Multiple Autism-Linked Genes Mediate Synapse Elimination via Proteasomal Degradation of a Synaptic Scaffold PSD-95

SummaryThe activity-dependent transcription factor myocyte enhancer factor 2 (MEF2) induces excitatory synapse elimination in mouse neurons, which requires fragile X mental retardation protein (FMRP), an RNA-binding protein implicated in human cognitive dysfunction and autism. We report here that protocadherin 10 (Pcdh10), an autism-spectrum disorders gene, is necessary for this process. MEF2 and FMRP cooperatively regulate the expression of Pcdh10. Upon MEF2 activation, PSD-95 is ubiquitinated by the ubiquitin E3 ligase murine double minute 2 (Mdm2) and then binds to Pcdh10, which links it to the proteasome for degradation. Blockade of the Pcdh10-proteasome interaction inhibits MEF2-induced PSD-95 degradation and synapse elimination. In FMRP-lacking neurons, elevated protein levels of eukaryotic translation elongation factor 1 α (EF1α), an Mdm2-interacting protein and FMRP target mRNA, sequester Mdm2 and prevent MEF2-induced PSD-95 ubiquitination and synapse elimination. Together, our findings reveal roles for multiple autism-linked genes in activity-dependent synapse elimination

Dual targeting of CCR2 and CX3CR1 in an arterial injury model of vascular inflammation

<p>Abstract</p> <p>Objectives</p> <p>The chemokine receptors CCR2 and CX3CR1 are important in the development of coronary artery disease. The purpose of this study is to analyze the effect of a novel CCR2 inhibitor in conjunction with CX3CR1 deletion on vascular inflammation.</p> <p>Methods</p> <p>The novel CCR2 antagonist MRL-677 was characterized using an in vivo model of monocyte migration. To determine the relative roles of CCR2 and CX3CR1 in vascular remodeling, normal or CX3CR1 deficient mice were treated with MRL-677. After 14 days, the level of intimal hyperplasia in the artery was visualized by paraffin sectioning and histology of the hind limbs.</p> <p>Results</p> <p>MRL-677 is a CCR2 antagonist that is effective in blocking macrophage trafficking in a peritoneal thioglycollate model. Intimal hyperplasia resulting from vascular injury was also assessed in mice. Based on the whole-blood potency of MRL-677, sufficient drug levels were maintained for the entire 14 day experimental period to afford good coverage of mCCR2 with MRL-677. Blocking CCR2 with MRL-677 resulted in a 56% decrease in the vascular injury response (n = 9, p < 0.05) in normal animals. Mice in which both CCR2 and CX3CR1 pathways were targeted (CX3CR1 KO mice given MRL-677) had an 88% decrease in the injury response (n = 6, p = 0.009).</p> <p>Conclusion</p> <p>In this study we have shown that blocking CCR2 with a low molecular weight antagonist ameliorates the inflammatory response to vascular injury. The protective effect of CCR2 blockade is increased in the presence of CX3CR1 deficiency suggesting that CX3CR1 and CCR2 have non-redundant functions in the progression of vascular inflammation.</p

Editor's Choice - Carotid Stenosis Treatment : Variation in International Practice Patterns

Objectives: The aim was to determine current practice for the treatment of carotid stenosis among 12 countries participating in the International Consortium of Vascular Registries (ICVR). Methods: Data from the United States Vascular Quality Initiative (VQI) and the Vascunet registry collaboration (including 10 registries in Europe and Australasia) were used. Variation in treatment modality of asymptomatic versus symptomatic patients was analysed between countries and among centres within each country. Results: Among 58,607 procedures, octogenarians represented 18% of all patients, ranging from 8% (Hungary) to 22% (New Zealand and Australia). Women represented 36%, ranging from 29% (Switzerland) to 40% (USA). The proportion of carotid artery stenting (CAS) among asymptomatic patients ranged from 0% (Finland) to 26% (Sweden) and among symptomatic patients from 0% (Denmark) to 19% (USA). Variation among centres within countries for CAS was highest in the United States and Australia (from 0% to 80%). The overall proportion of asymptomatic patients was 48%, but varied from 0% (Denmark) to 73% (Italy). There was also substantial centre level variation within each country in the proportion of asymptomatic patients, most pronounced in Australia (0-72%), Hungary (5-55%), and the United States (0-100%). Countries with fee for service reimbursement had higher rates of treatment in asymptomatic patients than countries with population based reimbursement (OR 5.8, 95% CI 4.4-7.7). Conclusions: Despite evidence about treatment options for carotid artery disease, the proportion of asymptomatic patients, treatment modality, and the proportion of women and octogenarians vary considerably among and within countries. There was a significant association of treating more asymptomatic patients in countries with fee for service reimbursement. The findings reflect the inconsistency of the existing guidelines and a need for cooperation among guideline committees all over the world. (C) 2017 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.Peer reviewe

Bright Metal-Poor Stars from the Hamburg/ESO Survey. I. Selection and Follow-up Observations from 329 Fields

We present a sample of 1777 bright (9<B<14) metal-poor candidates selected from the Hamburg/ESO Survey (HES). Despite saturation effects present in the red portion of the HES objective-prism spectra, the data were recoverable and quantitative selection criteria could be applied to select the sample. Analyses of medium-resolution (~2 A) follow-up spectroscopy of the entire sample, obtained with several 2 to 4 m class telescopes, yielded 145 new metal-poor stars with metallicity [Fe/H]<-2.0, of which 79 have [Fe/H]<-2.5, and 17 have [Fe/H]<-3.0. We also obtained C/Fe estimates for all these stars. From this, we find a frequency of C-enhanced ([C/Fe]>1.0) metal-poor ([Fe/H]<-2.0) giants of 9% +- 2%, which is lower than previously reported. However, the frequency raises to similar (>20%) and higher values with increasing distance from the Galactic plane. Although the numbers of stars at low metallicity are falling rapidly at the lowest metallicities, there is evidence that the fraction of carbon-enhanced metal-poor stars is increasing rapidly as a function of declining metallicity. For ~60 objects, high-resolution data have already been obtained; one of these, HE 1327-2326, is the new record holder for the most iron-deficient star known.Comment: 29 pages (emulateapj), accepted for publication in Ap

Peri-Operative Management of Patients Undergoing Fenestrated-Branched Endovascular Repair for Juxtarenal, Pararenal and Thoracoabdominal Aortic Aneurysms: Preventing, Recognizing and Treating Complications to Improve Clinical Outcomes

The advent and refinement of complex endovascular techniques in the last two decades has revolutionized the field of vascular surgery. This has allowed an effective minimally invasive treatment of extensive disease involving the pararenal and the thoracoabdominal aorta. Fenestrated-branched EVAR (F/BEVAR) now represents a feasible technical solution to address these complex diseases, moving the proximal sealing zone above the renal-visceral vessels take-off and preserving their patency. The aim of this paper was to provide a narrative review on the peri-operative management of patients undergoing F/BEVAR procedures for juxtarenal abdominal aortic aneurysm (JAAA), pararenal abdominal aortic aneurysm (PRAA) or thoracoabdominal aortic aneurism (TAAA). It will focus on how to prevent, diagnose, and manage the complications ensuing from these complex interventions, in order to improve clinical outcomes. Indeed, F/BEVAR remains a technically, physiologically, and mentally demanding procedure. Intraoperative adverse events often require prolonged or additional procedures and complications may significantly impact a patient’s quality of life, health status, and overall cost of care. The presence of standardized preoperative, perioperative, and postoperative pathways of care, together with surgeons and teams with significant experience in aortic surgery, should be considered as crucial points to improve clinical outcomes. Aggressive prevention, prompt diagnosis and timely rescue of any major adverse events following the procedure remain paramount clinical needs

Deriving and critiquing an empirically-based framework for pharmaceutical ethics.

Background: The pharmaceutical industry has been responsible for major medical advances, but the industry has also been heavily criticized. Such criticisms, and associated regulatory responses, are no doubt often warranted, but do not provide a framework for those who wish to reason systematically about the moral dimensions of drug development. We set out to develop such a framework using Beauchamp and Childress’s “four principles” as organizing categories. Methods: We conducted a qualitative interview study of people working in the “medical affairs” departments of pharmaceutical companies to determine: (1) whether our data could meaningfully be organized under the headings of “autonomy,” “beneficence,” “nonmaleficence,” and “justice”; (2) how principles might be expressed in this particular commercial setting; and (3) if these principles are expressed, whether and how competing principles are balanced. We then critiqued these findings using existing normative theory. Results: Our interviews demonstrated that three of Beauchamp and Childress’ four principles were salient to our participants: beneficence, non-maleficence, and justice. Within each of these principles, participants had two broad ethical orientations: an altruistic public focus (“other-ness”) and a commitment to their companies (“firm-ness”). Our participants also demonstrated efforts to balance these principles and highlighted the importance of phronesis (or practical wisdom) in balancing and enacting principles. Notably, however, our participants did not spontaneously emphasize the importance of autonomy. Conclusions: It is possible to use qualitative empirical research, together with normative analysis, to derive a framework for pharmaceutical ethics. We suggest that our framework would be useful for those who wish to reason ethically within, or in collaboration with, the pharmaceutical industry. Keywords: Empirical ethics, principle-based ethics, pharmaceutical industry, pharmaceutical ethics, qualitative researchNHMRC Career Development Fellowship APP106356

A multi-institutional experience in adventitial cystic disease

AbstractBackgroundAdventitial cystic disease (ACD) is an unusual arteriopathy; case reports and small series constitute the available literature regarding treatment. We sought to examine the presentation, contemporary management, and long-term outcomes using a multi-institutional database.MethodsUsing a standardized database, 14 institutions retrospectively collected demographics, comorbidities, presentation/symptoms, imaging, treatment, and follow-up data on consecutive patients treated for ACD during a 10-year period, using Society for Vascular Surgery reporting standards for limb ischemia. Univariate and multivariate analyses were performed comparing treatment methods and factors associated with recurrent intervention. Life-table analysis was performed to estimate the freedom from reintervention in comparing the various treatment modalities.ResultsForty-seven patients (32 men, 15 women; mean age, 43 years) were identified with ACD involving the popliteal artery (n = 41), radial artery (n = 3), superficial/common femoral artery (n = 2), and common femoral vein (n = 1). Lower extremity claudication was seen in 93% of ACD of the leg arteries, whereas patients with upper extremity ACD had hand or arm pain. Preoperative diagnosis was made in 88% of patients, primarily using cross-sectional imaging of the lower extremity; mean lower extremity ankle-brachial index was 0.71 in the affected limb. Forty-one patients with lower extremity ACD underwent operative repair (resection with interposition graft, 21 patients; cyst resection, 13 patients; cyst resection with bypass graft, 5 patients; cyst resection with patch, 2 patients). Two patients with upper extremity ACD underwent cyst drainage without resection or arterial reconstruction. Complications, including graft infection, thrombosis, hematoma, and wound dehiscence, occurred in 12% of patients. Mean lower extremity ankle-brachial index at 3 months postoperatively improved to 1.07 (P < .001), with an overall mean follow-up of 20 months (range, 0.33-9 years). Eight patients (18%) with lower extremity arterial ACD required reintervention (redo cyst resection, one; thrombectomy, three; redo bypass, one; balloon angioplasty, three) after a mean of 70 days with symptom relief in 88%. Lower extremity patients who underwent cyst resection and interposition or bypass graft were less likely to require reintervention (P = .04). One patient with lower extremity ACD required an above-knee amputation for extensive tissue loss.ConclusionsThis multi-institutional, contemporary experience of ACD examines the treatment and outcomes of ACD. The majority of patients can be identified preoperatively; surgical repair, consisting of cyst excision with arterial reconstruction or bypass alone, provides the best long-term symptomatic relief and reduced need for intervention to maintain patency

Outcomes of “Anterior Versus Posterior Divisional Branches of the Hypogastric Artery as Distal Landing Zone for Iliac Branch Devices”: The International Multicentric R3OYAL Registry

Objective: The aim of this multicentric registry was to assess the outcomes of “anteRior versus posteRior divisional bRanches Of the hYpogastric artery as distAl landing zone for iLiac branch devices (R3OYAL).” Methods: The main exposure of interest for the purpose of this study was the internal iliac artery (IIA) divisional branch (anterior vs posterior) that was used as distal landing zone. Early endpoints included technical success and adverse events. Late endpoints included survival, primary/secondary IIA patency, and IIA branch instability. Results: A total of 171 patients were included in the study, of which 50 received bilateral implantation of iliac branch devices (IBDs). This resulted in a total of 221 incorporated IIAs included in the final analysis, of which 40 were anterior divisional branches and 181 were posterior divisional branches. Technical success was high in both groups (anterior division: 98% vs posterior division: 100%, P =.18). Occurrence of any adverse event was noted in 14% of patients in both groups (P = 1.0). The overall rate of freedom from the composite IBD branch instability did not show significant differences between patients receiving distal landing in the anterior or posterior division of the IIA at 3 years (79% vs 87%, log-rank test =.215). The 3-year estimates of IBD patency were significantly lower in patients who received distal landing in the anterior divisional branch than those who received distal landing in the posterior divisional branch (primary patency: 81% vs 96%, log-rank test =.009; secondary patency: 81% vs 97%, log-rank test <.001). Conclusions: The use of the anterior or posterior divisional branches of the IIA as distal landing zone for IBD implantation shows comparable profiles in terms of immediate technical success, perioperative safety, and side-branch instability up to 3 years. However, IBD patency at 3 years was higher when the distal landing zone was achieved within the posterior divisional branch of the IIA. Clinical Impact: The results from this large multicentric registry confirm that use of the anterior or posterior divisional branches of the internal iliac artery (IIA) as distal landing zone for implantation of iliac branch devices (IBD) shows comparable profiles of safety and feasibility, thereby allowing to extend the indications for endovascular repair of aorto-iliac aneurysms to cases with unsuitable anatomy within the IIA main trunk. Although mid-term rates of device durability and branch instability seem to be similar, the rates of primary and secondary IBD patency at three years was favored when the distal landing zone was achieved in the posterior divisional branch of the IIA

A Regulatory Mechanism Involving TBP-1/Tat-Binding Protein 1 and Akt/PKB in the Control of Cell Proliferation

TBP-1 /Tat-Binding Protein 1 (also named Rpt-5, S6a or PSMC3) is a multifunctional protein, originally identified as a regulator of HIV-1-Tat mediated transcription. It is an AAA-ATPase component of the 19S regulative subunit of the proteasome and, as other members of this protein family, fulfils different cellular functions including proteolysis and transcriptional regulation. We and others reported that over expression of TBP-1 diminishes cell proliferation in different cellular contexts with mechanisms yet to be defined. Accordingly, we demonstrated that TBP-1 binds to and stabilizes the p14ARF oncosuppressor increasing its anti-oncogenic functions. However, TBP-1 restrains cell proliferation also in the absence of ARF, raising the question of what are the molecular pathways involved. Herein we demonstrate that stable knock-down of TBP-1 in human immortalized fibroblasts increases cell proliferation, migration and resistance to apoptosis induced by serum deprivation. We observe that TBP-1 silencing causes activation of the Akt/PKB kinase and that in turn TBP-1, itself, is a downstream target of Akt/PKB. Moreover, MDM2, a known Akt target, plays a major role in this regulation. Altogether, our data suggest the existence of a negative feedback loop involving Akt/PKB that might act as a sensor to modulate TBP-1 levels in proliferating cells