Cystatin C as a marker of early changes of renal function in Fabry nephropathy.

BACKGROUND: A sensitive, feasible and reproducible marker for renal function is necessary to evaluate the clinical efficacy of enzyme replacement therapy (ERT) in Fabry nephropathy. Serum creatinine has some limitations and cystatin C has been proposed, in other nephropathies, as a useful marker of renal function. The use of cystatin C as a marker of glomerular filtration rate (GFR) was investigated in Fabry patients receiving ERT. METHODS: Renal function was evaluated with serum creatinine, serum cystatin C and estimated GFR (through Modification of Diet in Renal Disease [MDRD], Cockcroft-Gault [C&G] and Hoek formulae) in 21 Fabry patients receiving ERT with agalsidase alfa for 3 years and in 13 Fabry patients receiving agalsidase alfa for 4 years. RESULTS: During years of ERT while serum creatinine remained stable, cystatin C values showed a significant, increasing trend right from the first year of ERT. CONCLUSIONS: In Fabry disease, cystatin C is a sensitive and reliable marker of renal function, and it should be taken into account when evaluating GFR trends during ERT.

Urocortins improve dystrophic skeletal muscle structure and function through both PKA- and Epac-dependent pathways.

In Duchenne muscular dystrophy, the absence of dystrophin causes progressive muscle wasting and premature death. Excessive calcium influx is thought to initiate the pathogenic cascade, resulting in muscle cell death. Urocortins (Ucns) have protected muscle in several experimental paradigms. Herein, we demonstrate that daily s.c. injections of either Ucn 1 or Ucn 2 to 3-week-old dystrophic mdx(5Cv) mice for 2 weeks increased skeletal muscle mass and normalized plasma creatine kinase activity. Histological examination showed that Ucns remarkably reduced necrosis in the diaphragm and slow- and fast-twitch muscles. Ucns improved muscle resistance to mechanical stress provoked by repetitive tetanizations. Ucn 2 treatment resulted in faster kinetics of contraction and relaxation and a rightward shift of the force-frequency curve, suggesting improved calcium homeostasis. Ucn 2 decreased calcium influx into freshly isolated dystrophic muscles. Pharmacological manipulation demonstrated that the mechanism involved the corticotropin-releasing factor type 2 receptor, cAMP elevation, and activation of both protein kinase A and the cAMP-binding protein Epac. Moreover, both STIM1, the calcium sensor that initiates the assembly of store-operated channels, and the calcium-independent phospholipase A(2) that activates these channels were reduced in dystrophic muscle by Ucn 2. Altogether, our results demonstrate the high potency of Ucns for improving dystrophic muscle structure and function, suggesting that these peptides may be considered for treatment of Duchenne muscular dystrophy.

Angiotensin-converting enzyme inhibition improves vascular function in rheumatoid arthritis.

BACKGROUND: The excess in cardiovascular risk in patients with rheumatoid arthritis provides a strong rationale for early therapeutical interventions. In view of the similarities between atherosclerosis and rheumatoid arthritis and the proven benefit of angiotensin-converting enzyme inhibitors in atherosclerotic vascular disease, it was the aim of the present study to delineate the impact of ramipril on endothelial function as well as on markers of inflammation and oxidative stress in patients with rheumatoid arthritis. METHODS AND RESULTS: Eleven patients with rheumatoid arthritis were included in this randomized, double-blind, crossover study to receive ramipril in an uptitration design (2.5 to 10 mg) for 8 weeks followed by placebo, or vice versa, on top of standard antiinflammatory therapy. Endothelial function assessed by flow-mediated dilation of the brachial artery, markers of inflammation and oxidative stress, and disease activity were investigated at baseline and after each treatment period. Endothelial function assessed by flow-mediated dilation increased from 2.85+/-1.49% to 4.00+/-1.81% (P=0.017) after 8 weeks of therapy with ramipril but did not change with placebo (from 2.85+/-1.49% to 2.84+/-2.47%; P=0.88). Although systolic blood pressure and heart rate remained unaltered, diastolic blood pressure decreased slightly from 78+/-7 to 74+/-6 mm Hg (P=0.03). Tumor necrosis factor-alpha showed a significant inverse correlation with flow-mediated dilation (r=-0.408, P=0.02), and CD40 significantly decreased after ramipril therapy (P=0.049). CONCLUSIONS: Angiotensin-converting enzyme inhibition with 10 mg/d ramipril for 8 weeks on top of current antiinflammatory treatment markedly improved endothelial function in patients with rheumatoid arthritis. This finding suggests that angiotensin-converting enzyme inhibition may provide a novel strategy to prevent cardiovascular events in these patients.

Fonction ventriculaire gauche après revascularisation pour occlusion d'une coronaire d'une durée de 1-2 heures [Left ventricular function following revascularization for occlusion of a coronary artery lasting 1 to 2 hours].

The time-lag between coronary occlusion and irreversible damage to the myocardium is ill-defined in man. In 10 patients the changes in left ventricular function have been studied after coronary occlusion during diagnostic or therapeutic cardiac catheterization of 1-2 hours' duration. Revascularization was achieved either surgically or through intracoronary streptokinase infusion. The interval between occlusion and onset of extracorporal circulation or reopening was 61 to 119 minutes. Despite enzyme elevation (CPK, CK-MB, SGOT) and appearance of Q-waves in 5 patients, no significant alteration of left ventricular function was noted on repeat cardiac catheterization 10 to 230 days after the accident. These observations, suggest that coronary occlusion of 1-2 hours' duration fails to produce significant irreversible damage to the myocardium despite electrocardiographic and enzymatic signs of myocardial infarction.

Aggregation and errors in management accounting

Il est important pour les entreprises de compresser les informations détaillées dans des sets d'information plus compréhensibles. Au chapitre 1, je résume et structure la littérature sur le sujet « agrégation d'informations » en contrôle de gestion. Je récapitule l'analyse coûts-bénéfices que les comptables internes doivent considérer quand ils décident des niveaux optimaux d'agrégation d'informations. Au-delà de la perspective fondamentale du contenu d'information, les entreprises doivent aussi prendre en considération des perspectives cogni- tives et comportementales. Je développe ces aspects en faisant la part entre la comptabilité analytique, les budgets et plans, et la mesure de la performance. Au chapitre 2, je focalise sur un biais spécifique qui se crée lorsque les informations incertaines sont agrégées. Pour les budgets et plans, des entreprises doivent estimer les espérances des coûts et des durées des projets, car l'espérance est la seule mesure de tendance centrale qui est linéaire. A la différence de l'espérance, des mesures comme le mode ou la médiane ne peuvent pas être simplement additionnés. En considérant la forme spécifique de distributions des coûts et des durées, l'addition des modes ou des médianes résultera en une sous-estimation. Par le biais de deux expériences, je remarque que les participants tendent à estimer le mode au lieu de l'espérance résultant en une distorsion énorme de l'estimati¬on des coûts et des durées des projets. Je présente également une stratégie afin d'atténuer partiellement ce biais. Au chapitre 3, j'effectue une étude expérimentale pour comparer deux approches d'esti¬mation du temps qui sont utilisées en comptabilité analytique, spécifiquement « coûts basés sur les activités (ABC) traditionnelles » et « time driven ABC » (TD-ABC). Au contraire des affirmations soutenues par les défenseurs de l'approche TD-ABC, je constate que cette dernière n'est pas nécessairement appropriée pour les calculs de capacité. Par contre, je démontre que le TD-ABC est plus approprié pour les allocations de coûts que l'approche ABC traditionnelle. - It is essential for organizations to compress detailed sets of information into more comprehensi¬ve sets, thereby, establishing sharp data compression and good decision-making. In chapter 1, I review and structure the literature on information aggregation in management accounting research. I outline the cost-benefit trade-off that management accountants need to consider when they decide on the optimal levels of information aggregation. Beyond the fundamental information content perspective, organizations also have to account for cognitive and behavi¬oral perspectives. I elaborate on these aspects differentiating between research in cost accounti¬ng, budgeting and planning, and performance measurement. In chapter 2, I focus on a specific bias that arises when probabilistic information is aggregated. In budgeting and planning, for example, organizations need to estimate mean costs and durations of projects, as the mean is the only measure of central tendency that is linear. Different from the mean, measures such as the mode or median cannot simply be added up. Given the specific shape of cost and duration distributions, estimating mode or median values will result in underestimations of total project costs and durations. In two experiments, I find that participants tend to estimate mode values rather than mean values resulting in large distortions of estimates for total project costs and durations. I also provide a strategy that partly mitigates this bias. In the third chapter, I conduct an experimental study to compare two approaches to time estimation for cost accounting, i.e., traditional activity-based costing (ABC) and time-driven ABC (TD-ABC). Contrary to claims made by proponents of TD-ABC, I find that TD-ABC is not necessarily suitable for capacity computations. However, I also provide evidence that TD-ABC seems better suitable for cost allocations than traditional ABC.

Acid-sensing channels in human bladder: expression, function and alterations during bladder pain syndrome.

Purpose: To examine the possible role of H+-activated acid-sensing ion channels (ASICs) in pain perception we characterized their expression in bladder dome biopsies of Bladder Pain Syndrome (BPS) patients and controls, in cultured human urothelium and in urothelial TEU-2 cells.Materials and Methods: Cold cut biopsies from the bladder dome were obtained in 8 asymptomatic controls and 28 patients with symptoms of BPS. ASIC expression was analyzed by QPCR and immunofluorescence. The channel function was measured by electrophysiology.Results: ASIC1a, ASIC2a and ASIC3 mRNAs were detected in human bladder. Similar amounts of ASIC1a and -3 were detected in detrusor smooth muscle, whereas in urothelium ASIC3 levels were higher than -1a. ASIC2a mRNA levels were lower than either -1a or -3 in both layers. ASIC currents were measured in TEU-2 cells and in primary cultures of human urothelium, and ASIC expression was confirmed by QPCR. Differentiation of TEU-2 cells caused an up-regulation of ASIC2a and ASIC3, and a down-regulation of ASIC1a mRNAs. BPS patients showed an up-regulation of ASIC2a and -3 mRNA, whereas ASIC1a remained unchanged. In contrast, the mRNA levels of TRPV1 were down-regulated during BPS. All differences were statistically significant (p<0.05)Conclusions: Several different ASIC subunits are expressed in human bladder and TEU-2 cells, where their levels are regulated during urothelial differentiation. An up-regulation of ASIC2a and -3 in BPS suggests their involvement in increased pain and hyperalgesia. A down-regulation of TRPV1 mRNA levels might indicate a different regulatory mechanism, controlling its expression in human bladder.

Activation mechanisms of the protease MALT1 and cleavage of one of its targets - the ribonuclease Regnase-1- in lymphocytes and lymphoma cell lines

Persistent infection induces an adaptive immune response that is mediated by T and B lymphocytes. Upon triggering with an antigen, these cells become activated and turn into fast expanding cells able to efficiently defend the host. Lymphocyte activation is controlled by a complex composed of CARMA1, BCL10 and MALT1 which regulates the NF-KB signaling pathway upon antigen triggering. Abnormally high expression or activity of either one of these three proteins can favor the development of lymphomas, while genetic defects in the pathway are associated with immunodeficiency. MALT1 was identified as a paracaspase sharing homology with other cysteine proteases, namely caspases and metacaspases. In order to be active, caspases need to dimerize. Based on their sequence similarity with MALT1, we hypothesized that dimerization might also be a mechanism of activation employed by MALT1. To address this assumption, we performed a bioinformatics modelling based on the crystal structures of several caspases. Our model suggested that the MALT1 caspase-like domain can indeed form dimers. This finding was later confirmed by several published crystal structures of MALT1. In the dimer interface of our model, we noticed the presence of charged amino acids that could potentially form salt bridges and thereby hold both monomers together. Mutation of one of these residues, E549, into alanine completely blocked the catalytic activity of MALT1. Additionally, we provided evidence for a role of E549 in promoting the MALTl-dependent growth of cells derived from diffuse large B cell lymphoma (DLBCL) of the aggressive B cell-like type (ABC). To our initial surprise, the E549A mutation showed only a partial defect in dimerization, indicating that additional residues are essential to form a stable dimer. The MALT1 crystal structures revealed a key function for E549 in stabilizing the catalytic site of the protease via its interaction with an arginine which is located next to the catalytic active cysteine. In an additional study, we discovered that MALT1 monoubiquitination is required for the catalytic activity of the protease. Interestingly, we found that the MALT1 dimer interface mutant E549A could not be monoubiquitinated. Based on these findings, we suggest that correct formation of the dimer interface is a prerequisite for monoubiquitination. In a second project, we discovered a novel target of the protease MALT1, the ribonuclease Regnase¬la It was described that the RNase activity of Regnase-1 negatively regulates immune responses. We could show that in ABC DLBCL cell lines, Regnase-1 is not only cleaved by MALT1 but also phosphorylated, at least in part, by the inhibitor of KB kinase (IKK). Both regulations appear to restrain the RNase function of Regnase-1 and thereby allow the production of pro-survival proteins. In conclusion, our studies further highlight and explain the importance of the catalytic activity of MALT1 for the activation of lymphocytes and provide additional knowledge for the development of specific drugs targeting the catalytic activity of MALT1 for immunomodulation and treatment of lymphomas.  SUMMARY IN FRENCH PhD Thesis Katrin Cabalzar 2 SUMMARY IN FRENCH Une infection persistante induit une réponse immunitaire adaptative par l'intermédiaire des lymphocytes T et B. Quand elles reconnaissent l'antigène, ces cellules sont activées et se multiplient très rapidement pour défendre efficacement l'hôte. L'activation des lymphocytes est transmise par un complexe composé de trois protéines, CARMA1, BCL10 et MALT1, qui régule la voie de signalisation NF-KB lorsque l'antigène est reconnu. L'expression ou l'activité anormalement élevée de l'une de ces trois protéines peut favoriser le développement de lymphomes, tandis que des défauts génétiques de cette voie de signalisation sont associés à l'immunodéficience. MALT1 a été identifiée comme étant une paracaspase qui partage des séquences homologues avec d'autres protéases à cystéine, comme les caspases et les métacaspases. Pour être actives, les caspases ont besoin de dimériser. Etant donné leur similarité de séquence avec MALT1, nous avons supposé que la dimérisation pouvait aussi être un mécanisme d'activation utilisé par MALT1. Pour vérifier cette hypothèse, nous avons conçu un modèle bioinformatique à partir des structures cristallographiques de plusieurs caspases. Et notre modèle a suggéré que le domaine catalytique de MALT1 était effectivement capable de former des dimères. Cette découverte a été confirmée plus tard par des publications qui montrent des structures cristallographiques dimériques de MALT1. Dans l'interface du dimère de notre modèle, nous avons remarqué la présence d'acides aminés chargés qui pouvaient former des liaisons ioniques et ainsi réunir les deux monomères. La mutation de l'un de ces résidus, E549, pour une alanine, a complètement inhibé l'activité catalytique de MALT1. De plus, nous avons mis en évidence un rôle d'E549 dans la croissance dépendante de MALT1, des cellules dérivées de lymphomes B diffus à grandes cellules (DLBCL) de sous-type cellules B actives (ABC). Dans un premier temps nous avons été surpris de constater que cette mutation révélait seulement un défaut partiel de dimérisation, ce qui indique que des acides aminés supplémentaires sont indispensables pour former un dimère stable. Les structures cristallographiques de MALT1 ont révélé un rôle primordial d'E549 dans la stabilisation du site catalytique de la protéase via son interaction avec une arginine qui se trouve à côté de la cystéine du site actif. Dans une autre étude, nous avons découvert que la monoubiquitination de MALT1 est requise pour l'activité catalytique de la protéase. A remarquer que nous avons trouvé que le mutant E549A de l'interface dimère de MALT1 n'a pas pu être monoubiquitiné. Sur la base de ces résultats, nous suggérons que la formation correcte de l'interface du dimère est une condition préalable pour la monoubiquitination. Dans un second projet, nous avons découvert une nouvelle cible de la protéase MALT1, la ribonucléase Regnase-1. Il a été décrit que l'activité RNase de Regnase-1 régulait négativement les réponses immunitaires. Nous avons pu montrer que dans les lignées cellulaires ABC DLBCL, la Regnase-1 n'était pas seulement clivée par MALT1 mais également phosphorylée, au moins en partie, par la kinase de l'inhibiteur de KB (IKK). Les deux régulations semblent supprimer la fonction RNase de Regnase-1 et permettre ainsi la stabilisation de certains ARN messagers et la production de protéines favorisant la survie. En conclusion, nos études mettent en évidence le rôle-clé de la dimérisation de MALT1 et expliquent l'importance de l'activité catalytique de MALT1 pour l'activation des lymphocytes. Ainsi, nos résultats apportent des connaissances supplémentaires pour le développement de médicaments spécifiques ciblant l'activité catalytique de MALT1, qui pourraient être utiles pour modifier les réponses immunitaires et traiter des lymphomes.

Regulation of the Activity of the Dual-Function DnaA Protein in Caulobacter crescentus.

DnaA is a conserved essential bacterial protein that acts as the initiator of chromosomal replication as well as a master transcriptional regulator in Caulobacter crescentus. Thus, the intracellular levels of active DnaA need to be tightly regulated during the cell cycle. Our previous work suggested that DnaA may be regulated at the level of its activity by the replisome-associated protein HdaA. Here, we describe the construction of a mutant DnaA protein [DnaA(R357A)]. The R357 residue in the AAA+ domain of the C. crescentus DnaA protein is equivalent to the R334 residue of the E. coli DnaA protein, which is required for the Regulatory Inactivation of DnaA (RIDA). We found that the expression of the DnaA(R357A) mutant protein in C. crescentus, but not the expression of the wild-type DnaA protein at similar levels, causes a severe phenotype of over-initiation of chromosomal replication and that it blocks cell division. Thus, the mutant DnaA(R357A) protein is hyper-active to promote the initiation of DNA replication, compared to the wild-type DnaA protein. DnaA(R357A) could not replace DnaA in vivo, indicating that the switch in DnaA activity once chromosomal replication has started may be an essential process in C. crescentus. We propose that the inactivation of DnaA is the main mechanism ensuring that chromosomal replication starts only once per cell cycle. We further observed that the R357A substitution in DnaA does not promote the activity of DnaA as a direct transcriptional activator of four important genes, encoding HdaA, the GcrA master cell cycle regulator, the FtsZ cell division protein and the MipZ spatial regulator of cell division. Thus, the AAA+ domain of DnaA may play a role in temporally regulating the bifunctionality of DnaA by reallocating DnaA molecules from initiating DNA replication to transcribing genes within the unique DnaA regulon of C. crescentus.

Role of the REST/RE-1 system in beta-cell life, function and differentiation

SUMMARYDiabetes is characterized by insulin deficiency that results from the destruction of insulin-secreting pancreatic beta-cells (Type 1), or in part from beta-cell death and insulin secretion defects (Type 2). Therefore, understanding the mechanisms of beta cell neogenesis (to generate unlimited supply of beta cells for T1D transplantation] or identifying the specific genes that favors insulin secretion or beta-cell survival is of great importance for the management of diabetes. The transcriptional repressor RE-1 Silencing Transcription Factor (REST) restricts the expression of a large number of genes containing its binding element, called Repressor Element-1 (RE-1), to neurons and beta cells. To do so, REST is ubiquitously expressed but in neurons and beta cells. To identify these essential genes and their functional significance in beta cells, we have generated transgenic mice that express REST specifically in beta cells under the control of the rat insulin promoter (RIP-REST mice). This resulted in the repression of the RE-1- containing genes in beta cells, and we analyzed the consequences.We first showed that RIP-REST mice were glucose-intolerant because of a defective insulin secretion. To explain this defect, we identified that a subset of the REST target genes were necessary for insulin exocytosis, such as Snap25, Synaptotagmin (Syt) IX, Complexin II, and Ica512, and we further demonstrated that among the identified REST targets, Syt IV and VII were also involved in insulin release. We next analyzed a novel RIP-REST mouse line that featured diabetes and we showed that this defect was due to a major loss of beta-cell mass. To explain this phenotype, we identified REST target genes that were involved in beta-cell survival, such as Ibl, Irs2, Ica512 and Connexin36, and revealed that another REST target, Cdk5r2 is also involved in beta-cell protection. In a third part, we finally suggest that REST may be important for pancreatic endocrine differentiation, since transgenic mice expressing constitutive REST in pancreatic multipotent progenitors show impaired formation of Ngn3-expressing endocrine- committed precursors, and impaired formation of differentiated endocrine cells. Mapping the pattern of REST expression in wild type animals indicates that it is expressed in multipotent progenitors to become then excluded from endocrine cells. Preliminary results suggest that a downregulation of REST would result in relieved expression of at least the Mytl target, favoring subsequent acquisition of the endocrine competence by endocrine precursor cells.Thus, we propose that the REST/RE-1 system is an important feature for beta-cell neogenesis, function and survivalRESUMELe diabète se caractérise par une déficience en insuline qui résulte d'une destruction des cellules bêta (β) pancréatiques sécrétant l'insuline [Type 1], ou à un défaut de sécrétion d'insuline qui peut être associé à la mort des cellules β (Type 2). La compréhension des mécanismes de néogenèse des cellules β, ainsi que l'identification de gènes impliqués dans leur survie et dans le contrôle de la sécrétion d'insuline est donc importante pour le traitement du diabète. Le facteur de transcription de type répresseur, RE-1 Silencing Transcription Factor [REST], contribue à la spécificité d'expression dans les neurones et les cellules β, d'un grand nombre de gènes portant son motif de fixation, le Repressor Element-1 (RE-1). Pour cela, REST est exprimé dans toutes les cellules, sauf dans les neurones et les cellules β. Afin d'identifier les gènes cibles de REST ainsi que leur fonction au sein de la cellule β, nous avons généré des souris transgéniques qui expriment REST spécifiquement dans ces cellules, sous la dépendance du promoteur de l'insuline (souris RIP-REST]. Cette expression ectopique de REST a permis de diminuer l'expression des gènes contrôlés par REST, et d'en analyser les conséquences. Nous avons montré que les souris RIP-REST étaient intolérantes au glucose et que ceci était du à un défaut de sécrétion d'insuline. Pour expliquer ce phénotype, nous avons mis en évidence le fait que des gènes cibles de REST codent pour des protéines importantes pour l'exocytose de l'insuline, comme SNAP25, Synaptotagmin (Syt) IX, Complexin II ou ICA512. De plus, nous avons découvert deux nouvelles cibles de REST impliquées dans la sécrétion d'insuline, Syt IV et Syt VII. Par la suite, nous avons démontré qu'une nouvelle lignée de souris RIP-REST étaient atteintes d'un diabète sévère à cause d'une perte massive des cellules β. La disparition de ces cellules a été expliquée par l'identification de gènes cibles de REST impliqués dans la survie des cellules β, comme Ibl, Irs2, Ica512 ou la Connexine36. De plus, nous avons découvert qu'une nouvelle cible, Cdk5r2, était aussi impliquée dans la survie des cellules β. Dans une dernière partie, nous suggérons, grâce à l'analyse de nouvelles souris transgéniques exprimant constitutivement REST dans les cellules progénitrices du pancréas embryonnaire, que REST empêche la formation des précurseurs de cellules endocrines ainsi que la différenciation de ces cellules. L'analyse de l'expression de REST au cours du développement embryonnaire du pancréas indique que la diminution de l'expression de REST conduit en partie, à l'induction d'un de ses gènes cible Mytl, qui favorise la formation de précurseurs endocrines. Nous proposons donc que le système REST/RE-1 est important pour la génération, la fonction et la survie des cellules β.

Not all inflammatory markers are linked to kidney function: results from a population-based study.

BACKGROUND: Several studies have reported increased levels of inflammatory biomarkers in chronic kidney disease (CKD), but data from the general population are sparse. In this study, we assessed levels of the inflammatory markers C-reactive protein (hsCRP), tumor necrosis factor α (TNF-α), interleukin (IL)-1β and IL-6 across all ranges of renal function. METHODS: We conducted a cross-sectional study in a random sample of 6,184 Caucasian subjects aged 35-75 years in Lausanne, Switzerland. Serum levels of hsCRP, TNF-α, IL-6, and IL-1β were measured in 6,067 participants (98.1%); serum creatinine-based estimated glomerular filtration rate (eGFR(creat), CKD-EPI formula) was used to assess renal function, and albumin/creatinine ratio on spot morning urine to assess microalbuminuria (MAU). RESULTS: Higher serum levels of IL-6, TNF-α and hsCRP and lower levels of IL-1β were associated with a lower renal function, CKD (eGFR(creat) <60 ml/min/1.73 m(2); n = 283), and MAU (n = 583). In multivariate linear regression analysis adjusted for age, sex, hypertension, smoking, diabetes, body mass index, lipids, antihypertensive and hypolipemic therapy, only log-transformed TNF-α remained independently associated with lower renal function (β -0.54 ±0.19). In multivariate logistic regression analysis, higher TNF-α levels were associated with CKD (OR 1.17; 95% CI 1.01-1.35), whereas higher levels of IL-6 (OR 1.09; 95% CI 1.02-1.16) and hsCRP (OR 1.21; 95% CI 1.10-1.32) were associated with MAU. CONCLUSION: We did not confirm a significant association between renal function and IL-6, IL-1β and hsCRP in the general population. However, our results demonstrate a significant association between TNF-α and renal function, suggesting a potential link between inflammation and the development of CKD. These data also confirm the association between MAU and inflammation.

Generation and function of mouse central memory and effector memory T cells

1. SUMMARY Based on functional and homing properties, two subsets of memory T lymphocytes have been defined both in humans and in mice. Central memory T cells (TCM cells) express the lymph node homing receptors CD62L and CCR7, have poor effector function and proliferate efficiently upon antigenic stimulation. Effector memory T cells (TEM cells) do not express CCR7, are mostly CD62L negative and therefore are excluded from lymph nodes, but are able to migrate to sites of inflammation where they exert immediate effector function by producing inflammatory cytokines and cytotoxic mediators. In the present work we have addressed two questions that emerged since the definition of TCM and TEM cells. Firstly, what are the priming conditions for generation of TCM and TEM and, secondly, what is the migratory capacity of TCM and TEM cells in inflammatory conditions. By using naive TCR-transgenic OT-I CD8+ T cells and OT-II CD4+ T cells and ovalbumin pulsed-mature dendritic cells (DCs) we set up an in vitro system in which the strength of T cell stimulation is controlled by varying the ratio of T cells and DCs and the duration of DC-T cell interaction. Using this system we found that precursors of TCM and TEM cells are generated at different strength of stimulation and that T cells capable of persisting in vivo in the absence of antigen and of mounting recall responses is optimally induced by intermediate stimulatory strength. In addition, we found that lymph nodes draining sites of mature DC or adjuvant inoculation recruit CD8+ CD62L- CCR7- effector and TEM cells. CD8+ T cell recruitment in reactive lymph nodes requires CXCR3 expression on T cells and occurs through high endothelial venules (HEVs) in concert with HEV lurninal expression of the CXCR3 ligand CXCL9. In reactive lymph nodes, recruited T cells establish stable interactions with and kill antigen-bearing DCs, limiting the ability of these DCs to activate CD4+ and CD8+ T cells. Taken togther these data define conditions for the generation of TCM and TEM cells and define an inflammatory pathway of effector T cell migration in lymph nodes. The inducible recruitment of blood-borne effector and TEM CD8+ cells to lymph nodes may represent a mechanism for terminating primary and limiting secondary immune responses.

Comparative effects of GLP-1-(7-36) amide, oxyntomodulin and glucagon on rabbit gastric parietal cell function.

We have investigated in vitro, the effects of glucagon-like peptide-1-(7-36) amide (GLP-1-(7-36) amide), oxyntomodulin and glucagon on two rabbit parietal cell-enriched fractions (F3, F3n), with parietal cell contents of 60% and 88%, respectively. Histamine (10(-5) M) stimulated [14C]aminopyrine accumulation to an amount of 850% in excess of the basal level, whereas GLP-1-(7-36) amide (10(-7) M) and oxyntomodulin (10(-6) M) induced increases of 50% and 30%, respectively. With a histamine concentration of 10(-6) M, [14C]aminopyrine accumulation was stimulated to 498% in excess of the basal level; GLP-1-(7-36) amide (10(-7) M) and oxyntomodulin (10(-7) M) induced increases of 18% and 15%, respectively. With these parameters, oxyntomodulin[19-37] and glucagon were without effect. Specific binding of [125I]GLP-1-(7-36) amide to parietal cell plasma membranes was inhibited dose-dependently by GLP-1-(7-36) amide, oxyntomodulin and glucagon with inhibitory concentrations of 0.25 nM, 65 nM and 800 nM, respectively. No specific binding of [125I]oxyntomodulin or [125I]glucagon was detectable. GLP-1-(7-36) amide receptor mRNA was only detected in parietal cell-enriched fractions. GLP-1-(7-36) amide, oxyntomodulin and glucagon stimulated parietal cell cAMP production to similar maximal levels with median values close to 0.28 nM, 10.5 nM and 331.7 nM, whereas oxyntomodulin[19-37] had no effect. The maximal cAMP production induced by GLP-1-(7-36) amide, oxyntomodulin or glucagon was additive to that induced by histamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Cognition and brain function in schizotypy : a selective review

Schizotypy refers to a set of personality traits thought to reflect the subclinical expression of the signs and symptoms of schizophrenia. Here, we review the cognitive and brain functional profile associated with high questionnaire scores in schizotypy. We discuss empirical evidence from the domains of perception, attention, memory, imagery and representation, language, and motor control. Perceptual deficits occur early and across various modalities. Whilst the neural mechanisms underlying visual impairments may be linked to magnocellular dysfunction, further effects may be seen downstream in higher cognitive functions. Cognitive deficits are observed in inhibitory control, selective and sustained attention, incidental learning and memory. In concordance with the cognitive nature of many of the aberrations of schizotypy, higher levels of schizotypy are associated with enhanced vividness and better performance on tasks of mental rotation. Language deficits seem most pronounced in higher-level processes. Finally, higher levels of schizotypy are associated with reduced performance on oculomotor tasks, resembling the impairments seen in schizophrenia. Some of these deficits are accompanied by reduced brain activation, akin to the pattern of hypoactivations in schizophrenia spectrum individuals. We conclude that schizotypy is a construct with apparent phenomenological overlap with schizophrenia and stable inter-individual differences that covary with performance on a wide range of perceptual, cognitive and motor tasks known to be impaired in schizophrenia. The importance of these findings lies not only in providing a fine-grained neurocognitive characterisation of a personality constellation known to be associated with real-life impairments, but also in generating hypotheses concerning the aetiology of schizophrenia.

Objective evaluation of shoulder function using body-fixed sensors: a new way to detect early treatment failures?

Background: Variable definitions of outcome (Constant score, Simple Shoulder Test [SST]) have been used to assess outcome after shoulder treatment, although none has been accepted as the universal standard. Physicians lack an objective method to reliably assess the activity of their patients in dynamic conditions. Our purpose was to clinically validate the shoulder kinematic scores given by a portable movement analysis device, using the activities of daily living described in the SST as a reference. The secondary objective was to determine whether this device could be used to document the effectiveness of shoulder treatments (for glenohumeral osteoarthritis and rotator cuff disease) and detect early failures.Methods: A clinical trial including 34 patients and a control group of 31 subjects over an observation period of 1 year was set up. Evaluations were made at baseline and 3, 6, and 12 months after surgery by 2 independent observers. Miniature sensors (3-dimensional gyroscopes and accelerometers) allowed kinematic scores to be computed. They were compared with the regular outcome scores: SST; Disabilities of the Arm, Shoulder and Hand; American Shoulder and Elbow Surgeons; and Constant.Results: Good to excellent correlations (0.61-0.80) were found between kinematics and clinical scores. Significant differences were found at each follow-up in comparison with the baseline status for all the kinematic scores (P < .015). The kinematic scores were able to point out abnormal patient outcomes at the first postoperative follow-up.Conclusion: Kinematic scores add information to the regular outcome tools. They offer an effective way to measure the functional performance of patients with shoulder pathology and have the potential to detect early treatment failures.Level of evidence: Level II, Development of Diagnostic Criteria, Diagnostic Study. (C) 2011 Journal of Shoulder and Elbow Surgery Board of Trustees.