Conselho Nacional de Desenvolvimento Científico e Tecnológico / A síndrome dos ovários policísticos é uma desordem frequente e complexa, com grande variabilidade fenotípica, predominando os sinais de disfunção ovariana. Alterações metabólicas, inflamatórias e vasculares vinculadas à resistência à insulina são muito prevalentes nessa desordem podendo manifestar-se precocemente. O objetivo principal deste estudo foi investigar a presença de alterações microvasculares em mulheres jovens e não obesas portadoras da síndrome dos ovários policísticos, através de videocapilaroscopia periungueal e dosagem dos níveis séricos de endotelina-1. O objetivo secundário foi verificar a existência de associações entre os achados vasculares, níveis séricos de androgênios, parâmetros clínicos, bioquímicos, metabólicos e inflamatórios relacionados ao risco cardiovascular. Em estudo observacional, transverso e controlado avaliamos 12 mulheres com diagnóstico de síndrome dos ovários policísticos, segundo os critérios estabelecidos pelo consenso de Rotterdam e nove voluntárias saudáveis. A idade (22,82,3 X 24,62,7), o índice de massa corporal (22,53,4 X 23,73,1) e a circunferência da cintura (7510,1 X 77,38,1) foram semelhantes nos dois grupos. As portadoras da síndrome apresentavam hiperandrogenismo clínico. Não foram observadas diferenças significativas entre os grupos quando analisados os níveis séricos de estradiol, testosterona total, androstenediona ou o índice de testosterona livre, entretanto a SHBG mostrou-se significativamente mais baixa no grupo de estudo (p=0,011). A glicemia de jejum, insulina, HOMA-IR e o perfil lipídico foram normais e sem diferença entre os grupos. A amostra com síndrome dos ovários policísticos não apresentava intolerância à glicose ou Diabetes Mellitus pelo teste oral de tolerância à glicose. Os níveis séricos dos marcadores inflamatórios (leucócitos, ácido úrico, adiponectina, leptina e proteína c reativa) e do marcador de função endotelial avaliado também foram similares nos dois grupos. A velocidade de deslocamento das hemácias no basal e após oclusão foram significativamente menores nas pacientes de estudo (p=0,02), mas o tempo para atingir a VDHmax e os parâmetros relativos à morfologia e densidade capilar foram semelhantes. Não observamos correlação entre a velocidade de deslocamento das hemácias e níveis plasmáticos de endotelina-1, androgênios ou parâmetros de resistência insulínica. A velocidade de deslocamento das hemácias associou-se positivamente aos níveis plasmáticos de estradiol (r= 0,45, p<0,05) e negativamente aos de colesterol total e LDL colesterol (r= -0,52, p<0,05; r=-0,47, p<0,05, respectivamente). Em conclusão nossos resultados fornecem evidência adicional de dano precoce à função microvascular em mulheres portadoras de síndrome dos ovários policísticos. Através da capilaroscopia periungueal dinâmica, demonstramos que mulheres jovens com moderado hiperandrogenismo, sem obesidade, RI, hipertensão ou dislipidemia, já apresentam disfunção microvascular nutritiva, caracterizada por redução na velocidade de fluxo das hemácias no basal e após oclusão. Estes achados micro-circulatórios não foram acompanhados de elevações nos níveis plasmáticos de endotelina-1. / Polycystic ovary syndrome is a frequent and complex disorder, showing a great phenotypic variability, with predominance of signs of ovarian dysfunction and, more particularly, of hyperandrogenism and oligo-anovulatory cycles. This disorder shows a high prevalence of insulin resistance -related metabolic, inflammatory and vascular alterations, which may present at early stages. The main purpose of this study was to investigate the presence of microvascular alterations in young and non-obese women with polycystic ovary syndrome through periungueal videolaparoscopy and dosage of endothelin-1 serum levels. The secondary purpose was to verify further associations between vascular findings, serum androgen levels, and clinical, biochemical, metabolic and inflammatory parameters related to cardiovascular risk. We conducted an observational, transversal and controlled study to evaluate 12 women who, according to Rotterdam criteria, were diagnosed with polycystic ovary syndrome, and also nine healthy volunteers. Our selective process excluded from both groups women with smoking habits, as well as those who had made use of oral contraceptive, metformin or antilipemic drugs within three months prior to the beginning of the study. The age range (22,82,3 X 24,62,7), body mass index (22,53,4 X 23,73,1), and waist circumference (7510,1 X 77,38,1) were similar in both groups. Our patients with polycystic ovary syndrome presented clinical hyperandrogenism. Analysis of serum estradiol, total testosterone, androstenedione levels or testosterone free index disclosed no significant differences between the groups, although SHBG appeared to be expressively lower in the studied group (p=0.003). Fasting blood glucose test, insulin level, HOMA-IR and lipid profile showed normal results, and without difference between the groups. As disclosed by the oral glucose tolerance test, the group with PCOS did not present tolerance to either glucose or diabetes mellitus. When evaluated, the serum levels of inflammatory markers (leukocytes, uric acid, adinopectin, leptin and c-reactive protein) and of endothelial function marker (endothelin-1) were also similar in both groups. The red blood cell velocity at baseline and peak were significantly lower in patients with PCOS (p=0.02), although the timeframe to reach blood cell velocity at baseline and peak and the parameters referring to morphology and capillary density were similar between the groups. No association was observed between the speed of movement of red blood cells and plasma levels of endothelin-1, androgens or insulin resistance parameters. The velocity of movement of red blood cells was positively related to estradiol plasma levels (rho= 0.45, p<0.05) and negatively to the levels of total cholesterol and LDL cholesterol (rho= -0.52, p<0.05; rho=-0.47, p<0.05 respectively). Taken together, our results provide an additional evidence of early lesion to microvascular function in women with polycystic ovary syndrome. By using a simple procedure, namely the dynamic nailfoldvideocapillaroscopy, we demonstrated that young women with mild hyperandrogenism, who do not present obesity, insulin resistance, high blood pressure or dyslipidemia, already show a nutritional microvascular dysfunction, characterized by a reduced speed of red blood cells flow at basal level and after occlusion. Such microcirculatory findings were not accompanied by an increase of endothelin-1 plasma levels.

Introdução: este estudo avaliou o efeito do laser vermelho de baixa potência na viabilidade de retalhos cutâneos randômicos em ratos. Métodos: 40 ratos Wistar foram divididos em 4 grupos, aleatoriamente, onde 1 grupo foi utilizado como controle (G1) e os demais foram irradiados com laser de 670 nm, com 2,14 (G2), 5,36 (G3) e 20,36 J/cm2 (G4), respectivamente. Resultados: o G1 apresentou 49,35% da área do retalho necrosada, G2 39,14%, G3 47,01% e G4 29,17%. À análise estatística obtivemos diferença significativa apenas quando comparamos G4 com o G1 (p < 0,001). Conclusão: o LBP vermelho (20,36 J/cm2) é capaz de incrementar a viabilidade dos retalhos cutâneos randômicos em ratos / Introduction: This study assessed the effects of different LLLT doses on randomic skin flap rats. Methodology: 40 wistar rats were divided in four groups. The control group (CG) was not irradiated. The experimental groups were irradiated with different fluency: group 2 (G2) with 2,14 J/cm²; group 3 (G3) 5,36 J/cm² and group 4 (G4) 20,36 J/cm². The necrosis area was evaluated in the seventh postoperative day. Results: The CG shows 49,35% of necrosis area in the skin flap; G2, 39,14%; G3, 47,01% and G4, 29,17% respectively. There was a significantly difference when G4 was compared with CG`s skin flap necrosis area. Conclusion: Red LLLT with increases the survival in randomic skin flap rats

Summary<p>Brain dysfunction is a frequent complication of sepsis and is usually defined as “sepsis-associated encephalopathy” (SAE). Its pathophysiology is complex and related to a number of processes and pathways, while the exact mechanisms producing neurological impairment in septic patients have not been completely elucidated. Alterations in cerebral blood flow (CBF) have been suggested as a key component for the development of SAE. Reduction of CBF may be caused by cerebral vasoconstriction, induced either by inflammation or hypocapnia. More importantly, the natural mechanisms that protect the brain from reduced/inadequate CBF can be impaired in septic patients, especially in those with shock, and this further contributes to cerebral ischemia if blood pressure drops below a critical threshold. Hypercapnia is associated with a narrower autoregulatory plateau, which may potentially results in large CBF variations when mean arterial pressure (MAP) varies within usual targets. However, few data are available on the role of PaCO2 on cerebral autoregulation (CA). Finally, as SAE occurs also in patients without hemodynamic instability, alterations in brain tissue perfusion could occur independently from hypotension; thus, alterations in cerebral microcirculation, which largely regulates regional flow and blood-cellular nutrients exchanges, could contribute to SAE. In septic animals, these microcirculatory abnormalities could be implicated in the development of electrophysiological abnormalities observed during sepsis and contribute to neurological alterations. However, these findings were limited by several factors, including the technique used to assess the microcirculation, the short time of observation and the limited amount of fluid resuscitation used in those models. <p>In the first part of this work, I evaluated CA and the potential influence of PaCO2 on CA in patients with septic shock. In 21 mechanically ventilated patients, I observed that 14 of them had impaired CA. All the 7 patients with a PaCO2 ≥ 40 mmHg but only 7 of the 14 patients with a PaCO2 <40 mmHg had an impaired CA (p=0.046). Specifically, 4/9 (44%) patients with PaCO2 < 35 mmHg, 7/9 (77%) with PaCO2 between 35 and 42 mmHg, and 3/3 (100%) with PaCO2 > 42 mmHg had impaired CA. The Receiver Operating Characteristic (ROC) analysis showed that a PaCO2 threshold of 38 mmHg had a sensitivity of 50% and a specificity of 100% for the prediction of impaired CA, with an area under the ROC curve of 0.76 (95% confidence interval: 0.52–0.91).<p>In the second part of this work, I hypothesized that altered cerebral microcirculation may occur in the early phase of sepsis and contribute to brain hypoxia. In a clinically relevant model of ovine fecal peritonitis, I showed that there was a progressive deterioration of cerebral microvascular flow in septic animals (n=10) when compared to sham animals (n=5), starting already after 6 hours from sepsis induction and becoming significant at 12 hours thereafter. Moreover, changes in the cerebral microcirculation were not related to changes in MAP, cardiac output or blood lactate levels, suggesting that these alterations in the brain may occur even when global perfusion pressure is maintained, i.e. in non-hypotensive conditions. In a second study, including 10 septic and 5 sham animals, I found that cortical microvascular alterations were associated with decreased cerebral oxygenation. Furthermore, cerebral metabolic disturbances compatible with tissue hypoxia (i.e. increased brain lactate/pyruvate ratio, LPR) occurred mostly during shock, suggesting that hypotension is a critical factor in the development of anaerobic metabolism in the septic brain. Nevertheless, I showed in a third study (n=8) that the reversal of hypotension using vasopressor agents, although increased cerebral oxygenation and slightly reduced LPR, did not significantly influence the alterations of cerebral microcirculation and was associated with an increase in glutamate and glycerol, suggesting ongoing excitotoxicity and cellular damage. These alterations in cerebral microcirculation, oxygenation and metabolism may then contribute to the pathogenesis of SAE.<p><p><p><p><p>Résumé<p>La dysfonction cérébrale est une complication fréquente du sepsis et elle est généralement identifiée comme « encéphalopathie associée au sepsis » (sepsis-associated encephalopathy, SAE). La physiopathologie de la SAE est complexe et liée à des nombreux processus et voies de signalisation, même si les mécanismes qui induisent cette dysfonction cérébrale chez les patients en sepsis n’ont pas été clairement élucidés. Des anomalies du débit sanguin cérébral (cerebral blood flow, CBF) ont été proposées comme une des déterminants pour le développement de l’SAE. La réduction du CBF pourrait être induite par une vasoconstriction cérébrale, élicitée pas l’inflammation ou par l’hypocapnie. De plus, les mécanismes qui naturellement règlent le CBF pour qu’il soit ni diminué ni inadéquat aux besoins cellulaires peuvent être altérés pendant le sepsis, particulièrement en cas de choc septique, et ceci pourrait davantage contribuer au développement de zones d’hypoperfusion cérébrale si la pression artérielle diminue au-dessous d’un seuil critique. Un autre point important est que l’hypercapnie est associée à une diminution du plateau d’autorégulation du CBF, ce qui pourrait potentiellement causer des larges variations du CBF endéans des valeurs de pression artérielle considérés comme normaux en pratique clinique; malheureusement, très peu de données sont disponibles sur le rôle de la PaCO2 sur l’autorégulation cérébrale (cerebral autoregulation, CA). Enfin, vu que l’SAE survient aussi chez des patients qui n’ont pas d’instabilité hémodynamique, des anomalies de la perfusion cérébrale régionale pourraient se produire en absence de toute hypotension artérielle ;en effet, des altérations de la microcirculation cérébrale, qui règle le débit sanguin au niveau des tissues et l’échange d’oxygène et nutriments entre la circulation sanguine et le cellules, peuvent aussi contribuer au développement de la SAE. Dans des modelés expérimentaux de sepsis, les altérations microcirculatoires ont été associées à des troubles électrophysiologies et à la présence d’anomalies « cliniques ». Cependant, ces données ont été biaisées par le type de technique utilisée pour évaluer la microcirculation, le temps d’observation très court et la quantité limitée de fluides administrés au cours de la réanimation liquidienne dans ces modelés. <p>Dans la première partie de ce travail, j’ai décrit les anomalies de la CA et l’impact de la PaCO2 sur la CA chez des patients en choc septique. En étudiant 21 patients en ventilation mécanique, j’ai pu observer que 14 d’entre eux avaient une CA altérée, y compris 7/14 avec une PaCO2 < 40 mmHg et 7/7 avec une PaCO2 ≥ 40 mmHg (p = 0.046). De plus, 4/9 (44%) avec PaCO2 < 35 mmHg, 7/9 (77%) avec PaCO2 between 35 and 42 mmHg, and 3/3 (100%) avec PaCO2 > 42 mmHg avaient une CA altérée. L’analyse selon la « Receiver Operating Characteristic » (ROC) montrait une sensibilité de 50% et une spécificité de 100% pour prédire une CA altérée, avec un seuil de PaCO2 de 38 mmHg (l’aire sous la courbe de l’analyse ROC était à 0.76 [95% ICs: 0.52–0.91]).<p>Dans la deuxième partie de ce travail, j’ai émis l’hypothèse que des anomalies de la microcirculation cérébrale peuvent survenir dans la phase précoce du sepsis et contribuer au développement d’une hypoxie tissulaire. Dans un modelé de péritonite fécale induite chez le mouton, très proche de la situation clinique, j’ai pu montrer que il existe une détérioration progressive de la microcirculation cérébrale chez les animaux septiques (n-=10) quand comparés aux animaux témoins (n=5) qui commence déjà a la sixième heure de l’induction du sepsis and devient significative après 12 heures. De plus, les changement de la microcirculation cérébrale n’étaient pas corrélés à ceux de la pression artérielle, du débit cardiaque ou des taux de lactate, ce qui suggère que ces anomalies peuvent se produire aussi en conditions de stabilité hémodynamique. Dans une deuxième étude comprenant 10 animaux septique et 5 témoins, j’ai observé que les anomalies microcirculatoires étaient associées à une diminution de l’oxygénation cérébrale tissulaire. Toutefois, les anomalies du métabolisme cérébral compatible avec une hypoxie tissulaire (des valeurs élevées du rapport lactate/pyruvate, LPR) se développaient que dans la phase du choc septique, indiquant que l’hypotension artérielle est le facteur déterminant pour ces anomalies métaboliques au cours du sepsis. Cependant, dans une troisième étude sur 8 animaux en sepsis, j’ai démontré que la correction de l’hypotension par administration de vasopresseurs, même si elle était associée à une augmentation de l’oxygénation cérébral et une diminution du LPR, n’améliorait pas de façon significative la microcirculation cérébrale et s’accompagnait par une augmentation des taux de glutamate et glycérol, ce qui plaidait plutôt pour un excitoxicité persistante et une progression des lésions cellulaires. Toutes ces anomalies de microcirculation, oxygénation et métabolisme cérébral pourraient contribuer à la pathogenèse de l’SAE.<p> / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished

Background: To assess acute effects of bevacizumab (anti-VEGF therapy) on cerebral microvessels and systemic cardiovascular regulation. Design and subjects: 20 consecutive patients with colorectal cancer (median age: 60.4 years, range 45.5-73.9 years) received bevacizumab intravenously (5 mg/kg) uncoupled of chemotherapy. Prior to and within the first 24 hours after bevacizumab infusion, patients were investigated for retinal endothelial function. A series of a triple 24-hour ambulatory blood pressure measurement was conducted. Retinal endothelial function was determined as flicker light-induced vasodilation. The integrity of baroreflex arc and autonomic cardiovascular control was examined by stimulatory manoeuvres. Results: Bevacizumab therapy significantly reduced the vasodilatory capacity of retinal arterioles in response to flicker light. A slight decrease in diastolic pressure and heart rate was observed after bevacizumab infusion but this was unrelated to changes in retinal function. The pressure response upon nitroglycerin was largely preserved after bevacizumab infusion. The proportion of patients with abnormal nocturnal blood pressure regulation increased under anti-angiogenic therapy. Autonomic blood pressure control was not affected by bevacizumab treatment. Conclusions: Bevacizumab acutely impairs microvascular function independent of blood pressure changes. Imaging of the retinal microcirculation seems a valuable tool for monitoring pharmacodynamic effects of bevacizumab.

It is emerging that the brain’s vasculature consists of a highly spatially heterogeneous network; however, information on how various vascular characteristics differ between brain regions is still lacking. Furthermore, aging studies rarely acknowledge regional differences in the changes of vascular features. The density of the capillary bed is one vascular feature that is important for the adequate delivery of nutrients to brain tissue. Additionally, capillary density may influence regional cerebral blood flow, a parameter that has been repeatedly correlated to cognitive-behavioural performance. Age-related decline in capillary density has been widely reported in various animal models, yet important questions remain concerning whether there are regional vulnerabilities and what mechanisms could account for these regional differences, if they exist. Here we used confocal microscopy combined with a fluorescent dye-filling approach to label the vasculature, and subsequently quantified vessel length, tortuosity and diameter in 15 brain regions in young adult and aged mice. Our data indicate that vessel loss was most pronounced in white matter followed by cortical, then subcortical gray matter regions, while some regions (visual cortex, amygdala, insular cortex) showed little decline with aging. Changes in capillary density are determined by a balance of pruning and sprouting events. Previous research showed that capillaries are naturally prone to plugging and prolonged obstructions often lead to vessel pruning without subsequent compensatory vessel sprouting. We therefore hypothesized that regional susceptibilities to plugging could help predict vessel loss. By mapping the distribution of microsphere-induced capillary obstructions, we discovered that regions with a higher density of persistent obstructions were more likely to show vessel loss with aging and vice versa. Although the relationship between obstruction density and vessel loss was strong, it was clear obstruction rates were insufficient to explain vessel loss on their own. For that reason, we subsequently used in vivo two-photon microscopy to track microsphere-induced capillary obstructions and vascular network changes over 24 days in two areas of cortex that showed different magnitudes of vessel loss and obstruction densities: visual and retrosplenial cortex. Surprisingly, we did not find evidence for differences in vessel pruning rates between areas, as we would have expected. Instead, we observed brain region-specific differences in recanalization times and rates of angiogenesis. These findings indicate that age-related vessel loss is region specific and that regional susceptibilities to capillary plugging and angiogenesis must be considered to explain these differences. Altogether, this work supports the overarching hypothesis that regional differences in vascular structure and function contribute to a regionally heterogeneous phenotype in the aging brain. / Graduate

<p>Oxygen (O2) plays a crucial role in the energy metabolism of complex multicellular life on earth. Due to the small and finite energy stores in the body, fine-tuned changes within the body are required to meet metabolic demand during skeletal muscle contractions, such as during exercise and activities of daily living. The skeletal muscle microcirculation is one of the last steps in the O2 transport pathway from the lungs to muscle cells and represents the largest surface area for O2 and substrate exchange. When skeletal muscle O2 uptake increases during contractions to meet metabolic demand, there must be an increase in muscle O2 delivery. To achieve these elevations in O2 delivery, vessel (arteriole) diameter in the microcirculation is increased, known as vasodilation. This process in the skeletal muscle microcirculation is regulated by several factors, such as neurohumoral, mechanical, endothelial, paracrine, and metabolic influences, which are imperative in properly regulating O2 delivery at rest and during muscular contractions. Two vasodilatory pathways of interest in this dissertation are the cyclooxygenase (COX) and nitric oxide (NO) vasodilatory pathways.</p> <p>The primary aim of my dissertation studies was to determine the mechanisms that modulate skeletal muscle oxygenation in health and to define the impact of a potentially effective intervention, whole-body chronic heat therapy (HT), to treat heart failure with preserved ejection fraction (HFpEF). In Chapter 2, we report that acute selective COX-2 inhibition had no effect on resting or exercising skeletal muscle microvascular oxygenation, pulmonary oxygen uptake, or exercise tolerance in healthy young humans. In Chapter 3, we report that NO, via phosphodiesterase type 5 inhibition, regulates myocyte O2 transport at rest and during recovery from muscle contractions in healthy young rats. In Chapter 4, we show that whole-body chronic HT promotes central and peripheral adaptations, which impact positively exercise tolerance in a pre-clinical rat model of HFpEF. Specifically, whole-body chronic HT had beneficial influences on exercise tolerance, skeletal muscle oxygenation from rest to contractions (driven, at least in part, by enhanced NO bioavailability), body composition, and cardiac function. Chapter 5 is a summary of the results and limitations of the projects presented in Chapters 2-4, with a brief discussion of potential future research directions. </p>

<p>Cilj: Kod trećine bolesnika sa akutnim ST-eleviranim infarktom (STEMI) nakon primarne angioplastike (pPCI) razvije se postinfarktno remodelovanje leve komore (LK). Cilj istraživanja je nalaženje ranih prediktora post-infarktnog remodelovanja leve komore nakon akutnog STEMI i pPCI. Metodologija: Uključeno je 210 ispitanika sa prvim akutnim STEMI prednjeg zida, lečenih pPCI. Urađena je ehokardiografija u prva 24h, a zatim nakon 6 meseci, kada su ispitanici podeljeni u 2 grupe: ispitivanu sa remodelovanjem (n=55; 26%) i kontrolnu bez remodelovanja (n=155; 74%). Ispitanici su klinički praćeni godinu dana. Rezultati i dikusija: Multivarijantnom regresionom analizom, kao najsnažniji rani prediktori post-infarktnog remodelovanja izdvojili su se: postojanje &quot;no reflow&quot; fenomena nakon pPCI (OR=30.0 95% CI, p&lt;0.0001), pojava dijastolne disfunkcije u prva 24h (OR=27.7 95% CI, p&lt;0.0001), povećan dijametar leve pretkomore - LA (OR=5.0 95% CI, p=0,044) i srčana slabost na prijemu - Killip klasa 2-4 (OR=3.4 95% CI, p=0.003.). Univarijantnom regresionom analizom, snažni prediktori su neadekvatna rezolucija ST segmenta - STR (OR 2.0 95% CI, p=0.024) i zbirni indeks zidne pokretljivosti &ndash; WMSI &gt;2 (OR 21.6 95% CI, p&lt;0.0001). Totalno ishemijsko vreme nije imalo uticaja na post-infarktno remodelovanje (p=0.546). Tokom jednogodi&scaron;njeg praćenja ispitanici sa post-infarktnim remodelovanjem su imali značajno veću incidencu glavnih neželjenih kardiolo&scaron;kih događaja: rehospitalizacija (61.8% vs 22.6%; p&lt;0.0001) / najvi&scaron;e rehospitalizacija zbog srčane slabosti (40% vs 2.6%; p&lt;0.0001), sa mortalitetom 5.5%/; reinfarkta (20% vs 7.1%; p=0.007); rekoronarografija (45.5% vs 18.1%; p&lt;0.0001); revaskularizacija (30.9% vs 11%; p=0.001). Zaključak: Kod pacijenata sa akutnim STEMI prednjeg zida lečenih pPCI, pojava &quot;no reflow&quot; fenomena, dijastolne disfunkcije, povećana LA i srčana slabosti na prijemu su najjači rani nezavisni prediktivni faktori za nastanak post-infarktnog remodelovanja. Značajni prediktori su i neadekvatna STR i WMSI&gt;2. Pacijenti sa post-infarktnim remodelovanjem imaju veću incidencu glavnih neželjenih kardiolo&scaron;kih događaja i mortaliteta.</p> / <p>Objective: Patients with ST-elevated myocardial infarction (STEMI) treated by primary angioplasty (pPCI) will develop left ventricular (LV) remodeling in one third of the cases. The purpose of this study is to determine early predictors of LV remodeling after acute STEMI and pPCI. Methods: 210 patients with a first acute anterior STEMI treated by pPCI were included. All participants underwent echocardiography in the first 24hrs and again after 6 months, after which they were divided into two groups: remodeling (n=55; 26%) and nonremodeling (n=155; 74%). Results and discussion: The most powerful independent early predictors were: &quot;no reflow&quot; after pPCI (OR=30.0 95% CI, p&lt;0.0001), diastolic dysfunction in the first 24hrs (OR=27.7 95% CI, p&lt;0.0001), increased diameter of the left atrium - LA (OR=5.0 95% CI, p=0.044) and at admission Killip class 2-4 (OR=3.4 95% CI, p=0.003), by multivariant regression analysis. Also, strong predictors were incomplete ST-resolution - STR (OR 2.0 95% CI, p=0.024) and Wall motion score index - WMSI &gt;2 (OR 21.6 95% CI, p&lt;0.0001), by univariant regression analysis. Total ischaemic time had no influence on LV remodeling. The group with remodeling had more frequent major adverse cardiac events (MACE) during one year follow-up: re-hospitalisation (61.8% vs 22.6%; p&lt;0.0001) / mostly re-hospitalisation due to heart failure (40% vs 2.6%; p&lt;0.0001) and mortality 5.5%; reinfarction (20% vs 7.1%; p=0.007); recoronagraphy (45.5% vs 18.1%; p&lt;0.0001); revascularisation (30.9% vs 11%; p=0.001). Conclusion: For the patients with a first acute anterior STEMI, treated by pPCI, development of &quot;no reflow&quot; after pPCI, diastolic dysfunction, increased LA and heart failure on admission are the most powerful early independent predictors for LV remodeling. Incomplete STR and WMSI&gt;2 are strong predictors too. Remodeling patients will have a more frequent incidence of MACE and mortality.</p>

La transplantation rénale est la stratégie de suppléance rénale la plus performante. Le renforcement des thérapeutiques ciblant la réponse cellulaire T (i) a conduit à réévaluer la réponse allogénique humorale et (ii) a souligné deux complications majeures de la pression immunosuppressive : l’infection à cytomégalovirus CMV et le risque de cancer. Dans le travail présenté ici, nous analysons d’abord l’impact histologique de deux de ces facteurs de détérioration de l’allogreffon rénal : l’infection à CMV avant une biopsie sur indication et la pathogénicité des anticorps anti-HLA dirigés contre le donneur, détectés par des techniques d’identification en Single Antigen in situ dans le greffon. Nous montrons ensuite comment les lymphocytes T (LT) γδ Vd2neg font le lien entre CMV et DSA : induits par le CMV, les LT γδ Vd2neg participent aux lésions médiées par les DSA par leur capacité à réaliser une lyse dépendante de l’anticorps (ADCC) impliquant le CD16. En plus de cette nouvelle fonction allogénique indirecte, les LT γδ Vd2neg possèdent une double réactivité anti-CMV et anti-tumoral. Nous présentons ici un modèle où les lymphocytes T γδ Vδ2neg s’activent spécifiquement de façon TCR dépendante par la reconnaissance d’un marqueur d’intégrité épithéliale (EphA2) : ils détournent le mécanisme d’interaction classique d’EphA2 avec ses ligands naturels éphrines A1 et A4 pour s’en faire un signal de costimulation, en s’appuyant sur le contexte de stress pour renforcer son activation. Collectivement, nos résultats contribuent à mieux préciser la bioréactivité et le rôle des LT γδ Vδ2neg en transplantation rénale. Nos données suggèrent que chez l'homme, a fortiori lorsqu’il est immunodéprimé, les LT γδ constituent un compartiment de surveillance lymphoide du stress, capable de censurer la dérégulation des cellules infectées ou transformées et de prendre part à la réponse allogénique par un mécanisme d’ADCC. / Kidney transplant is the most performant strategy for renal replacement therapy. Increasing treatment targetting T cell response has led (i) to reappraise the importance of humoral allogenic response, (ii) to underline two main complications subsequent to immunosuppressive pressure : cytomegalovirus infection and tumorigenesis. Here, we first report the pathological impact of two of these factors on kidney allograft deterioration : CMV infection prior a biopsy for cause and Donor Specific Alloantibodies (DSA) detected within the graft with single antigen flow bead assay. Then we showed that CMV-induced Vδ2neg γδ T cells are a new player and a potentially useful clinical biomarker in antibody-mediated lesions of kidney transplants. By engaging DSA on their Fcγ-receptor CD16, γδ T cells participate in allograft lesions mediated by DSA through antibody-dependent cell cytotoxicity (ADCC). In addition to this new indirect allogenic function, CMV-induced Vδ2neg γδ T cells displayed a dual anti-CMV and anti-tumor reactivity. Finally, we here identified EphA2 as a new stress-regulated antigen targetting by a non Vδ2neg γδ T cell clone, which recognition implies the hijacking of the natural EphA2-ephrin interactions to activation. These data suggest that in humans, a fortiori when immunosuppressed, γδ T cells compose a lymphoid stress-surveillance compartment, capable of recognizing the dysregulated state of infected or transformed cells and to take part to allogenic response through an ADCC mechanism.

Estudos demonstram que o treinamento aeróbio é capaz de reduzir a razão parede/luz (RP/L) de arteríolas musculares esqueléticas e reduzir a pressão arterial média, PAM (em hipertensos), além de causar bradicardia de repouso e aumentar a densidade de capilares e vênulas (em hipertensos e normotensos) após 13 semanas de treinamento. Investigamos em ratos normotensos (WKY, Wistar Kyoto) e hipertensos espontâneos (SHR) as alterações estruturais da microcirculação muscular esquelética, cardíaca e renal, relacionando-as aos valores de PAM e frequência cardíaca (FC) em diferentes fases de um protocolo de treinamento. Para tal, WKY e SHR (2 meses de idade) foram submetidos ao protocolo de treinamento físico de baixa intensidade por tempos crescentes (semanas 0, 1, 2, 4, 8 e 12) ou mantiveram-se sedentários (semanas 0 e 12). Ao final de cada tempo de estudo foram mensurados de modo direto a PAM e a FC e coletados coração, rim e músculos temporal, sóleo e gastrocnêmio. Realizou-se análise da RP/L e quantificação de capilares e vênulas (através do ácido periódico de Schiff). O treinamento aeróbio aumentou a densidade capilar e venular de WKY e SHR (apenas em territórios exercitados e com maior magnitude nos hipertensos), em seguida causou redução da razão parede/luz das arteríolas musculares esqueléticas (apenas em SHR, precocemente e em maior magnitude em territórios exercitados) e só então reduziu a PAM de SHR e a FC de WKY e SHR. A partir dos resultados obtidos, podemos dizer que alterações estruturais da microcirculação antecedem a melhora dos níveis pressóricos de hipertensos e ainda, são capazes de proporcionar melhoras vasculares aos normotensos / Previous observations have shown that aerobic training reduce the wall/lumen ratio (RW/L) of skeletal muscle arterioles and reduce mean arterial pressure (MAP) in hypertensive rats, cause bradycardia, and increase capillary and venular density also in hypertensive and normotensive rats after 13 weeks of training. We investigated simultaneously the time-course changes of arterioles remodeling, MAP, HR and capillary and venular density during the development of low-intensity exercise protocol. Normotensive rats (WKY, Wistar Kyoto) and spontaneously hypertensive (SHR), two-months old were submitted to aerobic training protocol (weeks 0, 1, 2, 4, 8 and 12) or remained sedentary (weeks 0 and 12). In each study time were measured the MAP and HR and collected heart, kidney, temporalis, soleus and gastrocnemius muscles to analyze the RW/L and quantificate capillaries and venules (by Periodic Acid-Schiff staining). Aerobic training increased capillary and venular density of WKY and SHR (only in exercised territories), caused a reduction of the RW/L of skeletal muscle arterioles (only in SHR, early and in greater magnitude in exercised territories) and only then reduced MAP of SHR and HR of WKY and SHR. The structural changes of microcirculation preceded improvement of blood pressure levels in hypertensive rats and provided vascular improvements to normotensive rats

Experimentelle Melanin-induzierte Uveitis (EMIU): Modulation der Leukozyten-Endothelzell-Interaktion durch Makrophagendepletion - intravitalmikroskopische Analysen. Einleitung: Die Experimentelle Melanininduzierte Uveitis (EMIU) dient als Modell für eine autoimmune Iridozyklitis und Choroiditis. Die frühe Entzündungsreaktion ist durch eine gesteigerte Leukozyten-Endothel-Interaktion gekennzeichnet. Um die Rolle von Makrophagen bei der Induktion der EMIU zu untersuchen, analysierten wir Veränderungen der Leukozyten-Endothel-Interaktionen in Irisvenolen anästhesierter Ratten nach Makrophagendepletion mit liposomalem Clodronat. Methoden: Die EMIU wurde durch intraperitoneale Injektion einer Emulsion aus 250 µg bovinen Melanosomen in komplettem Freund Adjuvant und Pertussistoxin bei Lewis Ratten induziert. Die Tiere wurden mit 2 ml Clodronat-Liposomen (Clodronat-lip) an den Tagen 2; 1; 4; 6 beziehungsweise 8 nach Immunisierung behandelt. Kontrolltiere erhielten anstelle von Clodronat-lip Leerliposomen (Kontrolle). Für die Intravitalfluoreszenzmikroskopie wurden Leukozyten intravasal mit Rhodamin 6G gefärbt. Anschließend wurden die postkapillären Irisvenolen am 4.; 6.; 8. und 10. Tag untersucht, um die Zahl der rollenden und fest am Endothel adhärenten Leukozyten zu quantifizieren. Weitere Parameter wie Zellzahl und Proteingehalt des Kammerwassers, TNF-alpha und IFN-gamma im Plasma und das Differentialblutbild wurden zur Charakterisierung der Entzündungsreaktion herangezogen. Ergebnisse: Bei makrophagendepletierten Tieren konnten spaltlampenmikroskopisch keine entzündlichen Veränderungen des Vorderabschnittes beobachtet werden. Der prozentuale Anteil rollender Leukozyten war am 8. Tag mit 2 +/- 1.1 vs. 15.2 +/- 1.6; 5.2 +/- 0.5% (Clodronat-lip vs. EMIU; Kontrolle, Mittelwert +/- MSF, ANOVA, p