, Castelló i França. La present Tesi Doctoral estableix: • La metodologia per a modelar el Sistema Elèctric de Potència; • La sistematització del binomi causa (curt - circuit) – efecte (sot de tensió); • La personalització estadística de risc pel sot de tensió segons comarques; • Un sistema de protecció eficaç per a limitar la durada dels sots. La metodologia ha estat enfocada a la utilització sistemàtica, tal que per a cada curt - circuit esdevingut a la xarxa AT es pugui establir, en temps real, las capçaleres de subministrament afectades pel sot de tensió, així com la magnitud i la durada del mateix. L’entorn d’aplicació triat ha estat el Sistema Elèctric de Catalunya, per bé que la metodologia i sistemàtica són exportables, de forma natural, a qualsevol altre sistema elèctric trifàsic de corrent altern. / La implantación masiva del control digital en entornos industriales, científicos, comerciales, profesionales y domésticos ha puesto de manifiesto, durante los últimos veinte años, la gran sensibilidad de los mismos ante súbitos y breves descensos de tensión en la alimentación eléctrica procedente de la red: paradas de planta en procesos productivos, re – arranques en procesadores y sistemas de telecomunicación tienen lugar; y la causa de los mismos suele ser aparentemente inexplicable para los usuarios. La normalización de las consecuencias, en ocasiones, equivale a un día de producción nula. La escasa correlación mostrada por dichos fenómenos con anomalías en el sistema eléctrico cercano (un cliente padece consecuencias serias, mientras que el cliente vecino solamente ha percibido una oscilación en el alumbrado y ambos se alimentan del mismo tramo eléctrico) sumada con la ausencia contrastada de interrupción eléctrica supuso, en los inicios, un mayor grado de incertidumbre tanto para los consumidores como para las empresas eléctricas. Fue necesario analizar el problema a nivel “microscópico” y “macroscópico” para determinar la causa eficiente: registrar la forma de onda en el punto de suministro afectado y revisar todos los incidentes habidos en el Sistema Eléctrico en dicho instante. La causa: los huecos de tensión producidos por incidentes eléctricos en redes alejadas del suministro. Descensos súbitos (entre el 80 y el 10% del valor nominal) y rápidos (entre 10 ms y 1 s) en el valor eficaz de la tensión suministrada, sin paso por “cero” de la misma, producidos, principalmente, por cortocircuitos perfectamente detectados y eliminados en redes de Alta Tensión (AT), y situados muy lejos de la consecuencia observada. En el caso de Catalunya, se han contabilizado afectaciones ante cortocircuitos en interconexiones con Aragón, Castellón de la Plana y Francia. La presente Tesis Doctoral establece: • La metodología para modelar el Sistema Eléctrico de Potencia; • La sistematización para el binomio causa (cortocircuito) – efecto (hueco); • La personalización del riesgo estadístico de hueco vs. comarcas; • Un sistema protectivo eficaz para limitar duración de los huecos. Dicha metodología se ha orientado a la utilización sistemática, tal que para cada cortocircuito que tenga lugar en la red AT pueda establecerse, en tiempo real, las cabeceras de suministro afectadas por hueco de tensión, la magnitud y la duración del mismo. Como entorno de aplicación, se ha utilizado el Sistema Eléctrico de Catalunya, si bien la metodología y sistematización son exportables, de forma natural, a cualquier otro sistema eléctrico trifásico de corriente alterna. / The massive introduction of digital control in industrial, scientific, commercial, professional and domestic environments has revealed, over the last twenty years, the great sensitivity of them to sudden and short voltage dips in the electrical power grid: shutdowns of productive process plants, re - starts of processors and telecommunications systems take place, and the cause of them is often apparently inexplicable to the users. The normalization of the consequences sometimes is equivalent to a day without production. The weak correlation shown by these phenomena with anomalies in the nearby electrical system (i.e. in the same portion of a common distribution network, a customer may suffer serious consequences, while the adjacent customer has only percept a swing in the lighting) together with the absence of electrical power interruption represented, in the beginning, a great degree of uncertainty for both consumers and utilities. It was necessary to analyze the problem at the "microscopic" and "macroscopic" levels to determine the efficient cause: record the waveform at the affected plants and review all the disturbances occurred in the Power System at the same instant of time. The cause: voltage dips caused by electrical disturbances away from the supply. Sudden decreases (between 80 and 10% of the nominal value) and fast (between 10 ms and 1 s) in the supplied rms voltage, produced mainly by short-circuits perfectly detected and eliminated in High Voltage (HV) networks, and located far away from the observed consequence. In the case of Catalonia, affectations due to short-circuits in interconnects with Aragon, Castellón de la Plana and France have been recorded. This thesis provides: • A methodology useful to model the Power System; • A systematic analysis for cause – effect: from short – circuit to voltage dip; • A particularization voltage dip statistic risk for each county; • A reliable protective system to ensure time – limitation for voltage dips. The presented methodology is oriented to the systematic use, such that for every short - circuit that takes place in the HV network, the magnitude and duration of voltage dips that appear in the distribution can be established in real-time. As the application framework, the Catalan Power System is used, although the methodology and systematization are exportable, to any other alternating three-phase power system.

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OBJECTIF: La mauvaise clairance des lipoprotéines riches en triglycérides par le tissu adipeux blanc (TAB) entraîne l’hypertriglycéridémie, la résistance à l’insuline et la sécrétion hépatique d’apolipoprotéine B (apoB). Ce mémoire tente de déterminer si le LDL entraîne une clairance réduite des lipoprotéines riches en triglycérides par le TAB. MÉTHODES/RÉSULTATS: Suivant l’ingestion d’un repas riche en gras marqué à la trioléine-13C, des femmes obèses postménopausées avec apoB plasmatique élevé (> médiane 0.93 g/L, N=22, 98% sous forme de IDL/LDL) avaient une clairance réduite de triglycérides-13C et acides gras non-estérifiés-13C (AGNE), comparées à celles avec un apoB plus bas. L'aire sous la courbe à 6 heures des triglycérides-13C et AGNE-13C plasmatiques corrélait avec l'apoB, suggérant une moindre captation dans les tissus périphériques chez les femmes avec apoB élevé. Ex vivo, suivant une incubation de 4 heures de biopsies de TAB avec de la trioléine-3H, l’apoB des patientes corrélait négativement avec les lipides-3H intracellulaires. Le traitement des biopsies de TAB des participantes avec leur propre LDL menait à une réduction de l’hydrolyse et de la captation de la trioléine-3H et à l’accumulation d’AGNE-3H dans le médium. In vitro, le LDL inhibait l’activité de la LPL. De plus, les adipocytes 3T3-L1 différenciés en présence de LDL avaient une hydrolyse et une captation réduite des lipoprotéines riches en trioléine-3H. CONCLUSION: Ce mémoire suggère que le LDL diminue la clairance des lipoprotéines riches en triglycérides par le TAB humain, ce qui pourrait expliquer la résistance à l’insuline observée chez des sujets avec apoB élevé. / OBJECTIVE: Delayed plasma clearance of postprandial triglyceride-rich lipoproteins (TRL) by white adipose tissue (WAT) promotes hypertriglyceridemia, insulin resistance and hepatic secretion of apoB-lipoproteins. The aim of this memoir was to examine whether low-density lipoproteins (LDL) induced delayed clearance of TRL by WAT. METHOD/RESULTS: Six hours following the ingestion of a high-fat meal, 22 postmenopausal obese women were separated based on plasma apoB levels (above/below median of 0.93 g/L). The high apoB group had delayed plasma clearance of postprandial triglyceride and non-esterified fatty acids (NEFA) compared to women with low apoB. There was no group difference in triolein oxidation rate, suggesting a lower NEFA uptake and storage in peripheral tissue in women with high apoB. Ex vivo, following a 4 hour incubation of participant’s WAT with synthetic 3H-triolein-TRL, plasma apoB correlated negatively with incorporated 3H-lipids. Incubation of women’s WAT with their own LDL (90% of apoB-lipoproteins in plasma) decreased 3H-TRL hydrolysis and increased medium 3H-NEFA accumulation. In vitro, LDL directly inhibited LPL activity. Finally, LDL-differentiated 3T3-L1 adipocytes had lower 3H-TRL hydrolysis and 3H-NEFA storage. CONCLUSION: This thesis suggests that LDL delay clearance and storage of TRL in human WAT, possibly explaining the increased insulin resistance observed in subjects with high apoB.