Delayed sternal closure does not reduce complications associated with coagulopathy and right ventricular failure after left ventricular assist device implantation

Abstract

Delayed sternal closure (DSC) is occasionally adopted after implantation of left ventricular assist device (LVAD). Recent studies suggest that DSC be used for high risk group of patients with coagulopathy, hemodynamic instability or right ventricular failure. However, whether DSC is efficacious for bleeding complication or right ventricular failure is not known. This study is single center analysis of 52 patients, who underwent LVAD implantation. Of those 52 patients, 40 consecutive patients underwent DSC routinely. The sternum was left open with vacuum assist device after implantation of LVAD. Perioperative outcome of the patients who underwent routine DSC were compared with 12 patients who had immediate sternal closure (IC). Mean Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) level of IC group and DSC group were 2.7 and 2.6, respectively. Postoperative bleeding (643 vs. 1469 ml, p < 0.001), duration of inotropic support (109 vs. 172 h, p = 0.034), and time to extubation (26 vs. 52 h, p = 0.005) were significantly increased in DSC group. Length of ICU stay (14 vs. 15 days, p = 0.234) and hospital stay (28 vs. 20 days, p = 0.145) were similar. Incidence of right ventricular failure and tamponade were similar in the two groups. Routine DSC after implantation of an LVAD did not prove to be beneficial in reducing complications associated with coagulopathy and hemodynamic instability including cardiac tamponade or right ventricular failure. We suggest that DSC be selectively applied for patients undergoing LVAD implant.

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Fluoride-catalyzed Nucleophilic Addition of PhSCF2SiMe3 to Isatins: Synthesis of 3-(1',1'-Difluoroalkyl)-3-hydroxyindolin-2-ones

Synthesis of 3-(1',1'-difluoroalkyl)-3-hydroxyindolin-2-ones employing α,α-difluoro-α-phenylsulfanyl-α-trimethylsilylmethane (PhSCF2SiMe3) as a gem-difluoromethylene building block is described. The reaction entailed fluoride-catalyzed nucleophilic addition of PhSCF2SiMe3 to isatin derivatives followed by reductive cleavage of a phenylsulfanyl group leading to 3-(difluoromethyl)-3-hydroxyindolin-2-ones in good yields. Under similar reduction conditions, in the presence of activated olefins, an intermolecular radical trapping reactions took place to yield 3-(1',1'-difluoroalkyl)-3-hydroxyindolin-2-ones.

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Efficacy and Tolerability of Phytomedicines in Multiple Sclerosis Patients: A Review

Abstract

Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disorder of the central nervous system (CNS) that can cause cognition, mobility, and sensory impairments. It is considered one of the most common non-traumatic causes of disability in the world. The aim of the present article was to review the clinical evidence related to medicinal plants in the management of MS symptoms. Electronic databases, including the Cochrane Library, Pubmed, and Scopus, were searched for entries from 1966 to February 2017. Only clinical studies were included in this review. Different medicinal plants have positive effects on MS, including Andrographis paniculata, Boswellia papyrifera, Ruta graveolens, Vaccinium spp., Camellia sinensis, Panax ginseng, Aloysia citrodora, Ginkgo biloba, Oenothera biennis, and Cannabis sativa. C. sativa had the highest level of clinical evidence, supporting its efficacy in MS symptoms. Proanthocyanidins, ginkgo flavone glycosides, ginsenosides, epigallocatechin-3-gallate, cannabinoids (including delta-9-tetrahydrocannabinol and cannabidiol), boswellic acid, and andrographolide were presented as the main bioactive components of medicinal plants with therapeutic benefits in MS. The main complications of MS in which natural drugs were effective include spasticity, fatigue, scotoma, incontinence, urinary urgency, nocturia, memory performance, functional performance, and tremor. Herbal medicines were mostly well tolerated, and the adverse effects were limited to mild to moderate. Further well-designed human studies with a large sample size and longer follow-up period are recommended to confirm the role of medicinal plants and their metabolites in the management of MS.

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De novo mutations in HNRNPU result in a neurodevelopmental syndrome

Exome sequencing in the context of developmental disorders is a useful technique, but variants found need to be interpreted in the context of detailed phenotypic information. Whole gene deletions and loss-of-function-mutations in the HNRNPU gene have been associated with intellectual disability and seizures in some patients. However, a unifying syndromic phenotype has not been previously elucidated. Here, we report a total of seven patients (six patients identified through the Wellcome Trust Deciphering Developmental Disorders study, with one additional patient), who have heterozygous de novo mutations in HNRNPU. These were found via trio-based exome sequencing. All but one of the mutations is predicted to cause loss-of-function. These patients have dysmorphic features in common, including prominent eyebrows, long palpebral fissures, overhanging columella, and thin upper lip. All patients have developmental delay and intellectual disability (ID), ranging from moderate to severe. Seizures are common from early childhood. These initially occur in the context of febrile episodes. This series demonstrates common phenotypic features, including emerging dysmorphism, associated with heterozygous HNRNPU mutations. This allows us to define a novel neurodevelopmental syndrome, with a likely mechanism of haploinsufficiency.

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Coexistence of mutations in keratin 10 (KRT10) and the mitochondrial genome in a patient with ichthyosis with confetti and Leber's hereditary optic neuropathy

Ichthyosis with confetti (IWC) is a severe congenital genodermatosis characterized by ichthyosiform erythroderma since birth and confetti-like spots of normal skin appearing in childhood as a results of revertant mosaicism. This disorder is caused by mutations in KRT10 or KRT1 genes. We report a 16-year-old boy who presented ichthyosiform erythroderma with severe desquamation since birth and gradually worsening psycho-neurological symptoms (mental retardation, ataxia, dystonia, hypoacusis). The patient conspicuously lacked typical confetti-like spots at the age of 16. The molecular diagnostics by the whole exome sequencing showed a novel de novo (c.1374-2A>C) mutation in the KRT10 gene responsible for the development of IWC (KRT10 defect was confirmed by immunofluorescent study). Concurrently, the m.14484T>C mutation in mitochondrial MTND6 gene (characteristic for Leber's hereditary optic neuropathy or LHON) was detected in patient, his mother and brother. LHON causes frequent inherited blindness typically appearing during young adult life whose expression can be triggered by additional factors such as smoking or alcohol exposure. We speculate the effects of KRT10 and LHON mutations influence each other—skin inflammatory reaction due to severe ichthyosis might trigger the development of psychoneurological abnormalities whereas the mitochondrial mutation may reduce revertant mosaicism phenomenon resulting in the lack of confetti-like spots characteristic for IWC. However, based on a single case we should be cautious about attributing phenotypes to digenic mechanisms without functional data.

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Biallelic mutations in GPD1 gene in a Chinese boy mainly presented with obesity, insulin resistance, fatty liver, and short stature

Biallelic mutations in the GPD1 gene cause a rare autosomal recessive inherited disease known as transient infantile hypertriglyceridemia (OMIM #614480). To date, only five pathogenic variants have been reported in 15 patients from three studies. The clinical symptoms of the affected individuals present a certain degree of heterogeneity. Here, we describe a chinese adolescent patient who mainly presented with obesity, insulin resistance, fatty liver, and short stature. Targeted next-generation sequencing revealed a novel compound heterozygous variant in GPD1 gene (c.220-2A>G and c.820G>A; p.Ala274Thr). In vitro studies demonstrated that the Ala274Thr variant induced a decrease in GPD1 protein expression. Further in vitro investigation of the splicing pattern in a minigene construct in HEK293 cells showed that the c.220-2A>G variant generated an altered transcript with one cryptic splice site in exon 3, resulting in the loss of 69 bases in exon 3 (c.220_288del, p.74_96del). This is the first report involving an Asian who harbored GPD1 mutations. Our work not only expands the mutant spectrum of the GPD1 gene but also provides new insights on its resulting phenotype.

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Finding the genetic mechanisms of folate deficiency and neural tube defects—Leaving no stone unturned

Neural tube defects (NTDs) occur secondary to failed closure of the neural tube between the third and fourth weeks of gestation. The worldwide incidence ranges from 0.3 to 200 per 10,000 births with the United States of American NTD incidence at around 3–6.3 per 10,000 dependent on race and socioeconomic background. Human NTD incidence has fallen by 35–50% in North America due to mandatory folic acid fortification of enriched cereal grain products since 1998. The US Food and Drug Administration has approved the folic acid fortification of corn masa flour with the goal to further reduce the incidence of NTDs, especially among individuals who are Hispanic. However, the genetic mechanisms determining who will benefit most from folate enrichment of the diet remains unclear despite volumes of literature published on studies of association of genes with functions related to folate metabolism and risk of human NTDs. The advances in omics technologies provides hypothesis-free tools to interrogate every single gene within the genome of NTD affected individuals to discover pathogenic variants and methylation targets throughout the affected genome. By identifying genes with expression regulated by presence of folate through transcriptome profiling studies, the genetic mechanisms leading to human NTDs due to folate deficiency may begin to be more efficiently revealed.

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A randomized controlled trial of levodopa in patients with Angelman syndrome

Treatment for Angelman syndrome (AS) is currently limited to symptomatic interventions. A mouse model of AS has reduced calcium/calmodulin-dependent kinase II activity due to excessive phosphorylation of specific threonine residues, leading to diminished long-term potentiation. In a rat model of Parkinson disease, levodopa reduced phosphorylation of various proteins, including calcium/calmodulin-dependent kinase II. Further studies demonstrated that AS mice treated with levodopa performed better on rotarod testing than untreated AS mice. We conducted a multi-center double-blind randomized placebo-controlled 1-year trial of levodopa / carbidopa with either 10 or 15 mg/kg/day of levodopa in children with AS. The outcome of this intervention was assessed using either the Bayley Scales of Infant Development or the Mullen Scales of Early Learning, as well as the Vineland Adaptive Behavior Scales, and the Aberrant Behavior Checklist. Of the 78 participants enrolled, 67 participants received study medication (33 on levodopa, 34 on placebo), and 55 participants (29 on levodopa, 26 on placebo) completed the 1-year study. There were no clinically or statistically significant changes in any of the outcome measures over a 1-year period comparing the levodopa and placebo groups. The number of adverse events reported, including the more serious adverse events, was similar in both groups, but none were related to treatment with levodopa. Our data demonstrate that levodopa is well-tolerated by children with AS. However, in the doses used in this study, it failed to improve their neurodevelopment or behavioral outcome.

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Acellular Dermal Matrix: Treating Periocular Melanoma in a Patient with Xeroderma Pigmentosa

We report a 7-year-old girl with xeroderma pigmentosum (XP), who presented in our clinic with a large melanoma (35 × 50 × 20 mm, Breslow depth 18 mm) in the zygomatic-malar area. Palliative surgery was performed to maintain her residual vision and to reduce the pain caused by the compression of local structures. Because of the limited access of autologous skin grafts in pediatric patients with XP who are severely affected, we opted to use an acellular dermal matrix. There was 100% graft uptake, and the pain due to compression by the tumor was alleviated. This case demonstrates that acellular dermal matrices can be safely and effectively used in oncological facial reconstruction, especially in patients with progressive conditions such as XP.

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Harnessing Photochemical Shrinkage in Direct Laser Writing for Shape Morphing of Polymer Sheets

Abstract

Structures that change their shape in response to external stimuli unfold possibilities for more efficient and versatile production of 3D objects. Direct laser writing (DLW) is a technique based on two-photon polymerization that allows the fabrication of microstructures with complex 3D geometries. Here, it is shown that polymerization shrinkage in DLW can be utilized to create structures with locally controllable residual stresses that enable programmable, self-bending behavior. To demonstrate this concept, planar and 3D-structured sheets are preprogrammed to evolve into bio-inspired shapes (lotus flowers and shark skins). The fundamental mechanisms that control the self-bending behavior are identified and tested with microscale experiments. Based on the findings, an analytical model is introduced to quantitatively predict bending curvatures of the fabricated sheets. The proposed method enables simple fabrication of objects with complex geometries and precisely controllable shape morphing potential, while drastically reducing the required fabrication times for producing 3D, hierarchical microstructures over large areas in the order of square centimeters.

Programmable self-bending microsheets are fabricated by locally controlling residual stresses that occur due to photochemical shrinkage in direct laser writing. Capillary action, residual stresses, and adhesion forces are identified as driving factors for the shape transformations and quantified experimentally. Multilayer beam bending theory is applied to model and predict detachment and bending curvatures of the fabricated samples.

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GLEAM: a graph clustering framework based on potential game optimization for large-scale social networks

Abstract

With the growing explosion of online social networks, the study of large-scale graph clustering has attracted considerable interest. Most of traditional methods view the graph clustering problem as an optimization problem based on a given objective function; however, there are few methodical theories for the emergence of clusters over real-life networks. In this paper, each actor in online social networks is viewed as a selfish player in a non-cooperative game. The strategy associated with each node is defined as the cluster membership vector, and each one's incentive is to maximize its own social identity by adopting the most suitable strategy. The definition of utility function in our game model is inspired by the conformity psychology, which is defined as the weighted average of one's social identity by participating different clusters. With this setting, the proposed game can well match a potential game. So that the cluster could be shaped by the actions of those closely interactive users who adopt the same strategy in a Nash equilibrium. To this end, we propose a novel Graph cLustering framework based on potEntial gAme optiMization (GLEAM) for parallel graph clustering. It first utilize the cosine similarity to weight each edge in the original network. Then, an initial partition, including a number of clusters dominated by those potential "leader nodes", is created by a fast heuristic process. Third, a potential game-based weighted Modularity optimization is used to improve the initial partition. Finally, we introduce the notion of potentially attractive cluster, and then discover the overlapping partition of the graph using a simple double-threshold procedure. Three phases in GLEAM are carefully designed for parallel execution. Experiments on real-world networks analyze the convergence inside GLEAM, and demonstrate the high performance of GLEAM by comparing it with the state-of-the-art community detection approaches in the literature.

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From research to practice: results of 7300 mortality retrospective case record reviews in four acute hospitals in the North-East of England

Introduction

Monitoring hospital mortality using retrospective case record review (RCRR) is being adopted throughout the National Health Service (NHS) in England with publication of estimates of avoidable mortality beginning in 2017. We describe our experience of reviewing the care records of inpatients who died following admission to hospital in four acute hospital NHS Foundation Trusts in the North-East of England.

Methods

RCRR of 7370 patients who died between January 2012 and December 2015. Cases were reviewed by consultant reviewers with support from other disciplines and graded in terms of quality of care and preventability of deaths. Results were compared with the estimates published in the Preventable Incidents, Survival and Mortality (PRISM) studies, which established the original method.

Results

34 patients (0.5%, 95% CI 0.3% to 0.6%) were judged to have a greater than 50% probability of death being preventable. 1680 patients (22.3%, 95% CI 22.4% to 23.3%) were judged to have room for improvement in clinical, organisational (or both) aspects of care or less than satisfactory care.

Conclusions

Reviews using clinicians within trusts produce lower estimates of preventable deaths than published results using external clinicians. More research is needed to understand the reasons for this, but as the requirement for NHS Trusts to publish estimates of preventable mortality is based on reviews by consultants working for those trusts, lower estimates of preventable mortality can be expected. Room for improvement in the quality of care is more common than preventability of death and so mortality reviews contribute to improvement activity although the outcome of care cannot be changed. RCRR conducted internally is a feasible mechanism for delivering quantitative analysis and in the future can provide qualitative insights relating to inhospital deaths.

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Improving access to City and Hackney adult mental health services

City and Hackney Adult Mental Health Referral and Assessment Service (CHAMHRAS) is the single point of entry for all mental health referrals to secondary services, with the exception of perinatal referrals, in the City and Hackney region of London, UK. CHAMHRAS was established in 2013 with the objective of providing a one-stop point of referral which screens urgent and non-urgent referrals of adults aged 18–65 to mental health services. This single point of entry simplifies the referral process to secondary mental health services—something service users have requested. It also enables rapid feedback on all referrals taken from general practitioners as well as other sources. The centralised nature of CHAMHRAS has also facilitated the monitoring of waiting times from receipt of referral to first face-to-face assessment across services. It was noted that the waiting time for the majority of patients was exceeding the 28-day target set by local commissioners. Indeed, in December 2014, only 30% of patients were being seen within this time frame. The aim of this quality improvement project has been to decrease the average waiting time from referral to first face-to-face assessment, and concomitantly increase the proportion of patients being assessed within the 28-day target period. The team identified potential sources of delay in the process of handling referrals, from receipt and triage, to forwarding to the relevant secondary service, and have tested change ideas such as the implementation of daily meetings to review referrals and the centralisation of appointment bookings to streamline the processes and minimise delays. The average waiting time from referral to first face-to-face assessment decreased by 34% and the proportion of patients being assessed within 28 days increased accordingly, exceeding 95% in the case of referrals from general practitioners (GP). We have listed changes that we intend to introduce with the aim of bringing waiting times down further.

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A local quality initiative to improve follow-up times for patients with heart failure

Introduction Heart failure is the most common cause of hospital admission in patients >65 years and around 50% of patients will be readmitted within 6 months. Inability to achieve timely outpatient follow-up may contribute to the high rates of avoidable rehospitalisation for this group of patients. Canadian guidelines recommend patients with heart failure should be seen within 14 days of discharge.

Methods An audit demonstrated that less than half of advanced heart failure patients were being followed up within 14 days. In an effort to improve postdischarge follow-up in our heart function clinic, we used process mapping and applied a series of iterative changes to the appointment booking system using Plan–Do–Study–Act cycles to reduce waste and standardise.

Results The primary outcome measure, tracked over a period of 20 months, was percentage of patients booked within 14 days. At baseline, 37% of patients were seen within 14 days. After our series of interventions related to streamlining and standardising the appointment booking process, 77% of patients were seen within 14 days and 100% of patients were seen within 21 days.

Conclusion The changes made to the appointment booking process were reproducible, sustainable, effective and required no additional resources or funding.

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GSE74991 Isolation of human iPSC and ESC-derived mesDA progenitor cells by immunomagnetic cells sorting (MACS)

Contributors : Daniela Lehnen ; Michail Knauel ; Silvia Rüberg ; Timon Hick ; Jutta I Kollet
Series Type : Expression profiling by array
Organism : Homo sapiens

Human embryonic and induced pluripotent stem cells are a promising cell source for the future treatment of Parkinson´s disease. It has been shown that mesencephalic dopaminergic (mesDA) neurons arise from the midbrain floor plate in which FOXA2 acts as a key transcription factor. We identified IAP which is specifically co-expressed with FOXA2 positive cells and is suitable to isolate mesDA progenitors utilizing MACS Technolog.The sorted iPSCs were viable, enriched for midbrain specific markers, lacked expression of pluripotency markers, and differentiated into mature dopaminergic neurons in vitro. IAP might be used as a tool to purify mesDA progenitor cells for regenerative therapy in PD patients

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Methods report: European S3-Guideline on the systemic treatment of psoriasis vulgaris – Update Apremilast and Secukinumab – EDF in cooperation with EADV and IPC

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Reliability of self-report measures of correlates of obesity-related behaviours in Hong Kong adolescents for the iHealt(H) and IPEN adolescent studies

This study examined the reliability of measures of correlates of dietary behaviours (DBs), physical activity (PA) and sedentary behaviour (SB) for Hong Kong adolescents.

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Integration of soil magnetometry and geochemistry for assessment of human health risk from metallurgical slag dumps

Abstract

The main objective of the study was an assessment of the pollution level of agricultural land located close to dumps of industrial waste remaining after former Zn and Pb ore processing in Poland. The integrated geophysical-geochemical methods were applied for assessment of soil quality with respect to trace element pollution. Additionally, human health risk induced by the contaminated arable soil and dusting slag heap was estimated. The investigations pointed out that soils in the vicinity of the metallurgical slag dump in Piekary were heavily polluted. Spatial distribution of magnetic susceptibility corresponding well with distribution of the content of potentially toxic elements indicated the local "pollution hotspots." Proper geophysical and geochemical data interpretation supported by statistical factor analysis enabled identification of three different sources of pollution including metallurgical slug dump as a main source, but also traffic pollution influencing the area located along the busy road and relatively strong influence of the geochemical background. Computed health hazard index revealed no adverse health effect to the farmers cultivating arable soil, but in the direct vicinity of dusting, slag dump health risk occurred, caused mostly by very toxic elements as As and Tl. In the future, investigation should be focused on contribution of different sources to the heavy metal pollution in soil-crop system in this area. It should be highlighted that a site-specific approach should be taken in order to redevelop this kind of area in order to reduce ecological and human health threat. The study proved the integrated two-stage geophysical-geochemical method to be a feasible, reliable, and cost-effective tool for identification of the extent of soil pollution and areas at risk.

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Development of a comprehensive screening method for more than 300 organic chemicals in water samples using a combination of solid-phase extraction and liquid chromatography-time-of-flight-mass spectrometry

Abstract

A comprehensive screening method for 311 organic compounds with a wide range of physicochemical properties (log Pow −2.2–8.53) in water samples was developed by combining solid-phase extraction with liquid chromatography–high-resolution time-of-flight mass spectrometry. Method optimization using 128 pesticides revealed that tandem extraction with styrene-divinylbenzene polymer and activated carbon solid-phase extraction cartridges at pH 7.0 was optimal. The developed screening method was able to extract 190 model compounds with average recovery of 80.8% and average relative standard deviations (RSD) of 13.5% from spiked reagent water at 0.20 μg L⁻¹, and 87.1% recovery and 10.8% RSD at 0.05 μg L⁻¹. Spike-recovery testing (0.20 μg L⁻¹) using real sewage treatment plant effluents resulted in an average recovery and average RSD of 190 model compounds of 77.4 and 13.1%, respectively. The method was applied to the influent and effluent of five sewage treatment plants in Kitakyushu, Japan, with 29 out of 311 analytes being observed at least once. The results showed that this method can screen for a large number of chemicals with a wide range of physicochemical properties quickly and at low operational cost, something that is difficult to achieve using conventional analytical methods. This method will find utility in target screening of hazardous chemicals with a high risk in environmental waters, and for confirming the safety of water after environmental incidents.

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Effects of tannery wastewater exposure on adult Drosophila melanogaster

Abstract

Our aim was to evaluate the effects of exposure to tannery wastewater on mortality and/or antioxidant enzyme system in adult wild-type Canton-S Drosophila melanogaster. Exposure to tannery wastewater induced a concentration-dependent lethality in adult Canton-S flies. Tannery wastewater was able to alter antioxidant enzyme activities, specifically glutathione peroxidase-like and glutathione S-transferase, in adult Canton-S D. melanogaster. We conclude that D. melanogaster is a reliable model to evaluate the toxicity induced by tannery wastewater.

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Hybrid ultrasound-MR guided HIFU treatment method with 3D motion compensation

Purpose

Treatments using high-intensity focused ultrasound (HIFU) in the abdominal region remain challenging as a result of respiratory organ motion. A novel method is described here to achieve 3D motion-compensated ultrasound (US) MR-guided HIFU therapy using simultaneous ultrasound and MRI.

Methods

A truly hybrid US-MR-guided HIFU method was used to plan and control the treatment. Two-dimensional ultrasound was used in real time to enable tracking of the motion in the coronal plane, whereas an MR pencil-beam navigator was used to detect anterior–posterior motion. Prospective motion compensation of proton resonance frequency shift (PRFS) thermometry and HIFU electronic beam steering were achieved.

Results

The 3D prospective motion-corrected PRFS temperature maps showed reduced intrascan ghosting artifacts, a high signal-to-noise ratio, and low geometric distortion. The k-space data yielded a consistent temperature-dependent PRFS effect, matching the gold standard thermometry within approximately 1°C. The maximum in-plane temperature elevation ex vivo was improved by a factor of 2. Baseline thermometry acquired in volunteers indicated reduction of residual motion, together with an accuracy/precision of near-harmonic referenceless PRFS thermometry on the order of 0.5/1.0°C.

Conclusions

Hybrid US-MR-guided HIFU ablation with 3D motion compensation was demonstrated ex vivo together with a stable referenceless PRFS thermometry baseline in healthy volunteer liver acquisitions. Magn Reson Med, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

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Case of multiple microcystic adnexal carcinomas on the sun-exposed area

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Total cell necrosis of metastatic malignant melanoma at the regional lymph node in a patient treatment with nivolumab

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Synergistic effects of interferon-beta and nivolumab in oral mucosal melanoma

Abstract

Mucosal melanoma is a rare aggressive cancer with a very poor prognosis. Clinical and pathological characteristics of mucosal melanoma differ from those of cutaneous melanoma and there are no established management guidelines for mucosal melanoma. Complete surgical excision is one of the most effective treatments for localized lesions, while targeted therapies and immunotherapies, such as monoclonal antibodies that target cytotoxic T-lymphocyte-associated molecule-4, and the programmed death (PD)-1/PD-ligand 1 pathway inhibitors, are treatment options for unresectable or metastatic lesions. Here, we describe the case of a patient with oral mucosal melanoma with multiple metastases. In our case, local injection of interferon (IFN)-β with dacarbazine–nimustine–vincristine therapy provided antitumor effects on an invasive tumor on the upper gingiva. Nivolumab therapy produced complete remission of lymph node and bone metastases. In contrast, the remaining in situ portion of oral mucosal melanoma on the hard palate was refractory to IFN-β monotherapy and nivolumab therapy. However, after administration of nivolumab, peritumoral injection of IFN-β showed rapid therapeutic effects. Our case suggested that nivolumab upregulated the antitumor effects of IFN-β, which induced the recruitment of CD8⁺ T cells into the tumor microenvironment contributing to the deletion of tumor cells. Combination therapy of IFN-β and nivolumab may be a potential treatment option for patients with oral mucosal melanoma.

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Immune reconstitution inflammatory syndrome in non-HIV immunosuppressed patients

Abstract

Immune reconstitution inflammatory syndrome (IRIS) represents a clinical phenomenon of immune-mediated inflammation against various antigens, including pathogenic microorganisms, drugs and unknown autoantigens, during recovery from immunosuppressed conditions. IRIS has become well recognized in HIV-infected populations. However, IRIS has seldom been recognized in HIV-negative immunocompromised patients. In the last 15 years, the immunopathogenesis of drug-induced hypersensitivity syndrome (DIHS) has been largely determined. Laboratory data and clinical observations support the idea that DIHS represents a prototype of non-HIV IRIS. Primary diseases in which non-HIV IRIS is secondary include severe cutaneous adverse drug reactions, such as DIHS, autoimmune diseases, collagen diseases, pregnancy and internal malignancies. Potential triggers of recovery from an immune deterioration state include a discontinuation or abrupt tapering of systemic steroids and/or immunosuppressants, withdrawal or reduced effects of anti-tumor necrosis factor-α antibodies, and the use of immune-checkpoint antagonists for the advanced stages of malignancies. Wide use of IRIS across large populations risks oversimplification but highlights a key unifying principle. Balanced sensitivity and specificity for its diagnostic criteria and classification are necessary for the establishment of clinical practice guidelines for non-HIV IRIS. Additionally, the development of a useful combination of biomarkers is currently an urgent issue.

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Bullous pemphigoid induced by ipilimumab in a patient with metastatic malignant melanoma after unsuccessful treatment with nivolumab

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Lymph node metastatic melanoma from ungual melanoma: Identification of somatic mutations in KIT and LZTR1

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Anaphylaxis due to ingestion of jellyfish with possible evidence of epicutaneous sensitization

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Osmotin Protects H9c2 Cells from Simulated Ischemia-Reperfusion Injury through AdipoR1/PI3K/AKT Signaling Pathway

Jianhua Liu, Hua Sui, Jianlin Zhao, Yan Wang

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Comparative Physiological, Biochemical, and Genetic Responses to Prolonged Waterlogging Stress in Okra and Maize Given Exogenous Ethylene Priming

Emuejevoke Vwioko, Onyekachukwu Adinkwu, Mohamed A. El-Esawi

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Continuous Release of Tumor-Derived Factors Improves the Modeling of Cachexia in Muscle Cell Culture

Robert W. Jackman, Jess Floro, Rei Yoshimine, Brian Zitin, Maythita Eiampikul, Kahlid El-Jack, Danielle N. Seto, Susan C. Kandarian

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DEEP Study: Does EQ-5D-5L measure the impacts of persistent orofacial pain?

Journal of oral rehabilitation

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Volumetry of the dominant intraprostatic tumour lesion: intersequence and interobserver differences on multiparametric MRI

The British Journal of Radiology

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Disproportionate cardiac hypertrophy during early postnatal development in infants born preterm

Pediatric Research

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Mucosal Antibodies to the C Terminus of Toxin A Prevent Colonization of Clostridium difficile

Infection and Immunity

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Serotonin reuptake inhibitors and mortality in epilepsy: A linked primary-care cohort study

Summary

Objective

Preliminary evidence suggests that serotonin reuptake inhibitor (SRI) use may increase postictal respiratory drive and prevent death. We sought to determine whether SRIs are associated with improved all-cause and possible seizure-specific mortality in patients with epilepsy.

Methods

Patients with epilepsy and a random 10:1 sample without epilepsy were extracted from The ClinicAl research using LInked Bespoke studies and Electronic health Records (CALIBER) resource. The hazard ratio (HR) of all-cause and possible seizure-specific mortality, treating SRI use as a time-varying covariate, was determined using the date of a second SRI prescription as exposure and in discrete 6-month periods over the entire duration of follow-up. We used Cox regression and competing risk models with Firth correction to calculate the HR. We controlled for age, sex, depression, comorbidity, (Charlson comorbidity index) and socioeconomic status (Index of Multiple Deprivation).

Results

We identified 2,718,952 eligible patients in CALIBER, of whom 16,379 (0.60%) had epilepsy. Median age and follow-up were 44 (interquartile range [IQR] 29–61]) and 6.4 years (IQR 2.4–10.4 years), respectively, and 53% were female. A total of 2,178 patients (13%) had at least two SRI prescriptions. Hazard of all-cause mortality was significantly elevated following a second prescription for an SRI (HR 1.64 95% confidence interval [95% CI] 1.44–1.86; p < 0.001). The HR was similar in 163,778 age, sex, and general practitioner (GP) practice-matched controls without epilepsy. Exposure to an SRI was not associated with seizure-related death (HR 1.08, 95% CI 0.59–1.97; 0.796).

Significance

There is no evidence in this large population-based cohort that SRIs protect against all-cause mortality or seizure-specific mortality. Rather, SRI use was associated with increased mortality, irrespective of epilepsy, which is probably due to various factors associated with the use of antidepressants. Larger studies with systematically collected clinical data are needed to shed further light on these findings.

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Latent-Profile Analysis Reveals Behavioral and Brain Correlates of Dopamine-Cognition Associations

Abstract

Evidence suggests that associations between the neurotransmitter dopamine and cognition are nonmonotonic and open to modulation by various other factors. The functional implications of a given level of dopamine may therefore differ from person to person. By applying latent-profile analysis to a large (n = 181) sample of adults aged 64–68 years, we probabilistically identified 3 subgroups that explain the multivariate associations between dopamine D_2/3R availability (probed with ¹¹C-raclopride-PET, in cortical, striatal, and hippocampal regions) and cognitive performance (episodic memory, working memory, and perceptual speed). Generally, greater receptor availability was associated with better cognitive performance. However, we discovered a subgroup of individuals for which high availability, particularly in striatum, was associated with poor performance, especially for working memory. Relative to the rest of the sample, this subgroup also had lower education, higher body-mass index, and lower resting-state connectivity between caudate nucleus and dorsolateral prefrontal cortex. We conclude that a smaller subset of individuals induces a multivariate non-linear association between dopamine D_2/3R availability and cognitive performance in this group of older adults, and discuss potential reasons for these differences that await further empirical scrutiny.

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Gamma-Band Oscillations Preferential for Nociception can be Recorded in the Human Insula

Abstract

Transient nociceptive stimuli elicit robust phase-locked local field potentials (LFPs) in the human insula. However, these responses are not preferential for nociception, as they are also elicited by transient non-nociceptive vibrotactile, auditory, and visual stimuli. Here, we investigated whether another feature of insular activity, namely gamma-band oscillations (GBOs), is preferentially observed in response to nociceptive stimuli. Although nociception-evoked GBOs have never been explored in the insula, previous scalp electroencephalography and magnetoencephalography studies suggest that nociceptive stimuli elicit GBOs in other areas such as the primary somatosensory and prefrontal cortices, and that this activity could be closely related to pain perception. Furthermore, tracing studies showed that the insula is a primary target of spinothalamic input. Using depth electrodes implanted in 9 patients investigated for epilepsy, we acquired insular responses to brief thermonociceptive stimuli and similarly arousing non-nociceptive vibrotactile, auditory, and visual stimuli (59 insular sites). As compared with non-nociceptive stimuli, nociceptive stimuli elicited a markedly stronger enhancement of GBOs (150–300 ms poststimulus) at all insular sites, suggesting that this feature of insular activity is preferential for thermonociception. Although this activity was also present in temporal and frontal regions, its magnitude was significantly greater in the insula as compared with these other regions.

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The Effects of Audiovisual Inputs on Solving the Cocktail Party Problem in the Human Brain: An fMRI Study

Abstract

At cocktail parties, our brains often simultaneously receive visual and auditory information. Although the cocktail party problem has been widely investigated under auditory-only settings, the effects of audiovisual inputs have not. This study explored the effects of audiovisual inputs in a simulated cocktail party. In our fMRI experiment, each congruent audiovisual stimulus was a synthesis of 2 facial movie clips, each of which could be classified into 1 of 2 emotion categories (crying and laughing). Visual-only (faces) and auditory-only stimuli (voices) were created by extracting the visual and auditory contents from the synthesized audiovisual stimuli. Subjects were instructed to selectively attend to 1 of the 2 objects contained in each stimulus and to judge its emotion category in the visual-only, auditory-only, and audiovisual conditions. The neural representations of the emotion features were assessed by calculating decoding accuracy and brain pattern-related reproducibility index based on the fMRI data. We compared the audiovisual condition with the visual-only and auditory-only conditions and found that audiovisual inputs enhanced the neural representations of emotion features of the attended objects instead of the unattended objects. This enhancement might partially explain the benefits of audiovisual inputs for the brain to solve the cocktail party problem.

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Age Differences in the Neural Mechanisms of Intertemporal Choice Under Subjective Decision Conflict

Abstract

Older decision-makers may capitalize on their greater experiences in financial decisions and by this offset decline in cognitive abilities. However, this pattern of results should reverse in situations that place high demands on cognitive control functions. In this study, we investigated how decision conflict affects the neural mechanisms of intertemporal decision-making in younger and older adults. To individually adjust the level of decision conflict we determined the indifference point (IDP) in intertemporal decision-making for each participant. During functional magnetic resonance imaging, participants performed choice options close to their IDP (high conflict) or far away from the IDP (low conflict). In younger adults, decision conflict leads to reduced delay discounting and lower discount rates are associated with higher working memory (WM) capacity. In older adults, high decision conflict is associated with enhanced discounting, hypoactivation in the ventral striatum as well diminished ventral striatal representations of differences in subjective values. Taken together, our results show that under enhanced decision conflict, younger adults engage in a more reflective decision mode that reflects individual differences in WM capacity. In contrast, older adults get more present-oriented under high demands on cognitive control and this decision bias is associated with changes in striatal value signaling.

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Metformin as a repurposed therapy in advanced non-small cell lung cancer (NSCLC): results of a phase II trial

Summary

Background Metformin has been shown to have anti-neoplastic activity in non-small cell lung cancer (NSCLC) in both preclinical and observational studies, however this has never been prospectively evaluated. This single-arm phase II trial, while not fully accrued, is the first known prospective study evaluating the use of metformin with chemotherapy in advanced NSCLC. Methods Patients received carboplatin AUC 5 + pemetrexed 500 mg/m2 IV every 21 days for 4 cycles. For patients who achieved at least stable disease, maintenance pemetrexed was administered until progression or toxicity. Metformin was initiated at 1000 mg/day for week 1, 1500 mg/day for week 2, then 2000 mg/day thereafter, in divided doses. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and adverse events (AE). Tumor tissue was tested for LKB1/STK11 mutations, and non-fasting serum insulin levels were longitudinally assessed. Results Of a planned 50 patients, 14 were enrolled. ORR was 23% and median PFS was 3.9 months. Median OS was 11.7 months. No LKB1/STK11 mutations were identified. The most common AE were fatigue (42.9%), anemia, and nausea (28.6% each). The most common grade III AE was nausea (14.3%). No grade IV AE occurred. Mean duration of metformin treatment was 5.6 months. Conclusion Adding metformin to chemotherapy for advanced NSCLC was safe but did not significantly improve clinical outcomes compared to historical phase III controls. These results are limited by the small sample size; larger trials are needed.

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Treatment-related serious adverse events and fatal adverse events with regorafenib in cancer patients: a meta-analysis of phase 3 randomized controlled trials

Summary

Regorafenib (Stivarga) is an oral small-molecule multikinase inhibitor commonly used against a variety of cancers. We performed a meta-analysis of all phase 3 randomized controlled trials (RCTs) of regorafenib to quantify the increased risk of SAEs and FAEs. We carried out a systematic search of electronic databases for studies published from inception to February 2017 without any restrictions. Eligibility criteria included phase 3 RCTs of tumors comparing regorafenib, alone or in combination with non-targeted chemotherapy (regorafenib arm) versus placebo or non-targeted chemotherapy (control arm). Data on SAEs and FAEs were extracted from each study and pooled to determine the overall incidence, relative risks (RRs) and 95% confidence intervals (CIs). A total of four phase 3 RCTs involving 1736 cancer patients met the eligibility criteria and were included. The overall incidence of SAEs and FAEs with regorafenib were 0.23 (95%CI, 0.05–0.40) and 0.02 (95%CI, 0.01–0.03), respectively. Compared with control, the summary RR of developing a regorafenib-related SAE was 1.60 (95%CI, 0.95–2.68, P=0.07), the summary RR of developing a regorafenib-related FAE was 1.71 (95%CI, 0.69–4.24, P=0.25). No evidence was found for the association between regorafenib and higher risk of SAEs and FAEs. This association varied significantly with cancer types (P=0.02) for SAEs but no evidence of heterogeneity was found for FAEs. This meta-analysis demonstrates no evidence for the association between regorafenib and higher risk of SAEs and FAEs. This analysis will be important when considering the trade-off of regorafenib treatment during clinical decision-making.

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A phase I study to assess the mass balance, excretion, and pharmacokinetics of [ 14 C]-ixazomib, an oral proteasome inhibitor, in patients with advanced solid tumors

Summary

This two-part, phase I study evaluated the mass balance, excretion, pharmacokinetics (PK), and safety of ixazomib in patients with advanced solid tumors. In Part A of the study, patients received a single 4.1 mg oral solution dose of [¹⁴C]-ixazomib containing ~500 nCi total radioactivity (TRA), followed by non-radiolabeled ixazomib (4 mg capsule) on days 14 and 21 of the 35-day PK cycle. Patients were confined to the clinic for the first 168 h post dose and returned for 24 h overnight clinic visits on days 14, 21, 28, and 35. Blood, urine, and fecal samples were collected during Part A to assess the mass balance (by accelerator mass spectrometry), excretion, and PK of ixazomib. During Part B of the study, patients received non-radiolabeled ixazomib (4 mg capsules) on days 1, 8, and 15 of 28-day cycles. After oral administration, ixazomib was rapidly absorbed with a median plasma T_max of 0.5 h and represented 70% of total drug-related material in plasma. The mean total recovery of administered TRA was 83.9%; 62.1% in urine and 21.8% in feces. Only 3.23% of the administered dose was recovered in urine as unchanged drug up to 168 h post dose, suggesting that most of the TRA in urine was attributable to metabolites. All patients experienced a treatment-emergent adverse event, which most commonly involved the gastrointestinal system. These findings suggest that ixazomib is extensively metabolized, with urine representing the predominant route of excretion of drug-related material.

Trial ID: ClinicalTrials.gov # NCT01953783.

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Mechanisms of cancer cell killing by sea cucumber-derived compounds

Summary

The aim of cancer therapy is to specifically eradicate tumor cells while causing minimal damage to normal tissues and minimal side-effects. Because of this, the use of natural substances with low toxicity is a good option. Sea cucumbers are one of many potential marine animals that contain valuable nutrients and medicinal properties. The medicinal value of sea cucumbers is attributed to the presence of bioactive agents with promising biological and pharmacological properties that include cytotoxic activity, induction of apoptosis, cell cycle arrest, inhibition of tumor growth, anti-metastatic and anti-angiogenic properties, and inhibition of drug resistance. This review discusses the mechanisms of cancer cell death induced by sea cucumber-derived compounds with regard to exploring the potential use of these marine natural products for cancer therapy.

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Holistic First Nations health strategy: Canada [Letters]

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Trends in deceased organ donation in Canada [Commentary]

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Effect of organ donation after circulatory determination of death on number of organ transplants from donors with neurologic determination of death [Research]

BACKGROUND:

To increase the available pool of organ donors, Ontario introduced donation after circulatory determination of death (DCD) in 2006. Other jurisdictions have reported a decrease in donations involving neurologic determination of death (NDD) after implementation of DCD, with a drop in organ yield and quality. In this study, we examined the effect of DCD on overall transplant activity in Ontario.

METHODS:

We examined deceased donor and organ transplant activity during 3 distinct 4-year eras: pre-DCD (2002/03 to 2005/06), early DCD (2006/07 to 2009/10) and recent DCD (2010/11 to 2013/14). We compared these donor groups by categorical characteristics.

RESULTS:

Donation increased by 57%, from 578 donors in the pre-DCD era to 905 donors in the recent DCD era, with a 21% proportion (190/905) of DCD donors in the recent DCD era. However, overall NDD donation also increased. The mean length of hospital stay before declaration for NDD was 2.7 days versus 6.0 days before withdrawal of life support and subsequent asystole in cases of DCD. The average organ yield was 3.73 with NDD donation versus 2.58 with DCD (p < 0.001). Apart from hearts, all organs from DCD donors were successfully transplanted. From the pre-DCD era to the recent DCD era, transplant activity in each era increased for all solid-organ recipients, including heart (from 158 to 216), kidney (from 821 to 1321), liver (from 477 to 657) and lung (from 160 to 305).

INTERPRETATION:

Implementation of DCD in Ontario led to increased transplant activity for all solid-organ recipients. There was no evidence that the use of DCD was pre-empting potential NDD donation. In contrast to groups receiving other organs, heart transplant candidates have not yet benefited from DCD.

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Think sepsis to stop deaths, urge advocates [News]

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Human papillomavirus vaccines [Practice]

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Drug importation into the United States: impact on Canada [Letters]

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Laryngeal stridor in rheumatoid arthritis [Practice]

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Call for more Lyme disease research [News]

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Always on call [Humanities]

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Enjoy every sandwich [Coda]

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Movement disorders with neuronal antibodies: syndromic approach, genetic parallels and pathophysiology

Abstract

Movement disorders are a prominent and common feature in many autoantibody-associated neurological diseases, a group of potentially treatable conditions that can mimic infectious, metabolic or neurodegenerative disease. Certain movement disorders are likely to associate with certain autoantibodies; for example, the characteristic dyskinesias, chorea and dystonia associated with NMDAR antibodies, stiff person spectrum disorders with GAD, glycine receptor, amphiphysin or DPPX antibodies, specific paroxysmal dystonias with LGI1 antibodies, and cerebellar ataxia with various anti-neuronal antibodies. There are also less-recognized movement disorder presentations of antibody-related disease, and a considerable overlap between the clinical phenotypes and the associated antibody spectra. In this review, we first describe the antibodies associated with each syndrome, highlight distinctive clinical or radiological 'red flags', and suggest a syndromic approach based on the predominant movement disorder presentation, age, and associated features. We then examine the underlying immunopathophysiology, which may guide treatment decisions in these neuroimmunological disorders, and highlight the exceptional interface between neuronal antibodies and neurodegeneration, such as the tauopathy associated with IgLON5 antibodies. Moreover, we elaborate the emerging pathophysiological parallels between genetic movement disorders and immunological conditions, with proteins being either affected by mutations or targeted by autoantibodies. Hereditary hyperekplexia, for example, is caused by mutations of the alpha subunit of the glycine receptor leading to an infantile-onset disorder with exaggerated startle and stiffness, whereas antibodies targeting glycine receptors can induce acquired hyperekplexia. The spectrum of such immunological and genetic analogies also includes cerebellar ataxias and some encephalopathies. Lastly, we discuss how these pathophysiological considerations could reflect on possible future directions regarding antigen-specific immunotherapies or targeting the pathophysiological cascades downstream of the antibody effects.

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TOR1A variants cause a severe arthrogryposis with developmental delay, strabismus and tremor

Abstract

Autosomal dominant torsion dystonia-1 is a disease with incomplete penetrance most often caused by an in-frame GAG deletion (p.Glu303del) in the endoplasmic reticulum luminal protein torsinA encoded by TOR1A. We report an association of the homozygous dominant disease-causing TOR1A p.Glu303del mutation, and a novel homozygous missense variant (p.Gly318Ser) with a severe arthrogryposis phenotype with developmental delay, strabismus and tremor in three unrelated Iranian families. All parents who were carriers of the TOR1A variant showed no evidence of neurological symptoms or signs, indicating decreased penetrance similar to families with autosomal dominant torsion dystonia-1. The results from cell assays demonstrate that the p.Gly318Ser substitution causes a redistribution of torsinA from the endoplasmic reticulum to the nuclear envelope, similar to the hallmark of the p.Glu303del mutation. Our study highlights that TOR1A mutations should be considered in patients with severe arthrogryposis and further expands the phenotypic spectrum associated with TOR1A mutations.

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Neuroinflammation and its relationship to changes in brain volume and white matter lesions in multiple sclerosis

Abstract

Brain magnetic resonance imaging is an important tool in the diagnosis and monitoring of multiple sclerosis patients. However, magnetic resonance imaging alone provides limited information for predicting an individual patient's disability progression. In part, this is because magnetic resonance imaging lacks sensitivity and specificity for detecting chronic diffuse and multi-focal inflammation mediated by activated microglia/macrophages. The aim of this study was to test for an association between 18 kDa translocator protein brain positron emission tomography signal, which arises largely from microglial activation, and measures of subsequent disease progression in multiple sclerosis patients. Twenty-one patients with multiple sclerosis (seven with secondary progressive disease and 14 with a relapsing remitting disease course) underwent T₁- and T₂-weighted and magnetization transfer magnetic resonance imaging at baseline and after 1 year. Positron emission tomography scanning with the translocator protein radioligand ¹¹C-PBR28 was performed at baseline. Brain tissue and lesion volumes were segmented from the T₁- and T₂-weighted magnetic resonance imaging and relative ¹¹C-PBR28 uptake in the normal-appearing white matter was estimated as a distribution volume ratio with respect to a caudate pseudo-reference region. Normal-appearing white matter distribution volume ratio at baseline was correlated with enlarging T₂-hyperintense lesion volumes over the subsequent year (ρ = 0.59, P = 0.01). A post hoc analysis showed that this association reflected behaviour in the subgroup of relapsing remitting patients (ρ = 0.74, P = 0.008). By contrast, in the subgroup of secondary progressive patients, microglial activation at baseline was correlated with later progression of brain atrophy (ρ = 0.86, P = 0.04). A regression model including the baseline normal-appearing white matter distribution volume ratio, T₂ lesion volume and normal-appearing white matter magnetization transfer ratio for all of the patients combined explained over 90% of the variance in enlarging lesion volume over the subsequent 1 year. Glial activation in white matter assessed by translocator protein PET significantly improves predictions of white matter lesion enlargement in relapsing remitting patients and is associated with greater brain atrophy in secondary progressive disease over a period of short term follow-up.

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