"Schlechthin nothwendiges wesen": en marge de la quatrieme antinomie

Le défi des antinomies joue un rôle décisif dans l'élaboration même de la pensée kantienne ; cela devient particulièrement significatif par rapport à l'Être absolument nécessaire, qui devrait dépasser le niveau des phénomènes même lorsque, comme l'on dit dans la thèse de la quatrième antinomie, l'on l'entend comme quelque chose du monde. Dans la structure même des antinomies nous sommes forcés à aller au-delà de l'expérience, à un Être qui dépasse radicalement le monde ; en ce sens, même à l'intérieur de la pensée kantienne, l'analogie classique reste la structure spécifique de la métaphysique, surtout par la possibilité de dire la transcendance sans la réduire jamais au niveau des phénomènes

Spielen Statine eine Rolle als adjuvante Therapie bei Entzündung? / Do statins play a role as an adjuvant therapy in inflammation?

Despite recent advances in management of patients in intensive care units, sepsis and septic shock are the major causes of morbidity and mortality. Prompt and adequate antibiotic therapy accompanied by surgical removal of the infectious material are the first-line therapy of choice. In addition, various immunomodulatory treatments have been investigated during the past decades. However, despite promising results in studies with animal models, studies in humans with antibodies against lipopolysaccharide (LPS), tumor necrosis factor and interleukin-1 have not been successful. In addition, high doses of steroids, immunoglobulins or antibodies against LPS and cytokines did not reduce mortality, probably owing to timing and dosage of these drugs. Prophylactic administration of immunomodulatory drugs cannot be recommended due to severe adverse effects. However, owing to pleiotropic effects of statins this class of cholesterol lowering drugs has been suggested to be beneficial as adjuvant therapy for sepsis. The present review summarizes the pathophysiology of sepsis as well as experimental and clinical evidence for the use of statins in sepsis.Trotz der Fortschritte der Medizin stellen schwere Entzündungsreaktionen wie die Sepsis eine wesentliche Ursache für Mortalität und Morbidität auf Intensivstationen dar. Zur kausalen Therapie gehört neben der Beseitigung der auslösenden Ursache durch chirurgische Maßnahmen vor allem eine effektive Antibiose. Weiterhin werden supportive Maßnahmen wie Kreislaufunterstützung, Nierenersatztherapie, Therapie von Gerinnungsstörungen und metabolischer Entgleisung zur Therapie eingesetzt. Darüber hinaus wurde in den vergangenen Jahren eine Vielzahl von immunomodulatorischen Therapien untersucht. Hierzu gehören neutralisierende Antikörper gegen Endotoxin oder proinflam-matorische Zytokine, Kortison, Immunglobuline und spezifische Gerinnungsinhibitoren. Neuere Studien weisen darauf hin, dass Statine (HMG-CoA-Reduktase-Inhibitoren) antientzündliche Wirkung haben und eine andauernde Statintherapie mit verminderter Inzidenz bakterieller Infektionen assoziiert ist. Aus diesem Grund wurden Statine als neue adjuvante Therpaie bei schweren Entzündungen und Sepsis vorgeschlagen. Im Gegensatz zu anderen antientzündlichen Therapien wäre hier auch ein prophylaktischer Einsatz bei Hochrisikopatienten, zum Beispiel vor elektiven chirurgischen Eingriffen, möglich. In der vorliegenden Arbeit sind die pathophysiologischen Grundlagen der Sepsis sowie die experimentelle Hintergründe und die ersten klinischen Daten zum Einsatz der Statine bei Sepsis zusammengefasst

Acute ingestion of a novel whey-derived peptide improves vascular endothelial responses in healthy individuals: a randomized, placebo controlled trial

<p>Abstract</p> <p>Background</p> <p>Whey protein is a potential source of bioactive peptides. Based on findings from <it>in vitro </it>experiments indicating a novel whey derived peptide (NOP-47) increased endothelial nitric oxide synthesis, we tested its effects on vascular function in humans.</p> <p>Methods</p> <p>A randomized, placebo-controlled, crossover study design was used. Healthy men (n = 10) and women (n = 10) (25 ± 5 y, BMI = 24.3 ± 2.3 kg/m²) participated in two vascular testing days each preceded by 2 wk of supplementation with a single dose of 5 g/day of a novel whey-derived peptide (NOP-47) or placebo. There was a 2 wk washout period between trials. After 2 wk of supplementation, vascular function in the forearm and circulating oxidative stress and inflammatory related biomarkers were measured serially for 2 h after ingestion of 5 g of NOP-47 or placebo. Macrovascular and microvascular function were assessed using brachial artery flow mediated dilation (FMD) and venous occlusion strain gauge plethysmography.</p> <p>Results</p> <p>Baseline peak FMD was not different for Placebo (7.7%) and NOP-47 (7.8%). Placebo had no effect on FMD at 30, 60, and 90 min post-ingestion (7.5%, 7.2%, and 7.6%, respectively) whereas NOP-47 significantly improved FMD responses at these respective postprandial time points compared to baseline (8.9%, 9.9%, and 9.0%; <it>P </it>< 0.0001 for time × trial interaction). Baseline reactive hyperemia forearm blood flow was not different for placebo (27.2 ± 7.2%/min) and NOP-47 (27.3 ± 7.6%/min). Hyperemia blood flow measured 120 min post-ingestion (27.2 ± 7.8%/min) was unaffected by placebo whereas NOP-47 significantly increased hyperemia compared to baseline (29.9 ± 7.8%/min; <it>P </it>= 0.008 for time × trial interaction). Plasma myeloperoxidase was increased transiently by both NOP-47 and placebo, but there were no changes in markers inflammation. Plasma total nitrites/nitrates significantly decreased over the 2 hr post-ingestion period and were lower at 120 min after placebo (-25%) compared to NOP-47 (-18%).</p> <p>Conclusion</p> <p>These findings indicate that supplementation with a novel whey-derived peptide in healthy individuals improves vascular function.</p

Established and Newly Proposed Mechanisms of Chronic Cyclosporine Nephropathy

Cyclosporine (CsA) has improved patient and graft survival rates following solid-organ transplantation and has shown significant clinical benefits in the management of autoimmune diseases. However, the clinical use of CsA is often limited by acute or chronic nephropathy, which remains a major problem. Acute nephropathy depends on the dosage of CsA and appears to be caused by a reduction in renal blood flow related to afferent arteriolar vasoconstriction. However, the mechanisms underlying chronic CsA nephropathy are not completely understood. Activation of the intrarenal renin-angiotensin system (RAS), increased release of endothelin-1, dysregulation of nitric oxide (NO) and NO synthase, up-regulation of transforming growth factor-beta1 (TGF-β1), inappropriate apoptosis, stimulation of inflammatory mediators, enhanced innate immunity, endoplasmic reticulum stress, and autophagy have all been implicated in the pathogenesis of chronic CsA nephropathy. Reducing the CsA dosage or using other renoprotective drugs (angiotensin II receptor antagonist, mycophenolate mofetil, and statins, etc.) may ameliorate chronic CsA-induced renal injury. This review discusses old and new concepts in CsA nephropathy and preventive strategies for this clinical dilemma

Efeitos da fisioterapia respiratória convencional versus aumento do fluxo expiratório na saturação de O2, freqüência cardíaca e freqüência respiratória, em prematuros no período pós-extubação

INTRODUÇÃO: Recém-nascidos (RN) prematuros apresentam elevada morbidade respiratória e necessidade de ventilação mecânica, assim, a fisioterapia respiratória é parte integrante da assistência neonatal. Objetivo: Comparar os efeitos da fisioterapia respiratória convencional (FRC) versus aumento do fluxo expiratório (AFE), na saturação de O2 (SpO2), freqüência cardíaca (FC) e na freqüência respiratória (FR) em prematuros no período pós-extubação. Método: Ensaio clínico randomizado realizado na UTI Neonatal do Hospital das Clínicas de BotucatuUNESP, comparando duas técnicas fisioterapêuticas, aplicadas em recém-nascidos prematuros, nas primeiras 48 horas pós-extubação. Para a análise estatística foram utilizados o teste t Student, Mann-Whitney, Qui-quadrado e o teste exato de Fisher, com nível de significância em 5%. Resultados: Os dois grupos de estudo: Grupo FRC (n= 20) e grupo AFE (n= 20), não diferiram quanto à idade gestacional (média de 28 semanas) e peso de nascimento (média de 1100 gramas). Em ambos os grupos a síndrome do desconforto respiratório (SDR) foi o principal diagnóstico. A mediana da idade no início da fisioterapia foi de sete dias no grupo AFE e 11 dias na FRC. Ambas as técnicas produziram aumento significativo da SpO2 aos 10 e 30 minutos, sem alterações na FR. A FC aumentou significativamente após a FRC e não se alterou após o AFE. Conclusão: Os resultados sugerem que o AFE é menos estressante que a FRC e pode ser aplicado em prematuros no período pós-extubação. Nestes recém-nascidos o AFE parece ser seguro e benéfico a curto prazo.<br>Background: Respiratory morbidity and the need for mechanical ventilation are very high among preterm infants. Chest physical therapy is therefore an essential component of neonatal care. Objective: To compare the effects of conventional chest physical therapy (CCP) and increased expiratory flow (IEF) on the oxygen saturation (SpO2), heart rate, and respiratory rate (RR) of preterm infants following extubation. Method: This was a randomized clinical trial, in the neonatal intensive care unit of Botucatu Medical School-UNESP, comparing two physical therapy techniques applied to preterm infants during the first 48 hours following extubation. Statistical analyses were performed using the Student t, Mann-Whitney, chi-squared and Fisher exact tests, with a significance level of 5%. Results:The two study groups, CCP (n = 20) and IEF (n = 20), presented similar gestational ages (mean = 28 weeks) and birth weights (mean = 1100 g). In both groups, respiratory distress syndrome was the main diagnosis. The median age for starting physical therapy was seven days in the IEF group and 11 days in the CCP group. Both techniques produced significantly increased SpO2 after 10 and 30 minutes of chest physical therapy, with no change in RR. There was a significant increase in heart rate after CCP, but no change occurred after IEF. Conclusion: Our data suggest that the IEF technique is less stressful than CCP and can be used for preterm infants following extubation. In these infants, IEF was seen to be safe and beneficial over the short term