Molecular Mechanisms Underlying the Nephroprotective Effects of PACAP in Diabetes

Diabetic nephropathy is the leading cause of end-stage renal failure and accounts for 30–40 % of patients entering renal transplant programmes. The nephroprotective effects of the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP38) against diabetes have been shown previously, but the molecular mechanisms responsible for these effects remain unknown. In the present study, we showed that PACAP treatment counteracted the diabetes-induced increase in the level of the proapoptotic pp38MAPK and cleaved caspase-3 and also decreased the p60 subunit of NFκB. The examined antiapoptotic factors, including pAkt and pERK1/2, showed a slight increase in the diabetic kidneys, while PACAP treatment resulted in a notable elevation of these proteins. PCR and Western blot revealed the downregulation of fibrotic markers, like collagen IV and TGF-β1 in the kidney. PACAP treatment resulted in increased expression of the antioxidant glutathione. We conclude that the nephroprotective effect of PACAP in diabetes is, at least partly, due to its antiapoptotic, antifibrotic and antioxidative effect in addition to the previously described antiinflammatory effect.     

Quantification of periaortic adipose tissue in contrast-enhanced CT angiography: technical feasibility and methodological considerations

The International Journal of Cardiovascular Imaging - To examine the feasibility of the quantification of abdominal periaortic fat tissue (PaFT) (tissue within − 45 to...     

Placental protein 13 (galectin-13) has decreased placental expression but increased shedding and maternal serum concentrations in patients presenting with preterm pre-eclampsia and HELLP syndrome

Placental protein 13 (PP13) is a galectin expressed by the syncytiotrophoblast. Women who subsequently develop preterm pre-eclampsia have low first trimester maternal serum PP13 concentrations. This study revealed that third trimester maternal serum PP13 concentration increased with gestational age in normal pregnancies (p < 0.0001), and it was significantly higher in women presenting with preterm pre-eclampsia (p = 0.02) and hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome (p = 0.01) than in preterm controls. Conversely, placental PP13 mRNA (p = 0.03) and protein, as well as cytoplasmic PP13 staining of the syncytiotrophoblast (p < 0.05) was decreased in these pathological pregnancies compared to controls. No differences in placental expression and serum concentrations of PP13 were found at term between patients with pre-eclampsia and control women. In contrast, the immunoreactivity of the syncytiotrophoblast microvillous membrane was stronger in both term and preterm pre-eclampsia and HELLP syndrome than in controls. Moreover, large syncytial cytoplasm protrusions, membrane blebs and shed microparticles strongly stained for PP13 in pre-eclampsia and HELLP syndrome. In conclusion, parallel to its decreased placental expression, an augmented membrane shedding of PP13 contributes to the increased third trimester maternal serum PP13 concentrations in women with preterm pre-eclampsia and HELLP syndrome.     

Analysis and correction of crosstalk effects in pathway analysis

Identifying the pathways that are significantly impacted in a given condition is a crucial step in understanding the underlying biological phenomena. All approaches currently available for this purpose calculate a P-value that aims to quantify the significance of the involvement of each pathway in the given phenotype. These P-values were previously thought to be independent. Here we show that this is not the case, and that many pathways can considerably affect each other''s P-values through a “crosstalk” phenomenon. Although it is intuitive that various pathways could influence each other, the presence and extent of this phenomenon have not been rigorously studied and, most importantly, there is no currently available technique able to quantify the amount of such crosstalk. Here, we show that all three major categories of pathway analysis methods (enrichment analysis, functional class scoring, and topology-based methods) are severely influenced by crosstalk phenomena. Using real pathways and data, we show that in some cases pathways with significant P-values are not biologically meaningful, and that some biologically meaningful pathways with nonsignificant P-values become statistically significant when the crosstalk effects of other pathways are removed. We describe a technique able to detect, quantify, and correct crosstalk effects, as well as identify independent functional modules. We assessed this novel approach on data from four experiments involving three phenotypes and two species. This method is expected to allow a better understanding of individual experiment results, as well as a more refined definition of the existing signaling pathways for specific phenotypes.The correct identification of the signaling and metabolic pathways involved in a given phenotype is a crucial step in the interpretation of high-throughput genomic experiments. Most approaches currently available for this purpose treat the pathways as independent. In fact, pathways can affect each other''s P-values through a phenomenon we refer to as crosstalk. This crosstalk may be due to the regulatory interactions among different pathways or to the gene overlap among pathways. In this work, we will use the term crosstalk to refer to the effect that pathways exercise on each other due to the presence of overlapping genes. Although it is intuitive that various pathways could influence each other, especially when they share genes, the presence and extent of this phenomenon have not been rigorously studied and, most importantly, there is no currently available technique able to quantify the amount of such crosstalk. There are three major categories of methods that aim to identify significant pathways: enrichment analysis (e.g., Fisher''s exact test–hypergeometric) (Tavazoie et al. 1999; Draghici et al. 2003); functional scoring (e.g., GSEA) (Mootha et al. 2003; Subramanian et al. 2005); and topology-based methods (e.g., impact analysis) (Draghici et al. 2007; Tarca et al. 2009). Another classification of gene set analysis methods is based on the definition of the null hypothesis and divides the methods into competitive and self-contained (Goeman and Bühlmann 2007; Nam and Kim 2008). In this work, we focus on competitive methods, and in particular on the Fisher''s exact test, although the problems identified likely apply also for self-contained methods.Here we show that the results of all these methods are affected by crosstalk effects and that this phenomenon is related to the structure of the pathways. We propose the first approach that can (1) detect crosstalk when it exists, (2) quantify its magnitude, (3) correct for it, resulting in a more meaningful ranking among pathways in a specific biological condition, and (4) identify novel functional modules that can play an independent role and have different functions than the pathway they are currently located on. This method is expected to allow a better understanding of individual experiment results, as well as a more refined definition of the existing signaling pathways for specific phenotypes.     

Preservative-free tafluprost/timolol fixed combination: a new opportunity in the treatment of glaucoma

Introduction: Medical therapy of glaucoma aims to maintain the patient’s visual function and quality of life. This generally commences with monotherapy, but it is often difficult to reach the predetermined target pressure with this approach. Fixed combinations (FCs) are therefore selected as the next step of the medical therapy algorithm. By employing a prostaglandin/timolol fixed combination (PTFC) the desired target 24-hour intraocular pressure can be reached in many glaucoma patients with the convenience of once-a-day administration and the associated high rate of adherence.

Areas covered: The current role and value of FCs in the medical therapy of glaucoma is critically appraised. Special attention is paid to the PTFCs and the emerging role of preservative-free PTFCs. This review summarizes existing information on the efficacy and tolerability of the new preservative-free tafluprost/timolol FC (Taptiqom®).

Expert opinion: The preservative-free tafluprost/timolol FC represents a promising stepwise treatment option for those patients whose intraocular pressure is insufficiently controlled with available monotherapy options. This novel FC has the potential to substantially improve glaucoma management and through evolution of the current glaucoma treatment paradigm, to become a core therapeutic option in the future. Nonetheless, future research is needed to better delineate the therapeutic role of current and future preservative-free FCs in glaucoma therapy.     

Three-dimensional finite element analysis of implant stability in the atrophic posterior maxilla: a mathematical study of the sinus floor augmentation

Sinus lifting is performed with a variety of materials and techniques without a precise knowledge of the quantity of augmentation. This study based on three-dimensional finite element analysis was designed to show which surgical procedure and which amount of peri-implant packing yields the best bony support for dental implants. Eight 3D-FE models were used. Four modeled standard situations simulated quantitatively different packing situations produced by differences in surgical approach: i. no packing; ii. thin 1 mm bony sheath; iii. oblique subcomplete packing; iv. complete bony peri-implant packing up to the implant end. A fifth model compared a standard implant with a length of 13.5 mm and a diameter of 3.75 mm with a 7-mm-long and 5-mm-thick implant. In three additional models the stress response of the bone-implant system was evaluated in the absence of a cortical layer, thus simulating an extreme degree of maxillary atrophy. In all models the modeled implants were loaded at their points of emergence with an assumed force of 100 N. The vector of the loading force was inclined 30 degrees posteriorly relative to the implant axis and 30 degrees away from the sagittal plane. The bone-implant interface was assumed to be perfect simulating full osseointegration. The final evaluation of the FE models showed complete peri-implant packing to reduce displacements of the implant tip by 32% vs. no sheathing/packing. Van Mises' equivalent stresses were used to assess the stresses in both human bone and titanium alloy implants. The highest stress levels in bone were predicted for the case without sufficient implant sheathing. In the models with adequate bony implant support, intrabony stresses were generally reduced by up to - 40%. The structural stiffness of the bone-implant system increased with the extent of sinus floor elevation. The results indicate that more extensive peri-implant packing reduces implant displacement, intrabony stresses and stresses at the bone-implant interface.     

Cardiovascular Efficacy and Safety of PCSK9 Inhibitors: Systematic Review and Meta-analysis Including the ODYSSEY OUTCOMES Trial

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are efficacious lipid-lowering agents, but more precise estimates of their effects on major adverse cardiovascular events (MACE), mortality, and safety are needed. We systematically reviewed and meta-analyzed randomized controlled trials with durations ≥ 6 months comparing MACE, mortality, and safety with PCSK9 inhibitors vs control. We searched CENTRAL, Embase, MedLine and the grey literature to November 7, 2018. From 2048 articles, we included 23 trials (n = 60,723). PCSK9 inhibitors reduced MACE (relative risk, 0.83; 95% confidence interval, 0.78-0.88), but did not clearly reduce mortality (relative risk, 0.93; 95% confidence interval, 0.85-1.02) or increase adverse events. In conclusion, PCSK9 inhibitors reduce nonfatal MACE, are well tolerated, but effects on mortality remain unclear.