In an early analysis of this trial, use of a magnetically levitated centrifugal continuous-flow circulatory pump was found to improve clinical outcomes, as compared with a mechanical-bearing axial ...continuous-flow pump, at 6 months in patients with advanced heart failure.
In a randomized noninferiority and superiority trial, we compared the centrifugal-flow pump with the axial-flow pump in patients with advanced heart failure, irrespective of the intended goal of support (bridge to transplantation or destination therapy). The composite primary end point was survival at 2 years free of disabling stroke (with disabling stroke indicated by a modified Rankin score of >3; scores range from 0 to 6, with higher scores indicating more severe disability) or survival free of reoperation to replace or remove a malfunctioning device. The noninferiority margin for the risk difference (centrifugal-flow pump group minus axial-flow pump group) was -10 percentage points.
Of 366 patients, 190 were assigned to the centrifugal-flow pump group and 176 to the axial-flow pump group. In the intention-to-treat population, the primary end point occurred in 151 patients (79.5%) in the centrifugal-flow pump group, as compared with 106 (60.2%) in the axial-flow pump group (absolute difference, 19.2 percentage points; 95% lower confidence boundary, 9.8 percentage points P<0.001 for noninferiority; hazard ratio, 0.46; 95% confidence interval CI, 0.31 to 0.69 P<0.001 for superiority). Reoperation for pump malfunction was less frequent in the centrifugal-flow pump group than in the axial-flow pump group (3 patients 1.6% vs. 30 patients 17.0%; hazard ratio, 0.08; 95% CI, 0.03 to 0.27; P<0.001). The rates of death and disabling stroke were similar in the two groups, but the overall rate of stroke was lower in the centrifugal-flow pump group than in the axial-flow pump group (10.1% vs. 19.2%; hazard ratio, 0.47; 95% CI, 0.27 to 0.84, P=0.02).
In patients with advanced heart failure, a fully magnetically levitated centrifugal-flow pump was superior to a mechanical-bearing axial-flow pump with regard to survival free of disabling stroke or reoperation to replace or remove a malfunctioning device. (Funded by Abbott; MOMENTUM 3 ClinicalTrials.gov number, NCT02224755 .).
This study was designed to evaluate whether subjects with amyloid beta (Aβ) pathology, detected using florbetapir positron emission tomorgraphy (PET), demonstrated greater cognitive decline than ...subjects without Aβ pathology. Sixty-nine cognitively normal (CN) controls, 52 with recently diagnosed mild cognitive impairment (MCI) and 31 with probable Alzheimer's disease (AD) dementia were included in the study. PET images obtained in these subjects were visually rated as positive (Aβ+) or negative (Aβ-), blind to diagnosis. Fourteen percent (10/69) of CN, 37% (19/52) of MCI and 68% (21/31) of AD were Aβ+. The primary outcome was change in ADAS-Cog score in MCI subjects after 36 months; however, additional outcomes included change on measures of cognition, function and diagnostic status. Aβ+ MCI subjects demonstrated greater worsening compared with Aβ- subjects on the ADAS-Cog over 36 months (5.66 ± 1.47 vs -0.71 ± 1.09, P = 0.0014) as well as on the mini-mental state exam (MMSE), digit symbol substitution (DSS) test, and a verbal fluency test (P < 0.05). Similar to MCI subjects, Aβ+ CN subjects showed greater decline on the ADAS-Cog, digit-symbol-substitution test and verbal fluency (P<0.05), whereas Aβ+ AD patients showed greater declines in verbal fluency and the MMSE (P < 0.05). Aβ+ subjects in all diagnostic groups also showed greater decline on the CDR-SB (P<0.04), a global clinical assessment. Aβ+ subjects did not show significantly greater declines on the ADCS-ADL or Wechsler Memory Scale. Overall, these findings suggest that in CN, MCI and AD subjects, florbetapir PET Aβ+ subjects show greater cognitive and global deterioration over a 3-year follow-up than Aβ- subjects do.
Tristetraprolin (TTP), a negative regulator of many pro-inflammatory genes, is strongly expressed in rheumatoid synovial cells. The mitogen-activated protein kinase (MAPK) p38 pathway mediates the ...inactivation of TTP via phosphorylation of two serine residues. We wished to test the hypothesis that these phosphorylations contribute to the development of inflammatory arthritis, and that, conversely, joint inflammation may be inhibited by promoting the dephosphorylation and activation of TTP.
The expression of TTP and its relationship with MAPK p38 activity were examined in non-inflamed and rheumatoid arthritis (RA) synovial tissue. Experimental arthritis was induced in a genetically modified mouse strain, in which endogenous TTP cannot be phosphorylated and inactivated. In vitro and in vivo experiments were performed to test anti-inflammatory effects of compounds that activate the protein phosphatase 2A (PP2A) and promote dephosphorylation of TTP.
TTP expression was significantly higher in RA than non-inflamed synovium, detected in macrophages, vascular endothelial cells and some fibroblasts and co-localised with MAPK p38 activation. Substitution of TTP phosphorylation sites conferred dramatic protection against inflammatory arthritis in mice. Two distinct PP2A agonists also reduced inflammation and prevented bone erosion. In vitro anti-inflammatory effects of PP2A agonism were mediated by TTP activation.
The phosphorylation state of TTP is a critical determinant of inflammatory responses, and a tractable target for novel anti-inflammatory treatments.
Instances of convergent or parallel evolution provide a potent model system for exploring contingency and determinism in evolutionary biology. Likewise, the multiple, independent habitat transitions ...from saltwater to freshwater biomes offer opportunity for studying convergent evolution within and among different vertebrate lineages. For example, stingrays have invaded freshwater habitats multiple times across different continents, sometimes even several times within the same clade (e.g., Dasyatidae). We evaluated the frequency of saltwater-freshwater invasions in stingrays, compared ecological and phenotypic diversification among freshwater and saltwater lineages, and assessed the degree of convergence among freshwater species. Despite not being morphologically distinct from saltwater stingrays, freshwater stingrays do expand the margins of stingray morphological diversity. According to our data, trophic specialists occupied non-overlapping regions of morphospace, with piscivores and molluscivores being distinct from other diet guilds. Freshwater stingrays as a group did not strongly converge morphologically, neither did freshwater rays from different lineages which shared similar niches. These findings could be explained by there not being enough time for convergence to occur among more ancient and more recent freshwater lineages. Alternatively, the different ancestral bauplans of various freshwater ray lineages and weak selection on optimal phenotypes could promote contingency in the form of evolution along paths of least resistance.
Abstract
Habitat transitions are key potential explanations for why some lineages have diversified and others have not—from Anolis lizards to Darwin's finches. The ecological ramifications of ...marine-to-freshwater transitions for fishes suggest evolutionary contingency: some lineages maintain their ancestral niches in novel habitats (niche conservatism), whereas others alter their ecological role. However, few studies have considered phenotypic, ecological, and lineage diversification concurrently to explore this issue. Here, we investigated the macroevolutionary history of the taxonomically and ecologically diverse Neotropical freshwater river rays (subfamily Potamotrygoninae), which invaded and diversified in the Amazon and other South American rivers during the late Oligocene to early Miocene. We generated a time-calibrated, multi-gene phylogeny for Potamotrygoninae and reconstructed evolutionary patterns of diet specialization. We measured functional morphological traits relevant for feeding and used comparative phylogenetic methods to examine how feeding morphology diversified over time. Potamotrygonine trophic and phenotypic diversity are evenly partitioned (non-overlapping) among internal clades for most of their history, until 20–16 mya, when more recent diversification suggests increasing overlap among phenotypes. Specialized piscivores (Heliotrygon and Paratrygon) evolved early in the history of freshwater stingrays, while later trophic specialization (molluscivory, insectivory, and crustacivory) evolved in the genus Potamotrygon. Potamotrygonins demonstrate ecological niche lability in diets and feeding apparatus; however, diversification has mostly been a gradual process through time. We suggest that competition is unlikely to have limited the potamotrygonine invasion and diversification in South America.
Given the increased use of stereotactic radiosurgical thalamotomy and other ablative therapies for tremor, new biomarkers are needed to improve outcomes. Using resting-state fMRI and MR tractography, ...we hypothesized that a "connectome fingerprint" can predict tremor outcomes and potentially serve as a targeting biomarker for stereotactic radiosurgical thalamotomy.
We evaluated 27 patients who underwent unilateral stereotactic radiosurgical thalamotomy for essential tremor or tremor-predominant Parkinson disease. Percentage postoperative improvement in the contralateral limb Fahn-Tolosa-Marin Clinical Tremor Rating Scale (TRS) was the primary end point. Connectome-style resting-state fMRI and MR tractography were performed before stereotactic radiosurgery. Using the final lesion volume as a seed, "connectivity fingerprints" representing ideal connectivity maps were generated as whole-brain R-maps using a voxelwise nonparametric Spearman correlation. A leave-one-out cross-validation was performed using the generated R-maps.
The mean improvement in the contralateral tremor score was 55.1% (SD, 38.9%) at a mean follow-up of 10.0 (SD, 5.0) months. Structural connectivity correlated with contralateral TRS improvement (
= 0.52;
= .006) and explained 27.0% of the variance in outcome. Functional connectivity correlated with contralateral TRS improvement (
= 0.50;
= .008) and explained 25.0% of the variance in outcome. Nodes most correlated with tremor improvement corresponded to areas of known network dysfunction in tremor, including the cerebello-thalamo-cortical pathway and the primary and extrastriate visual cortices.
Stereotactic radiosurgical targets with a distinct connectivity profile predict improvement in tremor after treatment. Such connectomic fingerprints show promise for developing patient-specific biomarkers to guide therapy with stereotactic radiosurgical thalamotomy.
Cite this as: J. M. Brown, K. Nemeth, N. M. Kushnir‐Sukhov, D. D. Metcalfe and E. Mezey, Clinical & Experimental Allergy, 2011 (41) 526–534.
Summary
Background
Mast cells (MCs) have a central role in ...the induction of allergic inflammation, such as seen in asthma, and contribute to the severity of certain autoimmune diseases, such as rheumatoid arthritis. The MC thus represents an important inflammatory cell, and one which has resisted therapeutic attempts to alter its role in disease.
Objective
Because bone marrow‐derived stromal cells (BMSC, also known as mesenchymal stem cells or MSCs) have been reported to alter allergic inflammation in vivo, we chose to study the interaction between mouse BMSC and mouse bone marrow‐derived MCs.
Methods
MC degranulation, cytokine production and chemotaxis were evaluated in vitro following co‐culture with BMSCs either in cell contact or a transwell. In addition, MC degranulation was assessed in vivo following administration of BMSCs in a model of passive cutaneous anaphylaxis and a peritoneal degranulation assay. Mechanisms of MC suppression by BMSCs were determined through use of inhibitors or antibodies to COX1, COX2, nitric oxide, indoleamine 2, 3‐dioxygenase, EP1–4 receptors, TGF‐β and IL‐10. Lastly, we utilized either BMSCs or MCs deficient in COX1, COX2 or EP1‐4 receptors to confirm the mechanisms of inhibition of MC function by BMSCs.
Results
We discovered that BMSCs will effectively suppress specific MC functions in vitro as well as in vivo. When MCs are cocultured with BMSCs to allow cell‐to‐cell contact, BMSCs suppressed MC degranulation, pro‐inflammatory cytokine production, chemokinesis and chemotaxis. Similarly, MC degranulation within mouse skin or the peritoneal cavity was suppressed following in vivo administration of BMSCs. Further, we found that these inhibitory effects were dependent on up‐regulation of COX2 in BMSCs; and were facilitated through the activation of EP4 receptors on MCs.
Conclusion and Clinical Relevance
These observations support the concept that BMSCs have the ability to suppress MC activation and therefore could be the basis for a novel cell based therapeutic approach in the treatment of MC driven inflammatory diseases.
Detection of volatile odorants by olfactory neurons is thought to result from direct activation of seven-transmembrane odorant receptors by odor molecules. Here, we show that detection of the
...Drosophila pheromone, 11-
cis vaccenyl acetate (cVA), is instead mediated by pheromone-induced conformational shifts in the extracellular pheromone-binding protein, LUSH. We show that LUSH undergoes a pheromone-specific conformational change that triggers the firing of pheromone-sensitive neurons. Amino acid substitutions in LUSH that are predicted to reduce or enhance the conformational shift alter sensitivity to cVA as predicted in vivo. One substitution, LUSH
D118A, produces a dominant-active LUSH protein that stimulates T1 neurons through the neuronal receptor components Or67d and SNMP in the complete absence of pheromone. Structural analysis of LUSH
D118A reveals that it closely resembles cVA-bound LUSH. Therefore, the pheromone-binding protein is an inactive, extracellular ligand converted by pheromone molecules into an activator of pheromone-sensitive neurons and reveals a distinct paradigm for detection of odorants.
Background
An accurate assessment of permanent pacemaker implantation (PPI) risk following transcatheter aortic valve replacement (TAVR) is important for clinical decision making. The aims of this ...study were to investigate the significance and utility of pre‐ and post‐TAVR ECG data and compare machine learning approaches with traditional logistic regression in predicting pacemaker risk following TAVR.
Methods
Five hundred fifity seven patients in sinus rhythm undergoing TAVR for severe aortic stenosis (AS) were included in the analysis. Baseline demographics, clinical, pre‐TAVR ECG, post‐TAVR data, post‐TAVR ECGs (24 h following TAVR and before PPI), and echocardiographic data were recorded. A Random Forest (RF) algorithm and logistic regression were used to train models for assessing the likelihood of PPI following TAVR.
Results
Average age was 80 ± 9 years, with 52% male. PPI after TAVR occurred in 95 patients (17.1%). The optimal cutoff of delta PR (difference between post and pre TAVR PR intervals) to predict PPI was 20 ms with a sensitivity of 0.82, a specificity of 0.66. With regard to delta QRS, the optimal cutoff was 13 ms with a sensitivity of 0.68 and a specificity of 0.59. The RF model that incorporated post‐TAVR ECG data (AUC 0.81) more accurately predicted PPI risk compared to the RF model without post‐TAVR ECG data (AUC 0.72). Moreover, the RF model performed better than logistic regression model in predicting PPI risk (AUC: 0.81 vs. 0.69).
Conclusions
Machine learning using RF methodology is significantly more powerful than traditional logistic regression in predicting PPI risk following TAVR.
Odorant binding proteins (OBPs) are extracellular proteins localized to the chemosensory systems of most terrestrial species. OBPs are expressed by nonneuronal cells and secreted into the fluid ...bathing olfactory neuron dendrites. Several members have been shown to interact directly with odorants, but the significance of this is not clear. We show that the
Drosophila OBP
lush is completely devoid of evoked activity to the pheromone 11-
cis vaccenyl acetate (VA), revealing that this binding protein is absolutely required for activation of pheromone-sensitive chemosensory neurons.
lush mutants are also defective for pheromone-evoked behavior. Importantly, we identify a genetic interaction between
lush and spontaneous activity in VA-sensitive neurons in the absence of pheromone. The defects in spontaneous activity and VA sensitivity are reversed by germline transformation with a
lush transgene or by introducing recombinant LUSH protein into mutant sensilla. These studies directly link pheromone-induced behavior with OBP-dependent activation of a subset of olfactory neurons.
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