Cholinergic control of striatal GABAergic microcircuits

Cholinergic interneurons (CINs) are essential elements of striatal circuits and functions. Although acetylcholine signaling via muscarinic receptors (mAChRs) has been well studied, more recent data indicate that postsynaptic nicotinic receptors (nAChRs) located on striatal GABAergic interneurons (GINs) are equally critical. One example is that CIN stimulation induces large disynaptic inhibition of striatal projection neurons (SPNs) mediated by nAChR activation of GINs. Although these circuits are ideally positioned to modulate striatal output, the neurons involved are not definitively identified because of an incomplete mapping of CINs-GINs interconnections. Here, we show that CINs modulate four GINs populations via an intricate mechanism involving co-activation of presynaptic and postsynaptic mAChRs and nAChRs. Using optogenetics, we demonstrate the participation of tyrosine hydroxylase-expressing GINs in the disynaptic inhibition of SPNs via heterotypic electrical coupling with neurogliaform interneurons. Altogether, our results highlight the importance of CINs in regulating GINs microcircuits via complex synaptic/heterosynaptic mechanisms

Direct Percutaneous Left Ventricular Access and Port Closure Pre-Clinical Feasibility

ObjectivesThis study sought to evaluate feasibility of nonsurgical transthoracic catheter-based left ventricular (LV) access and closure.BackgroundImplanting large devices, such as mitral or aortic valve prostheses, into the heart requires surgical exposure and repair. Reliable percutaneous direct transthoracic LV access and closure would allow new nonsurgical therapeutic procedures.MethodsPercutaneous direct LV access was performed in 19 swine using real-time magnetic resonance imaging (MRI) and an “active” MRI needle antenna to deliver an 18-F introducer sheath. The LV access ports were closed percutaneously using a commercial ventricular septal defect occluder and an “active” MRI delivery cable for enhanced visibility. We used “permissive pericardial tamponade” (temporary fluid instillation to separate the 2 pericardial layers) to avoid pericardial entrapment by the epicardial disk. Techniques were developed in 8 animals, and 11 more were followed up to 3 months by MRI and histopathology.ResultsImaging guidance allowed 18-F sheath access and closure with appropriate positioning of the occluder inside the transmyocardial tunnel. Of the survival cohort, immediate hemostasis was achieved in 8 of 11 patients. Failure modes included pericardial entrapment by the epicardial occluder disk (n = 2) and a true-apex entry site that prevented hemostatic apposition of the endocardial disk (n = 1). Reactive pericardial effusion (192 ± 118 ml) accumulated 5 ± 1 days after the procedure, requiring 1-time drainage. At 3 months, LV function was preserved, and the device was endothelialized.ConclusionsDirect percutaneous LV access and closure is feasible using real-time MRI. A commercial occluder achieved hemostasis without evident deleterious effects on the LV. Having established the concept, further clinical development of this approach appears realistic

IBMPFD disease-causing mutant VCP/p97 proteins are targets of autophagic-lysosomal degradation

The ubiquitin-proteasome system (UPS) degrades soluble proteins and small aggregates, whereas macroautophagy (autophagy herein) eliminates larger protein aggregates, tangles and even whole organelles in a lysosome-dependent manner. VCP/p97 was implicated in both pathways. VCP/p97 mutations cause a rare multisystem disease called IBMPFD (Inclusion Body Myopathy with Paget's Disease and Frontotemporal Dementia). Here, we studied the role IBMPFD-related mutants of VCP/p97 in autophagy. In contrast with the wild-type VCP/p97 protein or R155C or R191Q mutants, the P137L mutant was aggregate-prone. We showed that, unlike commonly studied R155C or R191Q mutants, the P137L mutant protein stimulated both autophagosome and autolysosome formation. Moreover, P137L mutant protein itself was a substrate of autophagy. Starvation- and mTOR inhibition-induced autophagy led to the degradation of the P137L mutant protein, while preserving the wild-type and functional VCP/p97. Strikingly, similar to the P137L mutant, other IBMPFD-related VCP/p97 mutants, namely R93C and G157R mutants induced autophagosome and autolysosome formation; and G157R mutant formed aggregates that could be cleared by autophagy. Therefore, cellular phenotypes caused by P137L mutant expression were not isolated observations, and some other IBMPFD disease-related VCP/p97 mutations could lead to similar outcomes. Our results indicate that cellular mechanisms leading to IBMPFD disease may be various, and underline the importance of studying different disease-associated mutations in order to better understand human pathologies and tailor mutation-specific treatment strategies

The global impact of the COVID-19 pandemic on the management and course of chronic urticaria

Introduction: The COVID-19 pandemic dramatically disrupts health care around the globe. The impact of the pandemic on chronic urticaria (CU) and its management are largely unknown. Aim: To understand how CU patients are affected by the COVID-19 pandemic; how specialists alter CU patient management; and the course of CU in patients with COVID-19. Materials and Methods: Our cross-sectional, international, questionnaire-based, multicenter UCARE COVID-CU study assessed the impact of the pandemic on patient consultations, remote treatment, changes in medications, and clinical consequences. Results: The COVID-19 pandemic severely impairs CU patient care, with less than 50% of the weekly numbers of patients treated as compared to before the pandemic. Reduced patient referrals and clinic hours were the major reasons. Almost half of responding UCARE physicians were involved in COVID-19 patient care, which negatively impacted on the care of urticaria patients. The rate of face-to-face consultations decreased by 62%, from 90% to less than half, whereas the rate of remote consultations increased by more than 600%, from one in 10 to more than two thirds. Cyclosporine and systemic corticosteroids, but not antihistamines or omalizumab, are used less during the pandemic. CU does not affect the course of COVID-19, but COVID-19 results in CU exacerbation in one of three patients, with higher rates in patients with severe COVID-19. Conclusions: The COVID-19 pandemic brings major changes and challenges for CU patients and their physicians. The long-term consequences of these changes, especially the increased use of remote consultations, require careful evaluation

Whole shaft visibility and mechanical performance for active MR catheters using copper-nitinol braided polymer tubes

<p>Abstract</p> <p>Background</p> <p>Catheter visualization and tracking remains a challenge in interventional MR.</p> <p>Active guidewires can be made conspicuous in "profile" along their whole shaft exploiting metallic core wire and hypotube components that are intrinsic to their mechanical performance. Polymer-based catheters, on the other hand, offer no conductive medium to carry radio frequency waves. We developed a new "active" catheter design for interventional MR with mechanical performance resembling braided X-ray devices. Our 75 cm long hybrid catheter shaft incorporates a wire lattice in a polymer matrix, and contains three distal loop coils in a flexible and torquable 7Fr device. We explored the impact of braid material designs on radiofrequency and mechanical performance.</p> <p>Results</p> <p>The incorporation of copper wire into in a superelastic nitinol braided loopless antenna allowed good visualization of the whole shaft (70 cm) <it>in vitro </it>and <it>in vivo </it>in swine during real-time MR with 1.5 T scanner. Additional distal tip coils enhanced tip visibility. Increasing the copper:nitinol ratio in braiding configurations improved flexibility at the expense of torquability. We found a 16-wire braid of 1:1 copper:nitinol to have the optimum balance of mechanical (trackability, flexibility, torquability) and antenna (signal attenuation) properties. With this configuration, the temperature increase remained less than 2°C during real-time MR within 10 cm horizontal from the isocenter. The design was conspicuous <it>in vitro </it>and <it>in vivo</it>.</p> <p>Conclusion</p> <p>We have engineered a new loopless antenna configuration that imparts interventional MR catheters with satisfactory mechanical and imaging characteristics. This compact loopless antenna design can be generalized to visualize the whole shaft of any general-purpose polymer catheter to perform safe interventional procedures.</p

A concept for integrated care pathways for atopic dermatitis—A GA2LEN ADCARE initiative

Introduction: The integrated care pathways for atopic dermatitis (AD-ICPs) aim to bridge the gap between existing AD treatment evidence-based guidelines and expert opinion based on daily practice by offering a structured multidisciplinary plan for patient management of AD. ICPs have the potential to enhance guideline recommendations by combining interventions and aspects from different guidelines, integrating quality assurance, and describing co-ordination of care. Most importantly, patients can enter the ICPs at any level depending on AD severity, resources available in their country, and economic factors such as differences in insurance reimbursement systems. Methods: The GA2LEN ADCARE network and partners as well as all stakeholders, abbreviated as the AD-ICPs working group, were involved in the discussion and preparation of the AD ICPs during a series of subgroup workshops and meetings in years 2020 and 2021, after which the document was circulated within all GAL2EN ADCARE centres. Results: The AD-ICPs outline the diagnostic procedures, possible co-morbidities, different available treatment options including differential approaches for the pediatric population, and the role of the pharmacists and other stakeholders, as well as remaining unmet needs in the management of AD. Conclusion: The AD-ICPs provide a multidisciplinary plan for improved diagnosis, treatment, and patient feedback in AD management, as well as addressing critical unmet needs, including improved access to care, training specialists, implementation of educational programs, assessment on the impact of climate change, and fostering a personalised treatment approach. By focusing on these key areas, the initiative aims to pave the way for a brighter future in the management of AD

Review of journal of cardiovascular magnetic resonance 2010

There were 75 articles published in the Journal of Cardiovascular Magnetic Resonance (JCMR) in 2010, which is a 34% increase in the number of articles since 2009. The quality of the submissions continues to increase, and the editors were delighted with the recent announcement of the JCMR Impact Factor of 4.33 which showed a 90% increase since last year. Our acceptance rate is approximately 30%, but has been falling as the number of articles being submitted has been increasing. In accordance with Open-Access publishing, the JCMR articles go on-line as they are accepted with no collating of the articles into sections or special thematic issues. Last year for the first time, the Editors summarized the papers for the readership into broad areas of interest or theme, which we felt would be useful to practitioners of cardiovascular magnetic resonance (CMR) so that you could review areas of interest from the previous year in a single article in relation to each other and other recent JCMR articles [1]. This experiment proved very popular with a very high rate of downloading, and therefore we intend to continue this review annually. The papers are presented in themes and comparison is drawn with previously published JCMR papers to identify the continuity of thought and publication in the journal. We hope that you find the open-access system increases wider reading and citation of your papers, and that you will continue to send your quality manuscripts to JCMR for publication