Imbalance of p75(NTR)/TrkB protein expression in Huntington's disease: Implication for neuroprotective therapies

Neuroprotective therapies based on brain-derived neurotrophic factor (BDNF) administration have been proposed for Huntington's disease (HD) treatment. However, our group has recently reported reduced levels of TrkB in HD mouse models and HD human brain suggesting that besides a decrease on BDNF levels a reduction of TrkB expression could also contribute to diminished neurotrophic support in HD. BDNF can also bind to p75 neurotrophin receptor (p75(NTR)) modulating TrkB signaling. Therefore, in this study we have analyzed the levels of p75(NTR) in several HD models, as well as in HD human brain. Our data demonstrates a p75(NTR)/TrkB imbalance in the striatum of two different HD mouse models, Hdh(Q111/111) homozygous knockin mice and R6/1 mice that was also manifested in the putamen of HD patients. The imbalance between TrkB and p75(NTR) levels in a HD cellular model did not affect BDNF-mediated TrkB activation of prosurvival pathways but induced activation of apoptotic cascades as demonstrated by increased JNK phosphorylation. Moreover, BDNF failed to protect mutant huntingtin striatal cells transfected with p75(NTR) against NMDA-mediated excitotoxicity, which was associated with decreased Akt phosphorylation. Interestingly, lack of Akt activation following BDNF and NMDA treatment correlated with increased PP1 levels. Accordingly, pharmacological inhibition of PP1 by okadaic acid (OA) prevented mutant huntingtin striatal cell death induced by NMDA and BDNF. Altogether, our findings demonstrate that the p75(NTR)/TrkB imbalance induced by mutant huntingtin in striatal cells associated with the aberrant activity of PP1 disturbs BDNF neuroprotection likely contributing to increasing striatal vulnerability in HD. On the basis of this data we hypothesize that normalization of p75(NTR) and/or TrkB expression or their signaling will improve BDNF neuroprotective therapies in HD. Cell Death and Disease (2013) 4, e595; doi:10.1038/cddis.2013.116; published online 18 April 201

Tailored two-dimensional finite-element formulations for ad-hoc analysis of waveguiding and mode-matching problems

The analysis of homogeneous closed waveguides is known to be one of the first, if not the very first, problems to be addressed with the finite element method (P. Silvester, “Finite element solution of homogeneous waveguide problems”, Alta Frequenza, vol. 38, pp. 313–317, 1969) in the framework of computational electromagnetics. Since this two-dimensional scalar case, many developments have followed: extension to three-dimensional analysis, derivation of curlconforming edge and higher-order elements, domain decomposition approaches, hybridization with other numerical or analytical methods, etc. This has led the finite element method to be considered one of the most well-established, reliable techniques to address cutting-edge problems in computational electromagnetics, with many reference books (G. Pelosi, R. Coccioli, S. Selleri, Quick Finite Elements for Electromagnetic Waves, Norwood, MA, USA: Artech House, 2009; J. Jin, The Finite Element Method in Electromagnetics, Hoboken, NJ, USA: Wiley, 2015). Despite these long-known advancements, resorting to solving the afore-mentioned (and, at first glance, simple) problem of computing the modes in any waveguiding cross-section still plays a key role in computer-aided design methodologies that rely on the modal description of the fields, as is the case of the mode-matching method. In this case, not only an accurate calculation of these modal fields is required, but also the capability to compute as many modes (without skipping a single one) as necessary to ensure convergence. If the problem demands for it, it is also imperative to have a straightforward division into different classes or types of modes according to symmetries and possible excitations, as well as a proper identification of degenerate modes. In this work, we will review some strategies and tailored two-dimensional finite-element formulations proposed by the authors to address some of the issues arising when analyzing waveguiding structures, especially focusing on obtaining proper modal decompositions of the fields to be used in further computer-aided design of waveguide devices through mode-matching techniques. Some of these strategies and formulations include the comparison of different types of meshes (structured quadrilateral vs. unstructured triangular) when the waveguide cross-sections have 90º corners, as well as the development of specific boundary conditions to model novel materials enclosing the waveguide (such as graphene) or to account for higher-order symmetries (such as rotational ones) in structures with a high number of degenerate modes. In the latter case, this is especially useful for devices conceived to operate with circular polarization

New drilling of the early Aptian OAE1a : the Cau core (Prebetic Zone, south-eastern Spain)

The Cretaceous was punctuated by several episodes of accelerated global change, defined as Oceanic Anoxic Events (OAEs), that reflect abrupt changes in global carbon cycling. The Aptian Oceanic Anoxic Event (OAE1a; 120 Ma) represents an excellent example, recorded in all major ocean basins, and associated with massive burial of organic matter in marine sediments. The OAE1a is concomitant with the "nannoconid crisis", which is characterized by a major biotic turnover, and a widespread demise of carbonate platforms. Many studies have been published over the last decades on OAE1a's from different sections in the world, and provide a detailed C-isotope stratigraphy for the event. Nevertheless, new high-resolution studies across the event are essential to shed light on the precise timing and rates of the multiple environmental and biotic changes that occurred during this critical period of Earth history. <br><br> Here we present a new drill core recovering an Aptian section spanning the OAE1a in southern Spain. The so-called Cau section was drilled in the last quarter of 2015. The Cau section is located in the easternmost part of the Prebetic Zone (Betic Cordillera), which represents platform deposits of the southern Iberian palaeomargin. The lower Aptian deposits of the Cau section belong to a hemipelagic unit (Almadich Formation), deposited in a highly subsident sector of the distal parts of the Prebetic Platform. Previous work on the early Aptian of the Cau succession has focused on stratigraphy, bioevents, C-isotope stratigraphy, and organic and elemental geochemistry. A more recent study based on biomarkers has presented a detailed record of the <i>p</i>CO₂ evolution across the OAE1a (Naafs et al., 2016). All these studies reveal that the Cau section represents an excellent site to further investigate the OAE1a, based on its unusually high sedimentation rate and stratigraphic continuity, the quality and preservation of fossils, and the well-expressed geochemical signatures

Renal Dysfunction in Patients with Chronic Liver Disease

Renal dysfunction in patients with chronic liver disease encompasses a clinical spectrum of hyponatremia, ascites, and hepatorenal syndrome. Clinical observation has suggested that patients with cirrhosis have hyperdynamic circulation, and recent studies strongly suggest that peripheral arterial vasodilatation and subsequent development of hyperdynamic circulation are responsible for disturbances in renal function. Arterial vasodilatation predominantly occurs in the splanchnic vascular bed, and seems to precede an increase in blood flow in the splanchnic circulation. Nitric oxide plays a central role in progressive vasodilatation, as evidenced by in vivo and in vitro studies. Renal dysfunction negatively affects the prognosis of patients with cirrhosis, as hyponatremia, ascites, and azotemia are associated with increased rate of complications and mortality. Recent advances in understanding the pathophysiology of renal dysfunction have enabled clinicians to develop new diagnostic criteria and therapeutic recommendations. Hepatorenal syndrome is regarded as a potentially reversible disorder, as systemic vasoconstrictors with concomitant albumin administration are emerging as a promising management option, especially in terms of providing bridging therapy for patients awaiting liver transplantation

MAU2 and NIPBL variants impair the heterodimerization of the cohesin loader subunits and cause Cornelia de Lange syndrome

The NIPBL/MAU2 heterodimer loads cohesin onto chromatin. Mutations inNIPBLaccount for most cases ofthe rare developmental disorder Cornelia de Lange syndrome (CdLS). Here we report aMAU2 variant causing CdLS, a deletion of seven amino acids that impairs the interaction between MAU2 and the NIPBL N terminus.Investigating this interaction, we discovered that MAU2 and the NIPBL N terminus are largely dispensable fornormal cohesin and NIPBL function in cells with a NIPBL early truncating mutation. Despite a predicted fataloutcome of an out-of-frame single nucleotide duplication inNIPBL, engineered in two different cell lines,alternative translation initiation yields a form of NIPBL missing N-terminal residues. This form cannot interactwith MAU2, but binds DNA and mediates cohesin loading. Altogether, our work reveals that cohesin loading can occur independently of functional NIPBL/MAU2 complexes and highlights a novel mechanism protectiveagainst out-of-frame mutations that is potentially relevant for other genetic conditions

Treatment With Simvastatin and Rifaximin Restores the Plasma Metabolomic Profile in Patients With Decompensated Cirrhosis

Patients with decompensated cirrhosis, particularly those with acute-on-chronic liver failure (ACLF), show profound alterations in plasma metabolomics. The aim of this study was to investigate the effect of treatment with simvastatin and rifaximin on plasma metabolites of patients with decompensated cirrhosis, specifically on compounds characteristic of the ACLF plasma metabolomic profile. Two cohorts of patients were investigated. The first was a descriptive cohort of patients with decompensated cirrhosis (n = 42), with and without ACLF. The second was an intervention cohort from the LIVERHOPE-SAFETY randomized, double-blind, placebo-controlled trial treated with simvastatin 20 mg/day plus rifaximin 1,200 mg/day (n = 12) or matching placebo (n = 13) for 3 months. Plasma samples were analyzed using ultrahigh performance liquid chromatography–tandem mass spectroscopy for plasma metabolomics characterization. ACLF was characterized by intense proteolysis and lipid alterations, specifically in pathways associated with inflammation and mitochondrial dysfunction, such as the tryptophan–kynurenine and carnitine beta-oxidation pathways. An ACLF-specific signature was identified. Treatment with simvastatin and rifaximin was associated with changes in 161 of 985 metabolites in comparison to treatment with placebo. A remarkable reduction in levels of metabolites from the tryptophan–kynurenine and carnitine pathways was found. Notably, 18 of the 32 metabolites of the ACLF signature were affected by the treatment. Conclusion: Treatment with simvastatin and rifaximin modulates some of the pathways that appear to be key in ACLF development. This study unveils some of the mechanisms involved in the effects of treatment with simvastatin and rifaximin in decompensated cirrhosis and sets the stage for the use of metabolomics to investigate new targeted therapies in cirrhosis to prevent ACLF development

Plasma copeptin as biomarker of disease progression and prognosis in cirrhosis

Lay summary: Copeptin is a fragment of the vasopressin precursor, a hormone that is known to be increased in patients with cirrhosis and that plays a role in the development of complications of the disease. Vasopressin is difficult to measure, but copeptin is a more stable molecule and is easier to measure in blood. Sola and Kerbert and colleagues have shown in a series of 361 patients that copeptin is markedly increased in patients with cirrhosis who develop complications during the following 3 months, compared to those patients who do not develop complications. Moreover, copeptin correlates with prognosis. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362