Additive Manufacturing and Performance of Architectured Cement‐Based Materials

Advanced Materials, EarlyView.


https://ift.tt/2MZWFBM

Exercise in muscle disorders: what is our current state?

Purpose of review Regular exercise improves muscle and cardiovascular function, which is why exercise is used as an adjuvant treatment in myopathies. In this review, we provide an update on recent exercise studies (from 2016) performed in humans with inherited myopathy. Recent findings Several studies provide new and interesting insight in the field of exercise in myopathies. A retrospective cohort study suggests that exercise may actually increase rate of disease progression in dysferlinopathy, and high intensity exercise, which is normally discouraged in muscle disorders because of the risk of muscle damage, is demonstrated to be an efficient time saving mode of exercise to train patients with facioscapulohumeral muscular dystrophy. Exoskeletons and antigravity trainers are examples of new devices, which provide an opportunity for very weak patients to train. Finally, several studies, including two randomized controlled trials, support the beneficial role of exercise as treatment of myopathy. Summary The reviewed studies extend previous knowledge about exercise, indicating that exercise is generally safe and well tolerated, and improves functional outcomes in patients with inherited muscle disease. However, recent studies also highlight the fact that the effect of exercise differs with mode of exercise and exercise prescriptions should be disease specific.

https://ift.tt/2LHI2Oy

Editorial introductions

No abstract available

https://ift.tt/2PNPpr3

Management of chronic inflammatory demyelinating polyradiculopathy

Purpose of review To review the recent advances in the management and treatment of chronic inflammatory demyelinating polyradiculopathy (CIDP). Recent findings Recent studies confirm the efficacy/safety of long-term intravenous immunoglobulin (IVIg) and short-term subcutaneous immunoglobulin (SCIg) therapy in CIDP. New outcome measures have been recently proposed and further studies evaluated the properties of those already in use. The presence of antibodies against proteins at the node of Ranvier was associated with specific clinical features and treatment response. Fingolimod adds to the list of immunosuppressive agents that failed to be effective in a controlled trial. Summary Several studies evaluating the best strategy to provide maintenance IVIg treatment in CIDP are in progress. SCIg were shown to be an alternative to IVIg for maintenance treatment while their efficacy as initial therapy should be further addressed. New outcome measures have been shown to be effective in detecting treatment response in clinical trials, but their use in clinical practice remains uncertain. Similarly unsettled is the role of nerve imaging techniques as biomarker in CIDP. The discovery of antibodies against proteins at the node of Ranvier has rekindled a keen interest in the pathogenesis of CIDP and the potential therapeutic role of new agents.

https://ift.tt/2LHHqIK

Neurophysiological biomarkers in amyotrophic lateral sclerosis

Purpose of review Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder of the motor neurons, characterized by upper motor neuron (UMN) and lower motor neuron (LMN) dysfunction. There have been significant technological advances in the development of neurophysiological biomarkers of UMN and LMN dysfunction in ALS. In this review, we discuss major advances in development of neurophysiological biomarkers in ALS, critiquing their potential in diagnosis and prognosis of ALS, as well as utility in monitoring treatment effects. Recent findings The threshold tracking transcranial magnetic stimulation (TMS) technique has established cortical hyperexcitability as an early and specific biomarker of UMN dysfunction in ALS, and associated with neurodegeneration. In addition to establishing cortical hyperexcitability as a pathophysiological mechanism, threshold tracking TMS has enabled an earlier diagnosis of ALS and provided a means of monitoring effects of therapeutic agents. Biomarkers of LMN dysfunction, including motor unit number estimation, the neurophysiological index, electrical impedance myography and axonal excitability techniques, have all exhibited utility in monitoring disease progression. Summary In addition to enhancing ALS diagnosis, the development of novel neurophysiological biomarkers has implications for clinical trials research and drug development, enabling the assessment of biological efficacy of agents in early stages of drug development.

https://ift.tt/2PS6y35

Myasthenia gravis: from autoantibodies to therapy

Purpose of review The current article reviews the recent advances in the field of myasthenia gravis, which span from autoantibody profiling and pathogenic mechanisms to therapy innovation. The overview is highlighting specifically the data and the needs of targeted treatments in the light of precision medicine in myasthenia gravis. Recent findings Novel data published recently further increased our knowledge on myasthenia gravis. The use of cell-based assays has greatly improved autoantibody detection in myasthenia gravis patients, and the mechanisms of action of these antibodies have been described. The role of Toll-like receptor activation in the generation of thymic alterations and anti-acetylcholine receptor autosensitization has been further investigated implementing our understanding on the relationships between innate immunity and autoimmunity. Additional studies have been focused on the alterations of T-cell/B-cell regulatory mechanisms in thymus and peripheral blood of myasthenia gravis patients. microRNAs and genetic factors are also emerging as key biomarkers in myasthenia gravis pathogenesis and prediction of drug efficacy in individual patients. Summary The recent immunological and pathological findings in myasthenia gravis promise to improve myasthenia gravis treatment, via the development of more precise and personalized therapies.

https://ift.tt/2LAt3WM

Proprioception 2.0: novel functions for muscle spindles

Purpose of review Muscle spindles are encapsulated mechanosensory receptors within skeletal muscle tissue that inform the central nervous system about the contractile status of each muscle. This information is required for any coordinated movement and for stable posture. This review summarizes recent findings regarding novel functions for proprioceptive feedback information, muscle spindle disease and the molecular basis of mechanoreception. Recent findings Muscle spindle function is not limited to regulating motor control but is also required for appropriate realignment of fractured bones, successful regeneration of spinal cord axons after injury and spinal alignment. Several proteins responsible for or modulating mechanotransduction in proprioceptive sensory neurons have been identified, including the Piezo2 channel as a candidate for the principal mechanotransduction channel. Many neuromuscular diseases are known to be accompanied by an impaired function of muscle spindles, resulting in a decline of motor performance and coordination in the patients. Summary Our knowledge regarding the molecular basis of muscle spindle function is still incomplete. However, increasing our understanding of mechanotransduction in muscle spindles is a prerequisite for finding appropriate strategies to prevent injuries due to unstable gait and frequent falls.

https://ift.tt/2MXkQAL

Nerve ultrasound and magnetic resonance imaging in the diagnosis of neuropathy

Purpose of review This review summarizes the most relevant developments in the fields of nerve ultrasound and MRI in the diagnosis of treatable inflammatory neuropathies over the last 18 months. Recent findings MRI and nerve ultrasound can accurately identify potentially treatable neuropathies and thereby help to improve diagnosis. Advanced MRI techniques also show potential to dissect pathophysiology. The apparent mismatch between nerve function and morphology is not surprising and reflects different dimensions of the disease process in neuropathies. Summary MRI and nerve ultrasound have become useful tools in the diagnosis of inflammatory neuropathies. Video Abstract https://ift.tt/2PPzatx

https://ift.tt/2LG1MCe

Malignant hyperthermia: still an issue for neuromuscular diseases?

Purpose of review We will give an overview of neuromuscular disorders that can be linked with malignant hyperthermia or malignant hyperthermia-like reactions, and suggest an appropriate approach to interpret the risks. Recent findings An increasing number of neuromuscular phenotypes have been linked to malignant hyperthermia susceptibility (MHS). This is for an important part due to the highly variable phenotype associated with mutations in the ryanodine receptor 1 gene (RYR1), the gene most frequently associated with MHS. A RYR1-mutation or a clinical RYR1-phenotype does not automatically translate in MHS, but precautions should be taken nonetheless. In addition, several other genes and phenotypes are now considered to be associated with MHS. In contrast, several neuromuscular diseases that were long thought to be linked to MHS are now known to cause malignant hyperthermia-like reactions instead of malignant hyperthermia. This is highly relevant as not only the given preoperative advice differs, but also acute treatment. Summary This review provides a summary of current evidence linking certain neuromuscular diseases to malignant hyperthermia or malignant hyperthermia-like reactions. We provide a guide for the clinician, to determine which patients are at risk of malignant hyperthermia or malignant hyperthermia-like reactions perioperatively, and to ensure adequate treatment in case such a severe acute complication occurs.

https://ift.tt/2LGizFk

Nerve and skin biopsy in neuropathies

Purpose of review To give an overview of recent data on the use of nerve and skin biopsy as a diagnostic tool in neuropathies. Recent findings Axonal damage in a biopsy from a patient with chronic inflammatory demyelinating polyradiculoneuropathy may point to the presence of autoantibodies to paranodal proteins. In nonsystemic vasculitis of the peripheral nervous system, nerve biopsy is still the only means to make a definite diagnosis. Increased autophagy has been found in idiopathic neuropathy and may also be a common final pathway in various types of neuropathy. Nerve biopsy has unexpectedly revealed familial amyloid neuropathy in a number of cases that were taken for idiopathic, for Charcot-Marie-Tooth disease, or for chronic inflammatory demyelinating polyradiculoneuropathy. Skin biopsy can differentiate between length-dependent and non-length-dependent small fiber neuropathy, which aids in the etiological differential diagnosis. It can also be used to identify small fiber involvement in mixed neuropathies and for follow-up studies. Summary Nerve biopsy is still the gold standard for the diagnosis of peripheral nerve vasculitis. In other indications, sural or superficial peroneal nerve biopsies are less frequently done, because less invasive methods have become available. Modern imaging methods allow localization of nerve damage, such that targeted fascicular biopsies can be done. Immunofluorescence staining of teased nerve fibers has contributed to the understanding of the pathophysiology of inflammatory neuropathies. Skin biopsy has become a routine method to diagnose small fiber neuropathy.

https://ift.tt/2POH9ag

Stem cell transplantation for amyotrophic lateral sclerosis

Purpose of review This review analyses the recent efforts to develop therapeutics using transplantation of stem cells for amyotrophic lateral sclerosis (ALS). Recent findings Stem cells are considered as a potential therapeutic for a variety of neurodegenerative diseases, in an effort to either replace cells that are lost, or to enhance the survival of the remaining cells. In ALS, meaningful attempts to verify the safety and feasibility of many cell transplantation approaches have only recently been completed or are underway. Due to the complexities of reconstructing complete motor neuron circuits in adult patients, current approaches aim rather to prolong the survival and function of existing motor neurons through paracrine effects or production of new interneurons or astrocytes. Recent trials showed that autologous mesenchymal stem cells can be safely injected intrathecally, transiently enhancing growth factor concentrations and anti-inflammatory cytokines into the cerebrospinal fluid. Likewise, a small pilot study investigating safety of autologous transplantation of regulatory T-cells for immunomodulation was recently completed. Finally, early phase trials demonstrated safety of direct surgical transplantation of heterologous fetal-derived neural progenitor cells into the spinal cord of ALS patients, as an attempt to provide a lasting source of local trophic support for motor neurons. Summary With clinical trials recently demonstrating that stem cell transplantation can be safe and well tolerated in ALS, the field is positioned to complete pivotal controlled trials to determine efficacy.

https://ift.tt/2LAsts4

Advances in management of Guillain–Barré syndrome

Purpose of review The clinical presentation of Guillain–Barré syndrome (GBS) is highly variable, which can make the diagnosis challenging. Intravenous immunoglobulin (IVIg) and plasma exchange are the cornerstones of treatment since decades. But despite these treatments, 25% initially progress in muscle weakness, 25% require artificial ventilation, 20% is still not able to walk independently after 6 months, and 2–5% die, emphasizing the need for better treatment. We summarize new developments regarding the diagnosis, prognosis, and management of GBS. Recent findings GBS is a clinical diagnosis that can be supported by cerebrospinal fluid examination and nerve conduction studies. Nerve ultrasound and MRI are potentially useful techniques to diagnose inflammatory neuropathies. Several novel infections have recently been associated to GBS. Evidence from experimental studies and recent phase 2 clinical trials suggests that complement inhibition combined with IVIg might improve outcome in GBS, but further studies are warranted. Prognostic models could guide the selection of patients with a relatively poor prognosis that might benefit most from additional IVIg or otherwise intensified treatment. Summary New diagnostic tools may help to have early and accurate diagnosis in difficult GBS cases. Increased knowledge on the pathophysiology of GBS forms the basis for development of new, targeted, and personalized treatments that hopefully improve outcome.

https://ift.tt/2N35Z7F

Bones and muscular dystrophies: what do we know?

Purpose of review Muscle and bone are intrinsically linked, and therefore, it is not surprising that many muscular dystrophies are associated with impaired bone health and increased risk of osteoporosis. Osteoporotic fracture is an important and preventable cause of morbidity and mortality. This article will firstly review the general causes of impaired bone health in muscular dystrophies and then focus on the evidence available for the diagnosis and treatment of osteoporosis in specific conditions. Recent findings With the exception of DMD, there is a paucity of data regarding bone health in muscular dystrophies. However, it appears that in common with all types of muscular dystrophies that cause a significant level of muscle weakness and disability there is an increased risk of falls, fractures and decreased vitamin D levels. A better understanding of the extent of the impaired bone health and underlying causes could help to identify potential new therapeutic agents and aid clinical care. Summary It would be prudent for clinicians to assess fracture risk in their muscular dystrophy patients and if appropriate, arrange surveillance and recommend vitamin D supplementation. Additionally, fracture should be considered in any patient presenting with new-onset bone pain.

https://ift.tt/2LCftSB

POEMS syndrome

Purpose of review To provide an overview of polyneuropathy organomegaly endocrinopathy M-protein and skin changes (POEMS) syndrome, detailing new insights into pathogenesis, prognostic factors, treatments, and outcome scores. Recent findings With the development of large multicentre national cohorts of patients, POEMS syndrome is evolving into a well characterized multisystem hematoneurological syndrome. Without early diagnosis significant disability results from the neuropathy. Vascular endothelial growth factor (VEGF) is a useful and accurate biomarker supporting diagnosis and following disease activity. The past decade has seen a number of therapeutics become available to patients with POEMS, repurposed from myeloma treatment. Simple treatment algorithms are based on the extent of monoclonal proliferation and the performance status of patients. Risk factors, prognostic scores, and their impact on outcome measures have been developed from deeply phenotyped patient cohorts to predict response rate, progression-free survival and overall survival. Summary Understanding links between the monoclonal lambda plasma cell disorder and resulting proinflammatory cytokine milieu is fundamental to determining POEMS syndrome pathophysiology. Similarities to chronic inflammatory demyelinating polyradiculoneuropathy and some other monoclonal proliferative diseases makes POEMS misdiagnosis common. A range of treatments are available, and more work to identify pathogenic mechanisms and treatment targets and prognostic scores will further enable treatment stratification for optimum outcomes.

https://ift.tt/2PQYdwo

Towards clinical outcome measures in myotonic dystrophy type 2: a systematic review

Purpose of review Myotonic dystrophies are the most frequent muscular dystrophies in adulthood; however, myotonic dystrophy type 2 (DM2) is by far less prevalent than myotonic dystrophy type 1 (DM1). Consequently, studies on large cohorts are lacking and disease-specific outcome measures have not been developed (see video abstract, Supplemental Digital Content 1, https://ift.tt/2PQ1JHu). The aim of this review is to systematically evaluate the outcome measures applied in patients with DM2 and to identify tests adopted from other neuromuscular disorders potentially suitable for DM2. A systematic review of functional tests and patient reported outcomes (PROs) previously used in DM2 has been performed. In addition, we reviewed functional tests and PROs previously used in neuromuscular diseases (NMDs). Based on this approach, we propose a battery of tests to be validated in DM2. Recent findings: No outcome measures or PROs have been validated in DM2. The most used PROs in DM2 were INQoL, SF-36, MPQ, and BPI. It is not clear whether it is better to use MMT or QMT to assess muscle strength. The algometer seems to be a useful tool to assess myalgia. No currently adopted tests or PROs seem effective to assess the mild myotonia of DM2. Several outcome measures used in other NMDs (e.g. 6MWT, QMFT, GSGC) might be suitable for DM2; however, their disease-specific validity needs to be explored. Summary Although DM2 has a milder and more heterogeneous phenotype than DM1, there is an urgent need to develop validated outcome measures in DM2. The current lack of validated DM2 tests will delay the start of therapeutic trials.

https://ift.tt/2LyB3HP

Multifocal motor neuropathy

Purpose of review Multifocal motor neuropathy (MMN) has specific clinical and electrophysiologic features but can be difficult to diagnose if cases are not typical. Intravenous immunoglobulin (IVIg) remains the core initial and long-term treatment. In this review, recent advances in the diagnosis, monitoring and treatment of MMN are discussed. Recent findings The pathology of MMN likely depends on immune-mediated attack of the nodes of Ranvier and paranodal regions leading to conduction block. Antiganglioside antibodies are present in over 50% of patients. The sensitivity of antibody detection can be improved by testing for GM1/galactocerebroside (GM1/GalC) complexes. Complement activation plays a key role in the pathophysiology of MMN. Subcutaneous immunoglobulins are an efficacious alternative to IVIg for maintenance therapy in MMN. Complement inhibitor eculizumab may be a potential future treatment, but further studies are necessary. Summary The European Federation of Neurological Societies (EFNS)/Peripheral Nerve Society (PNS) guidelines for the diagnosis of MMN are currently widely used but probably need revision. Nerve ultrasound and plexus/nerve MRI can be helpful in diagnostic dilemmas. Monitoring of disease and response to treatment may improve using disease-specific evaluation scales such as MMN-Rasch-built overall disability scale. Further research into the pathophysiology of MMN is necessary to direct future treatment strategies.

https://ift.tt/2BZSGAD

Ocular ptosis: differential diagnosis and treatment

Purpose of review The current article provides a brief summary of the clinical approach to congenital and acquired ptosis. An increasing number of publications analyze causes of ptosis or describe diagnostic tests or advances in ptosis genetics. The aim of our work is to summarize these findings and provide an updated algorithm for the diagnosis and treatment of patients with ptosis. This review covers important clinical research and studies relevant for neurologists recently published. Recent findings Ptosis is a common cause of referral to neuromuscular units. Knowledge of the different causes of this symptom has grown substantially in recent years, from diagnostic tests and genetics studies to potential new therapeutic agents, making it essential to keep up to date on the diagnostic and therapeutic relevance of these contributions. Summary We emphasize that ptosis should be studied as a complex symptom. Efforts should be made to identify accompanying neurologic or ophthalmologic signs in clinical examination that could lead to a diagnosis. A growing number of diagnostics tests are available in the field, especially in genetics. Meanwhile, surgery continues being the most used therapeutic approach for these patients.

https://ift.tt/2PQ1lc0

Diagnostics and treatment of neuromusuclar disorders – a role model for rare diseases?

No abstract available

https://ift.tt/2BZRWeP

Neuroinflammatory mechanisms in amyotrophic lateral sclerosis pathogenesis

Purpose of review Neuroinflammation is increasingly recognized as an important mediator of disease progression in patients with amyotrophic lateral sclerosis (ALS), and is characterized by reactive central nervous system (CNS) microglia and astroglia as well as infiltrating peripheral monocytes and lymphocytes. Anti-inflammatory and neuroprotective factors sustain the early phase of the disease whereas inflammation becomes proinflammatory and neurotoxic as disease progression accelerates. Initially, motor neurons sustain injuries through multiple mechanisms resulting from harmful mutations causing disruptions of critical intracellular pathways. Injured motor neurons release distress signal(s), which induce inflammatory processes produced by surrounding glial cells in the CNS as well as peripheral innate and adaptive immune cells. This review will focus on mechanisms of neuroinflammation and their essential contributions in ALS pathogenesis. Recent findings Regulatory T lymphocytes (Tregs) are a subpopulation of immunosuppressive T lymphocytes that become reduced and dysfunctional as the disease progresses in ALS patients. Their degree of dysfunction correlates with the extent and rapidity of the disease. Treg numbers are boosted in transgenic mutant SOD1 (mSOD1) mice through the passive transfer of Tregs or through treatment with an interleukin-2/ interleukin-2 monoclonal antibody complex and rapamycin. Treating the transgenic mice with either of these modalities delays disease progression and prolongs survival. In addition, Treg function is restored when dysfunctional Tregs are isolated from ALS patients and expanded ex vivo in the presence of interleukin-2 and rapamycin. Based on these findings, a first-in-human phase 1 trial has been completed in which expanded autologous Tregs were infused back into ALS patients as a potential treatment. The infusions were safe and shown to 'hit target' by enhancing both Treg numbers and suppressive functions. Summary A delicate balance between anti-inflammatory and proinflammatory factors modulates the rates of disease progression and survival times in ALS. Tipping the balance toward the anti-inflammatory mediators shows promise in slowing the progression of this devastating disease.

https://ift.tt/2PRpC1o

How useful is muscle ultrasound in the diagnostic workup of neuromuscular diseases?

Purpose of review This review focuses on developments in muscle ultrasound as a noninvasive and accurate tool for the diagnosis and follow-up of neuromuscular disease. It discusses current muscle ultrasound applications with already proven clinical value, and highlights recent technical developments that may further advance muscle ultrasounds' diagnostic qualities. Recent findings The sensitivity and specificity of muscle ultrasound for detecting a neuromuscular disorder are high (90–95%), and quantitative ultrasound is well suited to monitor disease progression in several disorders. Adding ultrasound to electromyography significantly improves diagnostic certainty in patients with suspected motor neuron disease, and ultrasound increases the detection of fasciculations with 30–50%. New developments include speckle tracking of tissue motion to quantify diaphragm excursions and diminished muscle contractility in dystrophy, and strain elastography to detect changes in muscle stiffness and anisotropy during contraction and in disease states. Deep learning algorithms are being developed to predict the presence of a muscle disease and differentiate between disorders. Summary Muscle ultrasound is excellent for screening, diagnosing, and follow-up of neuromuscular disease. New developments are underway to automate and objectify the diagnostic process, and to quantify tissue motion that can provide new insights in pathophysiology and serve as a biomarker.

https://ift.tt/2LGiu4u

Emerging antisense oligonucleotide and viral therapies for amyotrophic lateral sclerosis

Purpose of review Amyotrophic lateral sclerosis (ALS) is a rapidly fatal disease for which there is currently no effective therapy. The present review describes the current progress of existing molecular therapies in the clinical trial pipeline and highlights promising future antisense oligonucleotide (ASO) and viral therapeutic strategies for treating ALS. Recent findings The immense progress in the design of clinical trials and generation of ASO therapies directed towards superoxide dismutase-1 (SOD1) and chromosome 9 open reading frame 72 (C9orf72) repeat expansion related disease have been propelled by fundamental work to identify the genetic underpinnings of familial ALS and develop relevant disease models. Preclinical studies have also identified promising targets for sporadic ALS (sALS). Moreover, encouraging results in adeno-associated virus (AAV)-based therapies for spinal muscular atrophy (SMA) provide a roadmap for continued improvement in delivery and design of molecular therapies for ALS. Summary Advances in preclinical and clinical studies of ASO and viral directed approaches to neuromuscular disease, particularly ALS, indicate that these approaches have high specificity and are relatively well tolerated.

https://ift.tt/2N1myRn

RITA induces apoptosis in p53-null K562 leukemia cells by inhibiting STAT5, Akt, and NF-κB signaling pathways

Targeting oncogenic signaling pathways by small molecules has emerged as a potential treatment strategy for cancer. reactivation of p53 and induction of tumor cell apoptosis (RITA) is a promising anticancer small molecule that reactivates p53 and induces exclusive apoptosis in tumor cells. Less well appreciated was the possible effect of small molecule RITA on p53-null leukemia cells. In this study, we demonstrated that RITA has potent antileukemic properties against p53-null chronic myeloid leukemia (CML)-derived K562 cells. RITA triggered apoptosis through caspase-9 and caspase-3 activation and poly (ADP-ribose) polymerase cleavage. RITA decreased STAT5 tyrosine phosphorylation, although it did not inhibit phosphorylation of the direct BCR-ABL substrate CrkL. Real-time PCR analysis showed that RITA downregulates antiapoptotic STAT5 target genes Bcl-xL and MCL-1. The downregulation of nuclear factor-κB (NF-κB), as evidenced by inhibition of IκB-α phosphorylation and its degradation, was associated with inhibition of Akt phosphorylation in RITA-treated cells. Furthermore, consistent with the decrease of mRNA levels, protein levels of the nuclear factor-κB-regulated antiapoptotic (cIAP1, XIAP, and Bcl-2) and proliferative (c-Myc) genes were downregulated by RITA in K562 cells. In conclusion, the ability of RITA to inhibit prosurvival signaling pathways in CML cells suggests a potential application of RITA in CML therapeutic protocols. * Rashideh N. Mobaraki and Maryam Karimi contributed equally to the writing of this article. Correspondence to Majid Safa, PhD, Cellular and Molecular Research Center, Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Hemmat Highway 1449614535, Tehran, Iran Tel: +98 218 670 4711; fax: +98 218 862 2578; e-mail: safa.m@iums.ac.ir Received August 11, 2017 Accepted April 30, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

https://ift.tt/2NzubvI

Identification of a high‐risk subtype of intestinal‐type Japanese gastric cancer by quantitative measurement of the luminal tumor proportion

Cancer Medicine, EarlyView.


https://ift.tt/2N2lLQg

Novel therapeutic roles of MC‐4 in combination with everolimus against advanced renal cell carcinoma by dual targeting of Akt/pyruvate kinase muscle isozyme M2 and mechanistic target of rapamycin complex 1 pathways

Cancer Medicine, EarlyView.


https://ift.tt/2NwU7YH

Chimeric Antigen Receptor T Cells: Extending Translation from Liquid to Solid Tumors

Human Gene Therapy, Ahead of Print.


https://ift.tt/2PfMlD5

Increased adverse events associated with antiepileptic drugs in anti–leucine‐rich glioma‐inactivated protein 1 encephalitis

Epilepsia, EarlyView.


https://ift.tt/2wslPhY

Acute and long‐term consequences of exposure to organophosphate nerve agents in humans

Epilepsia, EarlyView.


https://ift.tt/2olnh20

Risk score predictive of mortality in status epilepticus according to a national database

Epilepsia, EarlyView.


https://ift.tt/2olX6bp

Parenteral phenobarbital in status epilepticus revisited: Mayo Clinic experience

Epilepsia, EarlyView.


https://ift.tt/2wxhKsY

Neuroimaging of status epilepticus

Epilepsia, EarlyView.


https://ift.tt/2wprSEQ

Mitochondrial diseases and status epilepticus

Epilepsia, EarlyView.


https://ift.tt/2Ntgmyx

Mechanisms of status epilepticus: α‐Amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor hypothesis

Epilepsia, EarlyView.


https://ift.tt/2onQzgu

EpiNet study of incidence of status epilepticus in Auckland, New Zealand: Methods and preliminary results

Epilepsia, EarlyView.


https://ift.tt/2wydsRR

Mammaprint™: a comprehensive review

Future Oncology, Ahead of Print.


https://ift.tt/2C0mrkV

Sudden unexpected death in epilepsy, periictal physiology, and the SUDEP‐7 Inventory

Epilepsia, EarlyView.


https://ift.tt/2MEff2H

Complementary and alternative medicine use among children with mental health issues: results from the National Health Interview Survey

Mental health issues in children have become a serious public health concern in the U.S. within the past few decades. Emerging evidence suggests that Complementary and Alternative Medicine (CAM) can be benefic...

https://ift.tt/2MYNWzC

Combinatorial Genetic Control of Rpd3S Through Histone H3K4 and H3K36 Methylation in Budding Yeast

Much of euchromatin regulation occurs through reversible methylation of histone H3 lysine-4 and lysine-36 (H3K4me and H3K36me). Using the budding yeast Saccharomyces cerevisiae, we previously found that levels of H3K4me modulated temperature sensitive alleles of the transcriptional elongation complex Spt6-Spn1 through an unknown H3K4me effector pathway. Here we identify the Rpd3S histone deacetylase complex as the H3K4me effector underlying these Spt6-Spn1 genetic interactions. Exploiting these Spt6-Spn1 genetic interactions, we show that H3K4me and H3K36me collaboratively impact Rpd3S function in an opposing manner. H3K36me is deposited by the histone methyltransferase Set2 and is known to promote Rpd3S function at RNA PolII transcribed open reading frames. Using genetic epistasis experiments, we find that mutations perturbing the Set2-H3K36me-Rpd3S pathway suppress the growth defects caused by temperature sensitive alleles of SPT6 and SPN1, illuminating that this pathway antagonizes Spt6-Spn1. Using these sensitive genetic assays, we also identify a role for H3K4me in antagonizing Rpd3S that functions through the Rpd3S subunit Rco1, which is known to bind H3 N-terminal tails in a manner that is prevented by H3K4me. Further genetic experiments reveal that the H3K4 and H3K36 demethylases JHD2 and RPH1 mediate this combinatorial control of Rpd3S. Finally, our studies also show that the Rpd3L complex, which acts at promoter-proximal regions of PolII transcribed genes, counters Rpd3S for genetic modulation of Spt6-Spn1, and that these two Rpd3 complexes balance the activities of each other. Our findings present the first evidence that H3K4me and H3K36me act combinatorially to control Rpd3S.

https://ift.tt/2PUfyEO

In Reply to McClelland and Jaboin

To the Editor: Illegal questions continue to be an issue during interview season (1). Although we agree that illegal questions can be a "gray zone," our study did demonstrate that the majority of applicants who were asked an illegal match question were not offended by said question. Nonetheless, the programs that solicited illegal information to inform their rank lists may be perceived as or considered "malignant." Ultimately, an applicant can never be certain what information acquired during the application process is actually used and in what way, especially with respect to final rank lists.

https://ift.tt/2PQCULx

In Regard to Sura et al

In keeping with the current focus on ethics in radiation oncology in the International Journal of Radiation Oncology, Biology, Physics, the recent survey-based study by Sura et al examining the incidence of illegal match questions posed to medical student radiation oncology applicants revealed that despite a significant reduction in illegal questions asked since 2013, more than two-thirds of candidates are still asked at least one illegal question during interviews (1-3). Although the nature of illegal questions regarding personal situations (eg, family intentions, relationship status) encouragingly has decreased, it remains disheartening that most programs continue to violate a commitment to the National Resident Matching Program (NRMP) that they entered in contract agreement regarding the issue of respecting an applicant's right to privacy and confidentiality (3).

https://ift.tt/2PQ7HI5

Issue Highlights

Olsen et al

https://ift.tt/2PfnGyv

In Regard to You et al and Teixidó et al

To the Editor: Based on randomized studies (1, 2), immune checkpoint inhibition (ICI) for advanced non-small cell lung cancer (NSCLC) is a growing treatment modality with established efficacy and safety. Stereotactic radiation therapy (SRT), including radiosurgery and hypofractionated protocols, is a standard treatment for limited intracranial metastatic disease. Furthermore, with technology advances in SRT, more than 10 lesions could be treated simultaneously (3).

https://ift.tt/2PQCgO0

In Regard to United Nations

The United Nations has designated the equality and empowerment of women as a sustainable development goal, with a target of achieving gender equality by 2030 (1). Many initiatives augmenting efforts to achieve this target have been suggested and implemented. We attempt herein to elucidate the status of women in medicine in India, with an emphasis on the field of radiation oncology, and we review the measures attempting to promote the participation of women in this field.

https://ift.tt/2C1MUyG

In Reply to Belkacemi and Tsoutsou

To the Editor: We thank Belkacemi et al for their interest in our article (1, 2). We agree with them regarding the impact of regional nodal irradiation in node-positive and high-risk node-negative women; however, our target population differs from the cited trials. Details of regional nodal irradiation data are provided in Table E1. Most patients (75%) received a dedicated supraclavicular field, which often includes level III nodes. Patients had level I to II axillary dissection; therefore, only 24% received an additional axillary field.

https://ift.tt/2okNWMh

Radiation but With Delayed Reconstruction

The Danish 82b trial revealed significant benefits from postmastectomy radiation therapy (PMRT) among premenopausal women, including a survival benefit in even a subset enrolled with node-negative disease (1). Although risks of locoregional recurrence in modern US series of patients with T3N0 disease have been modest, some women may harbor occult residual disease in areas like the internal mammary region that might never yield clinically appreciable locoregional recurrence but nevertheless serve as a nidus for distant metastases.

https://ift.tt/2BYNXPE

Erratum to: Comparison of Adjuvant Versus Salvage Radiotherapy Policies for Postprostatectomy Radiotherapy. Int J Radiat Oncol Biol Phys 2004;59:329-340.

Michael Hagan, MD, PhD,* Robert Zlotecki, MD, PhD,† Camillo Medina, MD,‡ Oscar Tercilla, MD,* Inoel Rivera, MD,‡ and Zev Wajsman, MD‡

https://ift.tt/2PR1xI2

Update on Requirements for Medical Dosimetry Certification in the United States

The purpose of this editorial is to provide an update on the certification process for medical dosimetrists in the United States for the information of the greater radiation oncology community. Since the first administration of the Medical Dosimetrists Certification Board's (MDCB's) pen-and-paper certification examination in 1988, the examination has been evolving as a psychometrically sound computer-based examination for certifying competency in medical dosimetry. The examination is continuously updated to reflect current practice and knowledge, and it has been accredited by the National Commission for Certifying Agencies.

https://ift.tt/2Pjp437

Post-mastectomy Radiation, All in

This 47-year-old premenopausal woman with T3N0 breast cancer has what some would consider borderline indications for postmastectomy radiation (PMRT). To specifically address the 3 questions posed: (1) Yes, I would offer PMRT; (2) I would treat the chest wall, supraclav, axilla, and internal mammary chain to 50 Gy; and (3) reconstruction would not affect my decision to treat.

https://ift.tt/2ol6BHW

Gastrointestinal Cancers—Carving Out the Optimal Local Therapies in the Gastrointestinal Tract

The Gastrointestinal Editorial Group is pleased to present seven articles in this edition of the Oncology Scan. The first article we discuss, Trans-Tasman Radiology Oncology Group (TROG) 03.01 trial compared RT alone versus chemoradiotherapy with 1 cycle of concurrent 5-FU/cisplatin for palliation of dysphagia. Results demonstrate a significant increase in toxicity, with a numerically modest, although statistically insignificant, improvement in dysphagia relief (1).

https://ift.tt/2C1MmsC

Meetings

October 21-24, 2018

https://ift.tt/2PNDSrR

Expanding Access to Radiation Therapy: An Update on Brazil's Current Challenges and Opportunities

Since our previous publication regarding Brazil's radiation therapy (RT) challenges and opportunities, much has been learned with respect to global RT shortfall (1-4). However, in the past few years, Brazil has experienced political and economic turmoil. Currently, the main obstacles to improving RT access (2) are reduced linear accelerator (LINAC) installed capacity, insufficient access to RT technologies, and inadequate remuneration (5). Thus, we aim to summarize the current challenges and achievements accomplished by the Brazilian RT Expansion Project (EXPANDE).

https://ift.tt/2Pk0CP4

Post-mastectomy Radiation Yes but Internal Mammary Nodes No

I would recommend adjuvant radiation therapy in this case (1). The volumes to cover should include the chest wall and regional nodes to 50 Gy in 25 fractions. Because this patient has a left-sided, node-negative tumor, I would exclude the internal mammary nodes based on the argument of a narrow risk:benefit ratio supported by the following data:

https://ift.tt/2omR4rb

To Treat or Not to Treat? A Postmastectomy Question

A 47-year-old premenopausal woman with no known family history of breast cancer and an unremarkable medical history presented to her primary care physician after palpating a mass in her left breast. A mammogram and ultrasound demonstrated a 3.2 × 1.3-cm mass at 3 o'clock, 4 cm from the nipple, in her left breast. A biopsy showed invasive ductal carcinoma, intermediate nuclear grade, with associated high-grade ductal carcinoma in situ (DCIS). Estrogen and progesterone receptors stained positive, HER2 was negative by FISH, and Ki67 was 25%.

https://ift.tt/2C0qhut

Radiation Safety and Cardiovascular Implantable Electronic Devices

In 2017, the Heart Rhythm Society (HRS) published guidelines on the safe delivery of radiation therapy (RT) to patients with cardiovascular implantable electronic devices (CIEDs) (1). Despite significant advancements in CIED technology, this is the first major professional society update on this topic since 1994, when the American Association of Physicists in Medicine (AAPM) published the report of Task Group No. 34 (TG-34) in response to early reports of RT-induced permanent implantable cardiac pacemaker (ICP) damage (2).

https://ift.tt/2PNEnlz

Physician Leadership Development: A Pilot Program for Radiation Oncology Residents

The modern practice of medicine is reliant on highly functioning teams, and physicians are often charged with leading these teams. Physician leadership has increasingly been recognized to correlate with hospital organizational success: Quality, innovation, and management scores are demonstrably higher in hospitals in which the chief executive officer (CEO) is a physician (1). Health care systems such as Mayo Clinic and Cleveland Clinic are notable for a longstanding history of CEOs who were trained as physicians first, and a disproportionate number of highly ranked hospitals are indeed led by physicians (1, 2).

https://ift.tt/2Pgu9Jq

"Transparency" as Mask? The EPA’s Proposed Rule on Scientific Data

The Environmental Protection Agency (EPA) recently proposed excluding from consideration in setting environmental standards any studies whose raw, individual-level data are not publicly available. This proposal was preceded by the wholesale exclusion from the EPA's scientific advisory boards of…

https://ift.tt/2Nwus2p

Prevalence and Factors Associated with Anemia among Pregnant Women Attending Antenatal Clinic at St. Paul’s Hospital Millennium Medical College, Addis Ababa, Ethiopia

Background. In pregnancy, anemia is an important factor associated with an increased risk of maternal, fetal, and neonatal mortality, poor pregnancy outcomes, and impaired cognitive development, particularly in developing countries like Ethiopia. This study aimed to assess prevalence and factors associated with anemia among pregnant women attending antenatal clinic at St. Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia. Method. A cross-sectional health facility based study was conducted on 284 pregnant women to assess prevalence and factors associated with anemia at St. Paul's Hospital Millennium Medical College from June to August 2014. Data on sociodemographic and clinical characteristics of the study participants were collected using a pretested structured questionnaire by interview and review of medical records. About 4 ml of venous blood was collected from each subject for peripheral blood film and complete blood counts (CBC). Binary Logistic regression analysis had been used to check for association between dependent and independent variables. In all cases, P value less than 0.05 was considered statistically significant. Result. The prevalence of anemia was found to be 11.6% (95 % CI; 7.8%-14.8%). Pregnant women in the second [AOR (95% CI), 6.72 (1.17-38.45), and P=0.03] and third trimester [AOR (95% CI), 8.31 (1.24-55.45), and P=0.029] were more likely to be anemic when compared to pregnant women in their first trimester. Pregnant women who did not receive iron/folic acid supplementation [AOR (95%CI), 4.03(1.49-10.92), and P=0.01] were more likely to be anemic when compared to pregnant women who did take supplementations. Conclusion. In this study the prevalence of anemia in pregnancy was low compared to the findings of others. Gestational age (trimester) and iron/folic acid supplementation were statistically associated with anemia. Therefore, iron supplementation and health education to create awareness about the importance of early booking for antenatal care are recommended to reduce anemia.

https://ift.tt/2LFK5CR

Comparison of the perioperative time courses of matrix metalloproteinase-9 (MMP-9) and its inhibitor (TIMP-1) during carotid artery stenting (CAS) and carotid endarterectomy (CEA)

Our aim was to compare the perioperative time courses of matrix metalloproteinase-9 (MMP-9) and its inhibitor (TIMP-1) in during carotid endarterectomy (CEA) and carotid artery stenting (CAS).

https://ift.tt/2PPFem0

Re-evaluation of the stroke prognostication using age and NIH Stroke Scale index (SPAN-100 index) in IVT patients — the-SPAN 10065 index

The SPAN-100 index adds patient age and baseline NIHSS-score and was introduced to predict clinical outcome after acute ischemic stroke (AIS). Even with high NIHSS-scores younger patients cannot reach a SPAN-1...

https://ift.tt/2PjcMYr

Hyponatremia is a potential predictor of progression in radiation-induced brain necrosis: a retrospective study

To investigate the prognostic value of hyponatremia, defined as serum sodium level 

https://ift.tt/2PPdmOQ

Outcomes following emergency laparotomy in Australian public hospitals

ANZ Journal of Surgery, EarlyView.


https://ift.tt/2Pnzy1B

Post‐mortem general surgeon reflection on decision‐making: a mixed‐methods study of mortality audit data

ANZ Journal of Surgery, EarlyView.


https://ift.tt/2wlWIhF

Anal squamous cell carcinoma: are we improving outcomes?

ANZ Journal of Surgery, EarlyView.


https://ift.tt/2Nz13ES

"Transparency" as Mask? The EPA’s Proposed Rule on Scientific Data

The Environmental Protection Agency (EPA) recently proposed excluding from consideration in setting environmental standards any studies whose raw, individual-level data are not publicly available. This proposal was preceded by the wholesale exclusion from the EPA's scientific advisory boards of…

https://ift.tt/2Nwus2p

The Supreme Court’s Crisis Pregnancy Center Case — Implications for Health Law

States frequently compel health professionals and commercial entities to disclose information relevant to patient or consumer decision making. For many years, such laws were presumed to be constitutional, despite the First Amendment's protection of free speech. But after the Supreme Court's…

https://ift.tt/2wnw8og

Semi-automatic measurements and description of the geometry of vascular tree based on Bézier spline curves: application to cerebral arteries

The geometry of the vessels is easy to assess in novel 3D studies. It has significant influence on flow patterns and this way the evolution of vascular pathologies such as aneurysms and atherosclerosis. It is ...

https://ift.tt/2PgmgDO

A case report of mucocutaneous tuberculosis after orthotopic liver transplantation: a challenging diagnosis

Mycobacterium tuberculosis is responsible for high morbidity and mortality in immune-compromised hosts.

https://ift.tt/2olg7L7

Deposition of respiratory virus pathogens on frequently touched surfaces at airports

International and national travelling has made the rapid spread of infectious diseases possible. Little information is available on the role of major traffic hubs, such as airports, in the transmission of resp...

https://ift.tt/2wzLCES

Successful use of combined blood purification techniques in splenectomised patient with septic shock in streptococcus pneumoniae infection – a case report

Septic cardiomyopathy represents cardiac impairment in sepsis and is a part of systemic involvement in sepsis. Cytokine storm is responsible for septic shock and for myocardial dysfunction of potentially rever...

https://ift.tt/2PP2T5R

Clinical and economic burden of pneumococcal disease in US adults aged 19–64 years with chronic or immunocompromising diseases: an observational database study

Despite the widespread availability of pneumococcal vaccines, rates of pneumococcal disease are disproportionately high in adults with chronic and immunocompromising conditions. This study investigated pneumoc...

https://ift.tt/2wwY3Bw

Pfizer Recalls a Type of Children's Liquid Advil

WEDNESDAY, Aug. 29, 2018 -- One lot of 4-ounce bottles of Children's Advil Suspension Bubble Gum Flavored is being recalled because a packaging problem could lead to an overdose, Pfizer Consumer Healthcare says. The dosage cup is marked in teaspoons...

https://ift.tt/2PPjOFh

Label Mix-Up Spurs Recall of Accord Blood Pressure Meds

WEDNESDAY, Aug. 29, 2018 -- One lot of high blood pressure medication is being recalled after a labeling mix-up, Accord Healthcare Inc. has announced. The recall is for 100-count bottles of hydrochlorothiazide tablets USP, 12.5 mg, lot PW05264. One...

https://ift.tt/2BZm6yP

U.S. Opioid Use Not Declining, Despite Focus on Abuse

WEDNESDAY, Aug. 29, 2018 -- Rates of opioid use in the United States do not appear to be declining, according to a study published online Aug. 1 in The BMJ. Molly Moore Jeffery, Ph.D., from the Mayo Clinic in Rochester, Minn., and colleagues used a...

https://ift.tt/2BYDbca

Emicizumab Prophylaxis Cuts Bleeding in Hemophilia A

WEDNESDAY, Aug. 29, 2018 -- For patients with hemophilia A without factor VIII inhibitors, emicizumab prophylaxis leads to a significantly reduced bleeding rate, according to a study published in the Aug. 30 issue of the New England Journal of...

https://ift.tt/2PNg4Ep

SGLT2 (sodium-glucose cotransporter-2) Inhibitors for Diabetes: Drug Safety Communication - Regarding Rare Occurrences of a Serious Infection of the Genital Area

Audience: Patient, Endocrinology, Health Professional, Pharmacy ISSUE: FDA is warning that cases of a rare but serious infection of the genitals and area around the genitals have been reported with the class of type 2 diabetes medicines called...

https://ift.tt/2POWFCY

Activation of pro-survival metabolic networks by 1,25(OH) 2 D 3 does not hamper the sensitivity of breast cancer cells to chemotherapeutics

Abstract

Background

We have previously identified 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], the bioactive form of vitamin D₃, as a potent regulator of energy-utilization and nutrient-sensing pathways in prostate cancer cells. In the current study, we investigated the effects of 1,25(OH)₂D₃ on breast cancer (BCa) cell metabolism using cell lines representing distinct molecular subtypes, luminal (MCF-7 and T-47D), and triple-negative BCa (MDA-MB-231, MDA-MB-468, and HCC-1143).

Methods

1,25(OH)₂D₃'s effect on BCa cell metabolism was evaluated by employing a combination of real-time measurements of glycolysis/oxygen consumption rates using a biosensor chip system, GC/MS-based metabolomics, gene expression analysis, and assessment of overall energy levels. The influence of treatment on energy-related signaling molecules was investigated by immunoblotting.

Results

We show that 1,25(OH)₂D₃ significantly induces the expression and activity of the pentose phosphate pathway enzyme glucose-6-phosphate dehydrogenase (G6PD) in all BCa cell lines, however differentially influences glycolytic and respiratory rates in the same cells. Although 1,25(OH)₂D₃ treatment was found to induce seemingly anti-oxidant responses in MCF-7 cells, such as increased intracellular serine levels, and reduce the expression of its putative target gene thioredoxin-interacting protein (TXNIP), intracellular reactive oxygen species levels were found to be elevated. Serine accumulation in 1,25(OH)₂D₃-treated cells was not found to hamper the efficacy of chemotherapeutics, including 5-fluorouracil. Detailed analyses of the nature of TXNIP's regulation by 1,25(OH)₂D₃ included genetic and pharmacological inhibition of signaling molecules and metabolic enzymes including AMP-activated protein kinase and G6PD, as well as by studying the ITCH (E3 ubiquitin ligase)-TXNIP interaction. While these investigations demonstrated minimal involvement of such pathways in the observed non-canonical regulation of TXNIP, inhibition of estrogen receptor (ER) signaling by tamoxifen mirrored the reduction of TXNIP levels by 1,25(OH)₂D₃, demonstrating that the latter's negative regulation of ER expression is a potential mechanism of TXNIP modulation.

Conclusions

Altogether, we propose that regulation of energy metabolism contributes to 1,25(OH)₂D₃'s anti-cancer effects and that combining 1,25(OH)₂D₃ with drugs targeting metabolic networks in tumor cells may lead to synergistic effects.

https://ift.tt/2MUCuFl

Characteristics of glycopeptide-resistant Staphylococcus aureus strains isolated from inpatients of three teaching hospitals in Warsaw, Poland

Vancomycin is still one of the most commonly used drug for treatment of severe methicillin-resistant Staphylococcus aureus (MRSA) infections. Vancomycin-resistant S. aureus (VRSA) strains are a serious danger for...

https://ift.tt/2wrhXia

Rationale and development of a business case for antimicrobial stewardship programs in acute care hospital settings

Antimicrobial stewardship programs (ASPs) have been shown to reduce inappropriate antimicrobial use and its consequences. However, these programs lack legislative requirements in many places and it can be diff...

https://ift.tt/2oiO0w6

Haplodeletion of Follistatin-like 1 Attenuates Radiation-induced Pulmonary Fibrosis in Mice

Radiation-induced pulmonary fibrosis (RIPF) is a complex pathophysiologic process and its mechanisms are poorly understood. This study investigated the role of Follistatin-like 1 (Fstl1) in RIPF. The findings confirmed the increased Fstl1 levels in serum and lung from patients with RIPF and animal models. Haploinsufficiency of Fstl1 attenuated radiation-induced lung fibrosis without affecting inflammatory response. The X-ray induced α-SMA expression and type I collagen deposit were decreased in Fstl1+/– lung fibroblasts.

https://ift.tt/2PPbdCQ

Late Effects of Radiation Prime the Brain Microenvironment for Accelerated Tumor Growth

For many years, research on recurrent glioblastoma has largely focused on therapyinduced immediate radiobiologic changes to the tumor and surrounding tissues. In this study, we demonstrate that substantially delayed effects of irradiation on the brain microenvironment lead to a remarkable pattern of aggressive tumor regrowth. This affords new insights into the highly aggressive tumor regrowth pattern observed following radiotherapy and provides an avenue for determining the cellular basis for the aggressiveness of recurrent GBM.

https://ift.tt/2LFeHV4

https://ift.tt/2BZ6tYb

Bilateral independent periodic discharges are associated with electrographic seizures and poor outcome: a case-control study

Bilateral independent periodic discharges (BIPDs; previously known as bilateral independent periodic lateralized epileptiform discharges or BIPLEDs) are EEG abnormalities consisting of discharges that occur repeatedly with a quantifiable and nearly regular inter-discharge interval, and independently (asynchronously) over each hemisphere. (Hirsch et al. 2013) The prevalence and clinical and prognostic significance of BIPDs in patients undergoing continuous EEG monitoring (CEEG) remains unclear. One study previously showed prevalence of 0.1% in unselected sets of inpatient and outpatient EEGs (Chatrian et al.

https://ift.tt/2wxEPM3

Neurophysiological Monitoring during Cervical Spine Surgeries: Longitudinal Costs and Outcomes

Cervical spine surgeries are among the most frequent and expensive procedures performed in the United States. They commonly address disabling neck pain that fails to respond to more conservative measures, through removal of removal of part or all of the damaged disc, sometimes followed by fusion of adjacent vertebrae with fixation using metallic implants (Irwin et al., 2005). Due to proximity of neural structures, the risks of cervical spine surgery include paralysis from spinal cord injury (iatrogenic myelopathy) and damage to exiting cervical nerve roots resulting in loss of function in the hands or arms (iatrogenic radiculopathy) (Cheung and Luk, 2016).

https://ift.tt/2oi7CAC

Nebulized terbutaline & ipratropium bromide vs terbutaline alone in acute exacerbation of COPD requiring noninvasive ventilation: a randomized double blind controlled trial

Academic Emergency Medicine, Volume 0, Issue ja, -Not available-.


https://ift.tt/2PjT1A8

Child Poverty: New Opportunities for Pediatricians

When the US Bureau of Labor Statistics announced in May that we had hit the lowest unemployment rate—3.9%—since 2000, few felt a wave of relief. Americans may be employed, but wages are stagnant. A review of workers in the labor market found men entering the market in 1983 had a 10%-19% decrease in median lifetime income compared with those entering in 1967.1 Further, an analysis of Congressional Budget Office data found widening income inequality; since 1979, those in the top 1% have had a 228% increase in their income, whereas the middle 60% and bottom 20% have had a 42% and 69% increase, respectively.

https://ift.tt/2LCTCuw

Passive Smoking Exacerbates Nicotinamide-Adenine Dinucleotide Phosphate Oxidase Isoform 2–Induced Oxidative Stress and Arterial Dysfunction in Children with Persistent Allergic Rhinitis

To characterize nicotinamide-adenine dinucleotide phosphate oxidase isoform 2 (NOX2), oxidative stress, and endothelial function in children with and without allergic rhinitis and to ascertain the effect of passive smoke exposure on these factors, because there is an established association between allergic rhinitis and increased cardiovascular risk in adults.

https://ift.tt/2BVD2Go

Fetal and neonatal growth restriction: new criteria, renew challenges

Beune et al published a statement on growth restriction in the newborn, building on a similar initiative in obstetrics.1,2 These statements press experts in both fields to critically evaluate their current diagnostic practices regarding fetal growth restriction.

https://ift.tt/2LCvsAl

Novel Lipid Thresholds for Screening Predict the Need for Pharmacotherapy

To identify non-high-density lipoprotein cholesterol (HDL-C) and HDL-C thresholds for pediatric nonfasting lipid screens that are more predictive of the need for lipid-lowering pharmacotherapy and estimate numbers of potentially avoidable fasting lipid panels.

https://ift.tt/2LCTBXu

The Oxygen Load Supplied during Delivery Room Stabilization of Preterm Infants Modifies the DNA Methylation Profile

To determine whether the amount of oxygen provided during postnatal stabilization changes the DNA methylome in preterm infants.

https://ift.tt/2PLhwHz

The Long Journey to Eradication of Hepatitis C Virus Infection Should Begin with the Smallest Victims

In this volume of The Journal, Epstein et al1 have made an important and timely contribution to our understanding of the need to improve hepatitis C virus (HCV) testing of pregnant women with opioid use disorder as well as their infants. The authors used electronic health records for a 10-year cohort of 879 women with opioid use disorder from an obstetric clinic serving women with substance use disorders. Only 85% of the women were screened for HCV. Of the 68% who were seropositive, only 72% had HCV RNA testing and 71% were viremic.

https://ift.tt/2LCz998

Early Antibiotic Exposure and Adverse Outcomes in Preterm, Very Low Birth Weight Infants

To determine whether antibiotic use in the first 14 postnatal days in preterm, very low birth weight (birth weight of ≤1500 g) infants is associated with risk after 14 days of age for late-onset sepsis, necrotizing enterocolitis (NEC), or death after controlling for severity of illness using the Clinical Risk Index in Babies II score, and determine whether duration of antibiotic exposure was associated with risk of adverse outcomes.

https://ift.tt/2C09Yh8

Early Mobilization in Critically Ill Children: A Systematic Review

To characterize how early mobilization is defined in the published literature and describe the evidence on safety and efficacy on early mobilization in critically ill children.

https://ift.tt/2PRaWiP

Do Short-Term Exercise Interventions Improve Cardiometabolic Risk Factors in Children?

To explore the impact of short-term exercise of varying intensity on traditional risk factors for cardiometabolic disease.

https://ift.tt/2PPHTMf

Chronic Bullous Dermatosis of Childhood and the String of Pearls Sign

A previously well 5-year-old boy presented to the emergency department with a 1-week history of pruritic papules on both elbows that had progressed to scattered annular lesions on his buttocks, elbows, and legs with interspersed tense bullae (Figure 1). He was not receiving any medication and remained systemically well throughout. The itching had not been relieved with antihistamine. He had no infectious contacts. He had a normal cardiovascular, respiratory, and abdominal examination and was afebrile with observations appropriate for his age.

https://ift.tt/2LE3V19

Reply

We thank Saxena et al for their thoughtful comments and suggestions. We agree that the issue of gastric residual volume evaluation for feeding advancement is important in infants of very low birth weight. However, a significantly larger proportion of infants born preterm have a birth weight >1500 g, yet there is a scarcity of evidence about the significance of gastric residual volumes and feeding advancement even in this relatively low-risk population group. Also, in many neonatal units including our center, it was the standard of care to rely on gastric residual volumes in decisions relating to the advancements of enteral feeds in all infants born preterm who required gavage feeds.

https://ift.tt/2PNM1fO

Proximal Preaxial Hallucal Polysyndactyly with Tibial Hemimelia: Diabetic Embryopathy

A 3-kg boy born full term with congenital malformations was born to a 23-year-old mother with type 2 diabetes for the past 3 years, class B, according to the White classification.1 She was managed initially with a diabetic diet and oral hypoglycemic agents. Her first antenatal check-up was performed at 11 weeks of gestation; thereafter, her blood glucose levels were monitored every 10-15 days. Due to uncontrolled diabetes (glycated hemoglobin A1c was 8.2% in second trimester), she was started on regular insulin along with oral hypoglycemic agents.

https://ift.tt/2MWFml3

The Relationship Between Ambient Air Pollution and Acute Ischemic Stroke: A Time-Stratified Case-Crossover Study in a City-State With Seasonal Exposure to the Southeast Asian Haze Problem

Studies are divided on the short-term association of air pollution with stroke. Singapore is exposed to seasonal transboundary haze. We aim to investigate the association between air pollution and stroke incidence in Singapore.

https://ift.tt/2wvz6Xc

SGLT2(sodium-glucose cotransporter-2) Inhibitors for Diabetes: Drug Safety Communication - Regarding Rare Occurrences of a Serious Infection of the Genital Area

[Posted 08/29/2018] AUDIENCE: Patient, Endocrinology, Health Professional, Pharmacy ISSUE: FDA is warning that cases of a rare but serious infection of the genitals and area around the genitals have been reported with the class of type 2 diabetes...

https://ift.tt/2NwxFyU

Virtual Reality Experiments with Physiological Measures

Virtual reality (VR) experiments can be difficult to implement and require meticulous planning. This protocol describes a method for the design and implementation of VR experiments that collect physiological data from human participants. The Experiments in Virtual Environments (EVE) framework is employed to accelerate this process.

https://ift.tt/2woJUan

Study Provides Closer Look at Postmenopausal Bleeding and Endometrial Cancer

A new study has found that 90% of postmenopausal women diagnosed with endometrial cancer reported vaginal bleeding before their diagnosis. Approximately 9% of postmenopausal women who saw a doctor for bleeding, the study showed, later received an endometrial cancer diagnosis.

https://ift.tt/2C0u3Us

Unique EMS training opportunity: The Center for Domestic Preparedness

Complete with a mock community and former hospital, the CDP gives responders the opportunity to train on emergency and disaster response

https://ift.tt/2LDsyvc

Immunohistochemical Detection of 5-Methylcytosine and 5-Hydroxymethylcytosine in Developing and Postmitotic Mouse Retina

The objective of this report is to describe the protocol for robust immunohistochemical detection of epigenetic markers, 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in developing and postmitotic mouse retina.

https://ift.tt/2PPTvie

Fasciae of the musculoskeletal system: normal anatomy and MR patterns of involvement in autoimmune diseases

Abstract

The fascial system is a three-dimensional continuum of connective tissues present everywhere throughout the body, from the head to the toes and from the skin to the bone. The current article aims to review the normal anatomy of the fasciae of the musculoskeletal system with macroscopic and microscopic correlations and to describe their appearance at MRI in normal subjects and in patients with autoimmune diseases of the musculoskeletal system.

Key Points

• The fascial system is a three-dimensional continuum of connective tissues.

• It is present everywhere throughout the body, from the head to the toes and from the skin to the bone.

• The normal fascial system is barely visible at MRI.

• MR patterns of fascial involvement in autoimmune diseases reflect the complex anatomy of the fasciae of the musculoskeletal system.

https://ift.tt/2PO8Fos

Foot-and-mouth disease virus induces lysosomal degradation of NME1 to impair p53-regulated interferon-inducible antiviral genes expression

Foot-and-mouth disease virus induces lysosomal degradation of NME1 to impair p53-regulated interferon-inducible antiviral genes expression

Foot-and-mouth disease virus induces lysosomal degradation of NME1 to impair p53-regulated interferon-inducible antiviral genes expression, Published online: 29 August 2018; doi:10.1038/s41419-018-0940-z

Foot-and-mouth disease virus induces lysosomal degradation of NME1 to impair p53-regulated interferon-inducible antiviral genes expression

https://ift.tt/2wqJNuW

Novel β-phenylacrylic acid derivatives exert anti-cancer activity by inducing Src-mediated apoptosis in wild-type KRAS colon cancer

Novel β-phenylacrylic acid derivatives exert anti-cancer activity by inducing Src-mediated apoptosis in wild-type KRAS colon cancer

Novel β-phenylacrylic acid derivatives exert anti-cancer activity by inducing Src-mediated apoptosis in wild-type KRAS colon cancer, Published online: 29 August 2018; doi:10.1038/s41419-018-0942-x

Novel β-phenylacrylic acid derivatives exert anti-cancer activity by inducing Src-mediated apoptosis in wild-type KRAS colon cancer

https://ift.tt/2NtKObT

The activation of microRNA-520h–associated TGF-β1/c-Myb/Smad7 axis promotes epithelial ovarian cancer progression

The activation of microRNA-520h–associated TGF-β1/c-Myb/Smad7 axis promotes epithelial ovarian cancer progression

The activation of microRNA-520h–associated TGF-β1/c-Myb/Smad7 axis promotes epithelial ovarian cancer progression, Published online: 29 August 2018; doi:10.1038/s41419-018-0946-6

The activation of microRNA-520h–associated TGF-β1/c-Myb/Smad7 axis promotes epithelial ovarian cancer progression

https://ift.tt/2wqJCjg

Human menstrual blood-derived stem cells promote functional recovery in a rat spinal cord hemisection model

Human menstrual blood-derived stem cells promote functional recovery in a rat spinal cord hemisection model

Human menstrual blood-derived stem cells promote functional recovery in a rat spinal cord hemisection model, Published online: 29 August 2018; doi:10.1038/s41419-018-0847-8

Human menstrual blood-derived stem cells promote functional recovery in a rat spinal cord hemisection model

https://ift.tt/2wyBYlQ

Subsurface landfill leachate contamination affects microbial metabolic potential and gene expression in the Banisveld aquifer

Abstract

Microbial communities in groundwater ecosystems can develop the capacity to degrade complex mixtures of chemicals resulting from pollution by landfill leachate. Monitoring this natural attenuation requires insight into the metabolic potential and activity of microbial communities. We contrasted the metagenomes and metatranscriptomes from a leachate-polluted aquifer downstream of the Banisveld (the Netherlands) landfill with uncontaminated groundwater, which revealed changes in microbial genomic content and activity. Banisveld landfill leachate contains mono-aromatic hydrocarbons and the assessment of natural attenuation of these compounds in the aquifer had been a focal point of research. In the contaminated groundwater, active microbial functions were the ones involved in degradation of complex carbon substrates and organic pollutants. We found that benzylsuccinate synthase genes—involved in the catabolism of toluene—were highly expressed close to the source of contamination, confirming the ongoing natural attenuation of organic mono-aromatic hydrocarbon pollution in this aquifer. Additionally, metatranscriptomes were indicative of phosphorus limitation that can constrain total microbial activity and agree with the low phosphate concentrations (<0.4 μmol/L) in this aquifer. Through the application of metagenomics and metatranscriptomics, we were able to determine functional potential and expression patterns to assess the natural attenuation processes and constraints on microbial communities.

https://ift.tt/2PimKcv

Interactive effects of dissolved nitrogen, phosphorus and litter chemistry on stream fungal decomposers

ABSTRACT

The enrichment of ecosystems by nutrients such as nitrogen (N) and phosphorus (P) has important ecological consequences. These include effects on plant litter decomposition in forest soils and forested headwater streams, where fungi play a pivotal role. However, our understanding of nutrient relationships on fungal communities associated with decomposing litter remains surprisingly incomplete. We conducted a fully factorial microcosm experiment with known communities of fungal decomposers from streams to assess the importance of dissolved N and P supply, as well as the atomic nutrient ratio (N:P), on fungal community succession, diversity, biomass and reproduction on three leaf-litter species differing in nutrient and lignin concentrations. Fungal biomass accrual and spore production were strongly controlled by external N supply, whereas P supply was much less important. The magnitude of these effects was mediated by litter quality, with stronger effects of dissolved N and P on lignin-poor and high N:P litter. N supply also influenced fungal diversity and species composition, acting as a pacemaker of community succession. Collectively, our data indicate that N was in much greater demand than predicted by standard stoichiometric models. The most parsimonious explanation for this deviation relates to the need of litter fungi to invest large amounts of N into degradative exoenzymes.

https://ift.tt/2MYweMF

Microbial community composition of a hydrocarbon reservoir 40 years after a CO2 enhanced oil recovery flood

Abstract

Injecting CO₂ into depleted oil reservoirs to extract additional crude oil is a common enhanced oil recovery (CO₂-EOR) technique. However, little is known about how in situ microbial communities may be impacted by CO₂ flooding, or if any permanent microbiological changes occur after flooding has ceased. Formation water was collected from an oil field that was flooded for CO₂-EOR in the 1980s, including samples from areas affected by or outside of the flood region, to determine the impacts of CO₂-EOR on reservoir microbial communities. Archaea, specifically methanogens, were more abundant than bacteria in all samples, while identified bacteria exhibited much greater diversity than the archaea. Microbial communities in CO₂-impacted and non-impacted samples did not significantly differ (ANOSIM: Statistic R = -0.2597, significance = 0.769). However, several low abundance bacteria were found to be significantly associated with the CO₂-affected group; very few of these species are known to metabolize CO₂ or are associated with CO₂-rich habitats. Although this study had limitations, on a broad scale, either the CO₂ flood did not impact the microbial community composition of the target formation, or microbial communities in affected wells may have reverted back to pre-injection conditions over the ca. 40 years since the CO₂-EOR.

https://ift.tt/2N5zLcg

Assessment of bacterial dependence on marine primary production along a northern latitudinal gradient

ABSTRACT

Recent observations in polar marine waters have shown that a large fraction of primary production may be lost to respiration by planktonic bacteria due to very low bacterial growth efficiencies in cold waters. Here we report that sea temperature may be a key factor (but not the only one) influencing the interaction between bacteria and primary production in North Atlantic and Arctic waters, suggesting that low primary production rates could not sustain bacterial carbon demand in the coldest Arctic waters. The use of freshly produced phytoplankton exudate by bacteria in early- and mid-summer was assessed, together with the bacterial uptake of dissolved inorganic nitrogen (DIN = nitrate and ammonium), in surface waters along a latitudinal gradient from the North Sea to the Arctic sea ice. Bacterial production was independent of the low primary production measured in the coldest waters. Under these conditions, heterotrophic bacteria can consume a large fraction of DIN and N-rich organic matter, making them strong contributors to N fluxes in these waters.

https://ift.tt/2LDHdGp

ANO7 is associated with aggressive prostate cancer

International Journal of Cancer, Volume 0, Issue ja, -Not available-.


https://ift.tt/2MFNcQw

Identification and characterization of TGFBI in circulating tumor cell subline from pancreatic cancer cell line

Cancer Science, Volume 0, Issue ja, -Not available-.


https://ift.tt/2olrxPb

Immuno‐regulatory influence of abundant MFG‐E8 expression by esophageal cancer treated with chemotherapy

Cancer Science, Volume 0, Issue ja, -Not available-.


https://ift.tt/2C1aaNa

Dynamic Proteomic and miRNA Analysis of Polysomes from Isolated Mouse Heart After Langendorff Perfusion

Here we present a protocol to perform polysome profiling on the isolated perfused mouse heart. We describe methods for heart perfusion, polysome profiling, and analysis of the polysome fractions with respect to mRNAs, miRNAs, and the polysome proteome.

https://ift.tt/2PilKFr

CDC: Greater Awareness of Valley Fever Needed Nationally

WEDNESDAY, Aug. 29, 2018 -- Greater nationwide awareness of the fungal infection Valley fever (coccidioidomycosis) is needed, according to a report published in the August issue of the U.S. Centers for Disease Control and Prevention's Emerging...

https://ift.tt/2MVUIpV

CDC: Most Babies Born in 2015 Started Out Breastfeeding

WEDNESDAY, Aug. 29, 2018 -- Most infants born in 2015 started breastfeeding, but many stopped earlier than recommended, according to a report card published by the U.S. Centers for Disease Control and Prevention. The CDC compiled data on...

https://ift.tt/2PbHFOk

Wording Used May Affect Thyroid Cancer Patients' Anxiety, Choices

WEDNESDAY, Aug. 29, 2018 -- The terminology used to describe small papillary thyroid cancers (PTCs) may affect patients' anxiety levels and treatment choices, according to a study published online Aug. 23 in JAMA Otolaryngology-Head & Neck...

https://ift.tt/2MYwyLw

PT Better After Hip Surgery Than Opioids in Younger Adults

WEDNESDAY, Aug. 29, 2018 -- Physical therapy management is associated with better outcomes for young patients undergoing arthroscopic hip surgery, compared to primary or exclusive opioid treatment, according to a study recently published in Physical...

https://ift.tt/2wmm9zy

Chronic Vaping Exerts Biological Effects on Lungs

WEDNESDAY, Aug. 29, 2018 -- Chronic vaping exerts biological effects on the lung, some of which may be mediated by the propylene glycol/vegetable glycerin (PG/VG) base, according to a study published in the July 1 issue of the American Journal of...

https://ift.tt/2PgJTMA

State Public Health Workforce Grew From 2013 to 2017

WEDNESDAY, Aug. 29, 2018 -- The state health department epidemiology workforce increased 22 percent from 2013 to 2017, according to research published in the Aug. 24 issue of the U.S. Centers for Disease Control and Prevention's Morbidity and...

https://ift.tt/2woTIRw

Marketplace Premiums Increase More With Monopolist Insurers

WEDNESDAY, Aug. 29, 2018 -- Affordable Care Act Marketplace premiums increase more in areas with monopolist insurers, according to a study published in the August issue of Health Affairs. Jessica Van Parys, Ph.D., from the City University of New...

https://ift.tt/2LE6r7I

Positive Link for BMI and Blood Pressure in Chinese Population

WEDNESDAY, Aug. 29, 2018 -- In a Chinese adult population (ages 35 to 80 years), there is a positive association between body mass index (BMI) and blood pressure (BP), according to a study published online Aug. 17 in JAMA Network Open. George C....

https://ift.tt/2wokzgL

High, Low Carbohydrate Diets Linked to Increased Mortality

WEDNESDAY, Aug. 29, 2018 -- Both high and low percentages of carbohydrates in diets are associated with increased mortality, according to a study published online Aug. 16 in The Lancet Public Health. Sara B. Seidelmann, M.D., from Brigham and...

https://ift.tt/2LB9PQI

Authors response: Association between IBD and Parkinsons disease: seek and you shall find?

Dr Weimers and colleagues have drawn attention1 to the possibility that our recently published observation of an association between IBD and Parkinson's disease (PD) in a nationwide Danish cohort study2 may reflect surveillance bias.

In a recently published Swedish cohort study, Dr Weimers and colleagues found that adjusting for number of healthcare visits during follow-up of patients with IBD attenuated the risk of developing PD markedly.3 They also found that the risk of future PD was proportional to the number of healthcare visits (<10 (reference) 10 -<20, 20 -<50, ≥50) during follow-up (up to 12 years).3

We had a number of methodological reasons for not adjusting for number of healthcare visits. For example, the Danish National Patient Register does not only record encounters with a physician but also with midwifes and nurses and encounters with relation to rehabilitation. We assume that these kinds of visits are less...

https://ift.tt/2PPUgZ0

Primum non nocere: is faecal microbiota transplantation doing harm to patients with IBS?

A recent paper in this journal1 caught my attention: In a well-designed placebo-controlled trial of faecal microbiota transplantation (FMT) in patients with IBS, 12 days of blinded provision of the transplant or placebo in capsules improved symptoms in patients randomised to placebo significantly better than in patients receiving FMT, for IBS symptom severity at 3 and 6 months, and for IBS quality of life at 1, 3 and 6 months of follow-up. Patients receiving FMT showed sustained alterations of their microbiota, obviously unrelated to the symptom burden.

Taking the effect of FMT on the gut microbiota in IBS aside (that has a scientific value by itself), these results not only imply that improvements seen with FMT in IBS in controlled2 and poorly or uncontrolled3 4 studies may be entirely due to placebo effects, on average 40% in IBS.5 It also implies that...

https://ift.tt/2BWmQ87

Cerebrospinal Fluid-Contacting Neurons Sense pH Changes and Motion in the Hypothalamus

CSF-contacting (CSF-c) cells are present in the walls of the brain ventricles and the central canal of the spinal cord and found throughout the vertebrate phylum. We recently identified ciliated somatostatin-/GABA-expressing CSF-c neurons in the lamprey spinal cord that act as pH sensors as well as mechanoreceptors. In the same neuron, acidic and alkaline responses are mediated through ASIC3-like and PKD2L1 channels, respectively. Here, we investigate the functional properties of the ciliated somatostatin-/GABA-positive CSF-c neurons in the hypothalamus by performing whole-cell recordings in hypothalamic slices. Depolarizing current pulses readily evoked action potentials, but hypothalamic CSF-c neurons had no or a very low level of spontaneous activity at pH 7.4. They responded, however, with membrane potential depolarization and trains of action potentials to small deviations in pH in both the acidic and alkaline direction. Like in spinal CSF-c neurons, the acidic response in hypothalamic cells is mediated via ASIC3-like channels. In contrast, the alkaline response appears to depend on connexin hemichannels, not on PKD2L1 channels. We also show that hypothalamic CSF-c neurons respond to mechanical stimulation induced by fluid movements along the wall of the third ventricle, a response mediated via ASIC3-like channels. The hypothalamic CSF-c neurons extend their processes dorsally, ventrally, and laterally, but as yet, the effects exerted on hypothalamic circuits are unknown. With similar neurons being present in rodents, the pH- and mechanosensing ability of hypothalamic CSF-c neurons is most likely conserved throughout vertebrate phylogeny.

SIGNIFICANCE STATEMENT CSF-contacting neurons are present in all vertebrates and are located mainly in the hypothalamic area and the spinal cord. Here, we report that the somatostatin-/GABA-expressing CSF-c neurons in the lamprey hypothalamus sense bidirectional deviations in the extracellular pH and do so via different molecular mechanisms. They also serve as mechanoreceptors. The hypothalamic CSF-c neurons have extensive axonal ramifications and may decrease the level of motor activity via release of somatostatin. In conclusion, hypothalamic somatostatin-/GABA-expressing CSF-c neurons, as well as their spinal counterpart, represent a novel homeostatic mechanism designed to sense any deviation from physiological pH and thus constitute a feedback regulatory system intrinsic to the CNS, possibly serving a protective role from damage caused by changes in pH.

https://ift.tt/2PT04kq

Brainstem Steering of Locomotor Activity in the Newborn Rat

Control of locomotion relies on motor loops conveying modulatory signals between brainstem and spinal motor circuits. We investigated the steering control of the brainstem reticular formation over the spinal locomotor networks using isolated brainstem–spinal cord preparations of male and female neonatal rats. First, we performed patch-clamp recordings of identified reticulospinal cells during episodes of fictive locomotion. This revealed that a spinal ascending phasic modulation of reticulospinal cell activity is already present at birth. Half of the cells exhibited tonic firing during locomotion, while the other half emitted phasic discharges of action potentials phase locked to ongoing activity. We next showed that mimicking the phasic activity of reticulospinal neurons by applying patterned electrical stimulation bilaterally at the ventral caudal medulla level triggered fictive locomotion efficiently. Moreover, the brainstem stimuli-induced locomotor rhythm was entrained in a one-to-one coupling over a range of cycle periods (2–6 s). Additionally, we induced turning like motor outputs by either increasing or decreasing the relative duration of the stimulation trains on one side of the brainstem compared to the other. The ability of the patterned descending command to control the locomotor output depended on the functional integrity of ventral reticulospinal pathways and the involvement of local spinal central pattern generator circuitry. Altogether, this study provides a mechanism by which brainstem reticulospinal neurons relay steering and speed commands to the spinal locomotor networks.

SIGNIFICANCE STATEMENT Locomotor function allows the survival of most animal species while sustaining the expression of fundamental behaviors. Locomotor activities adapt from moment to moment to behavioral and environmental changes. We show that the brainstem can control the spinal locomotor network outputs through phasic descending commands that alternate bilaterally. Manipulating the periodicity and/or the relative durations of the left and right descending commands at the brainstem level is efficient to set the locomotor speed and sustain directional changes.

https://ift.tt/2LAWIz2

Persistent Sodium Current Drives Excitability of Immature Renshaw Cells in Early Embryonic Spinal Networks

Spontaneous network activity (SNA) emerges in the spinal cord (SC) before the formation of peripheral sensory inputs and central descending inputs. SNA is characterized by recurrent giant depolarizing potentials (GDPs). Because GDPs in motoneurons (MNs) are mainly evoked by prolonged release of GABA, they likely necessitate sustained firing of interneurons. To address this issue we analyzed, as a model, embryonic Renshaw cell (V1^R) activity at the onset of SNA (E12.5) in the embryonic mouse SC (both sexes). V1^R are one of the interneurons known to contact MNs, which are generated early in the embryonic SC. Here, we show that V1^R already produce GABA in E12.5 embryo, and that V1^R make synaptic-like contacts with MNs and have putative extrasynaptic release sites, while paracrine release of GABA occurs at this developmental stage. In addition, we discovered that V1^R are spontaneously active during SNA and can already generate several intrinsic activity patterns including repetitive-spiking and sodium-dependent plateau potential that rely on the presence of persistent sodium currents (I_Nap). This is the first demonstration that I_Nap is present in the embryonic SC and that this current can control intrinsic activation properties of newborn interneurons in the SC of mammalian embryos. Finally, we found that 5 μm riluzole, which is known to block I_NaP, altered SNA by reducing episode duration and increasing inter-episode interval. Because SNA is essential for neuronal maturation, axon pathfinding, and synaptogenesis, the presence of I_NaP in embryonic SC neurons may play a role in the early development of mammalian locomotor networks.

SIGNIFICANCE STATEMENT The developing spinal cord (SC) exhibits spontaneous network activity (SNA) involved in the building of nascent locomotor circuits in the embryo. Many studies suggest that SNA depends on the rhythmic release of GABA, yet intracellular recordings of GABAergic neurons have never been performed at the onset of SNA in the SC. We first discovered that embryonic Renshaw cells (V1^R) are GABAergic at E12.5 and spontaneously active during SNA. We uncover a new role for persistent sodium currents (I_NaP) in driving plateau potential in V1^R and in SNA patterning in the embryonic SC. Our study thus sheds light on a role for INaP in the excitability of V1^R and the developing SC.

https://ift.tt/2LyAqOs

Cross‐sectional study of a UK cohort of neonatal vein of Galen malformation

Annals of Neurology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2oo1QND

Evaluation of no evidence of progression or active disease (NEPAD) in patients with primary progressive multiple sclerosis in the ORATORIO trial

Annals of Neurology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2C61tRw

Issue Information

Experimental Dermatology, Volume 27, Issue 9, Page 939-940, September 2018.


https://ift.tt/2om6H24

Altered expression of matrix remodelling associated 7 (MXRA7) in psoriatic epidermis: Evidence for a protective role in the psoriasis imiquimod mouse model

Experimental Dermatology, Volume 27, Issue 9, Page 1038-1042, September 2018.


https://ift.tt/2wEeNHd

Clinical Snippets

Experimental Dermatology, Volume 27, Issue 9, Page i-i, September 2018.


https://ift.tt/2ojRaQf

A Closely Associated Phospholipase C Regulates Cation Channel Function through Phosphoinositide Hydrolysis

In the hemaphroditic sea snail, Aplysia californica, reproduction is initiated when the bag cell neurons secrete egg-laying hormone during a protracted afterdischarge. A source of depolarization for the afterdischarge is a voltage-gated, nonselective cation channel, similar to transient receptor potential (TRP) channels. Once the afterdischarge is triggered, phospholipase C (PLC) is activated to hydrolyze phosphatidylinositol-4,5-bisphosphate (PIP₂) into diacylglycerol (DAG) and inositol trisphosphate (IP₃). We previously reported that a DAG analog, 1-oleoyl-2-acetyl-sn-glycerol (OAG), activates a prominent, inward whole-cell cationic current that is enhanced by IP₃. To examine the underlying mechanism, we investigated the effect of exogenous OAG and IP₃, as well as PLC activation, on cation channel activity and voltage dependence in excised, inside-out patches from cultured bag cell neurons. OAG transiently elevated channel open probability (P_O) when applied to excised patches; however, coapplication of IP₃ prolonged the OAG-induced response. In patches exposed to OAG and IP₃, channel voltage dependence was left-shifted; this was also observed with OAG, but not to the same extent. Introducing the PLC activator, m-3M3FBS, to patches increased channel P_O, suggesting PLC may be physically linked to the channels. Accordingly, blocking PLC with U-73122 ablated the m-3M3FBS-induced elevation in P_O. Treatment with m-3M3FBS left-shifted cation channel voltage dependence to a greater extent than exogenous OAG and IP₃. Finally, OAG and IP₃ potentiated the stimulatory effect of PKC, which is also associated with the channel. Thus, the PLC-PKC signaling system is physically localized such that PIP₂ breakdown products liberated during the afterdischarge modulate the cation channel and temporally influence neuronal activity.

SIGNIFICANCE STATEMENT Using excised patches from Aplysia bag cell neurons, we present the first evidence of a nonselective cation channel physically associating with phospholipase C (PLC) at the single-channel level. PLC-mediated breakdown of phospholipids generates diacylglycerol and inositol trisphosphate, which activate the cation channel. This is mimicked by exogenous lipids; furthermore, these second messengers left-shift channel voltage dependence and enhance the response of the channel to protein kinase C. PLC-mediated lipid signaling controls single-channel currents to ensure depolarization is maintained for an extended period of firing, termed the afterdischarge, when the bag cell neurons secrete egg-laying hormone to trigger reproduction.

https://ift.tt/2POuMew

Identification of VAPA and VAPB as Kv2 Channel-Interacting Proteins Defining Endoplasmic Reticulum-Plasma Membrane Junctions in Mammalian Brain Neurons

Membrane contacts between endoplasmic reticulum (ER) and plasma membrane (PM), or ER-PM junctions, are ubiquitous in eukaryotic cells and are platforms for lipid and calcium signaling and homeostasis. Recent studies have revealed proteins crucial to the formation and function of ER-PM junctions in non-neuronal cells, but little is known of the ER-PM junctions prominent in aspiny regions of mammalian brain neurons. The Kv2.1 voltage-gated potassium channel is abundantly clustered at ER-PM junctions in brain neurons and is the first PM protein that functions to organize ER-PM junctions. However, the molecular mechanism whereby Kv2.1 localizes to and remodels these junctions is unknown. We used affinity immunopurification and mass spectrometry-based proteomics on brain samples from male and female WT and Kv2.1 KO mice and identified the resident ER vesicle-associated membrane protein-associated proteins isoforms A and B (VAPA and VAPB) as prominent Kv2.1-associated proteins. Coexpression with Kv2.1 or its paralog Kv2.2 was sufficient to recruit VAPs to ER-PM junctions. Multiplex immunolabeling revealed colocalization of Kv2.1 and Kv2.2 with endogenous VAPs at ER-PM junctions in brain neurons from male and female mice in situ and in cultured rat hippocampal neurons, and KO of VAPA in mammalian cells reduces Kv2.1 clustering. The association of VAPA with Kv2.1 relies on a "two phenylalanines in an acidic tract" (FFAT) binding domain on VAPA and a noncanonical phosphorylation-dependent FFAT motif comprising the Kv2-specific clustering or PRC motif. These results suggest that Kv2.1 localizes to and organizes neuronal ER-PM junctions through an interaction with VAPs.

SIGNIFICANCE STATEMENT Our study identified the endoplasmic reticulum (ER) proteins vesicle-associated membrane protein-associated proteins isoforms A and B (VAPA and VAPB) as proteins copurifying with the plasma membrane (PM) Kv2.1 ion channel. We found that expression of Kv2.1 recruits VAPs to ER-PM junctions, specialized membrane contact sites crucial to distinct aspects of cell function. We found endogenous VAPs at Kv2.1-mediated ER-PM junctions in brain neurons and other mammalian cells and that knocking out VAPA expression disrupts Kv2.1 clustering. We identified domains of VAPs and Kv2.1 necessary and sufficient for their association at ER-PM junctions. Our study suggests that Kv2.1 expression in the PM can affect ER-PM junctions via its phosphorylation-dependent association to ER-localized VAPA and VAPB.

https://ift.tt/2POpwHt

A pancreatic zone at higher risk of fistula after enucleation

Abstract

Background

To determine predictive factors of postoperative pancreatic fistula (POPF) in patients undergoing enucleation (EN).

Methods

From 2005 to 2017, 47 patients underwent EN and had magnetic resonance imaging available for precise analysis of tumor location. Three pancreatic zones were delimited by the right side of the portal vein and the main pancreatic head duct (zone #3 comprising the lower head parenchyma and the uncinate process).

Results

The mortality and morbidity rates were 0% and 62%, respectively. POPF occurred in 23 patients (49%) and was graded as B or C (severe) in 15 patients (32%). Four patients (8.5%) developed a postoperative hemorrhage, and 5 patients (11%) needed a reintervention. In univariate and multivariate analyses, the pancreatic zone was the unique predictive factor of overall (P = .048) or severe POPF (P = .05). We did not observe any difference in postoperative courses when comparing the EN achieved in zones #1 and #2. We noted a longer operative duration (P = .016), higher overall (P = .017) and severe POPF (P = .01) rates, and longer hospital stays (P = .04) when comparing the EN achieved in zone #3 versus that in zones #1 and #2. Patients who underwent EN in zone #3 had a relative risk of developing a severe POPF of 3.22 compared with patients who underwent EN in the two other pancreatic zones.

Conclusion

Our study identifies the lower head parenchyma and the uncinate process as a high-risk zone of severe POPF after EN. Patients with planned EN in this zone could be selected and benefit from preoperative and/or intraoperative techniques to reduce the severe POPF rate.

https://ift.tt/2wyvrI9

Pa. EMS agency crews to wear ballistic vests when responding to calls

The service will use the donation of nearly $15,000 to buy bulletproof vests for each of its full-time employees and additional vests for part-timers

https://ift.tt/2PPaOjG

Using Rapid Serial Visual Presentation to Measure Set-Specific Capture, a Consequence of Distraction While Multitasking

This method uses a dynamic visual display to index costs of distraction during visual search, including both "contingent attentional capture" and "set-specific capture," which is a cost of distraction that occurs when the participants maintain multiple search goals simultaneously. This method has revealed basic mechanisms and limitations of visual attention.

https://ift.tt/2oiQbjl

Daphnane diterpenes inhibit the metastatic potential of B16F10 murine melanoma cells in vitro and in vivo

Abstract

Background

Melanoma is one of the most invasive and aggressive types of cancer with a very poor prognosis. Surgery remains the most efficient treatment prior melanoma invasion and metastasis formation. However, therapy becomes a challenge once the cancer cells colonized other tissues. At present, there are two main classes of therapies acting with a certain efficiency on metastatic melanoma: immune check point inhibitors (anti-PD1/PDL1) and targeted therapy such as Vemurafenib. Unfortunately, these therapies are not fully responsive, induce resistance and/or generate unwanted side effects. In this respect, it is important to continue to discover new cancer therapeutics. Here, we show that daphnane diterpenes type of compounds can prevent melanoma metastasis by inhibiting metastasis-associated matrix metalloproteinases expression without cytotoxicity.

Methods

Evaluation of the anti-metastasis effect of daphnane diterpenes-rich Thymelaea hirsuta extract (TH) and its bioactive component gnidilatidin was carried out in vitro using B16 murine melanoma cells and in vivo using male C57BL/6 J mice. Global gene expression in B16 cells was done using DNA microarray, validated using real-time PCR, to further understand the effect of daphnane diterpenes, specifically daphnane diterpenoid gnidilatidin.

Results

Oral administration of daphnane diterpenes-rich Thymelaea hirsuta extract (TH) suppressed MMP2 and MMP9 expression, decreasing lung tumor in mice injected with B16 murine melanoma cells. Validation of these observations in vitro showed reduced B16 cells migration, adhesion, and invasion. Results of microarray analysis of B16 cells treated with daphnane diterpenoid gnidilatidin from TH revealed an upregulation of tumor suppressor Egr1 while inhibiting metastasis-associated genes Id2 and Sytl2 expression. A downregulation of the melanoma oncogene microphthalmia-associated transcription factor (Mitf) was observed, and most likely caused by the inhibition of Id2, a gene that regulated HLH transcription factors such as MITF and also reported to promote tumor cell migration and invasion.

Conclusions

Daphnane diterpenes have inhibitory effect on the metastatic potential of B16 melanoma cells, and the results of this study provided evidence for their potential for use in the prevention and inhibition of melanoma metastasis.

https://ift.tt/2NsCppm

Knockdown of TIPE2 increases the proliferation in lipopolysaccharide-stimulated gastric cancer cells

Abstract

Background

Gastric cancer (GC) is one of the most common malignant diseases with high morbidity and mortality, especially in Asian countries. During the GC developing progress, TIPE2, a member of TNF-alpha induced protein 8-like (TNFAIP8L) family, may play important roles. However, the molecular mechanisms of TIPE2 contributing to cell proliferation and tumor growth are poorly understood in GC. We performed flow cytometry to detect the cell cycle of TIPE2-knockdown GC cells under lipopolysaccharide (LPS) stimulation.

Methods

We measured TIPE2 expression in tumor samples from 46 human GC patients at mRNA level by Realtime PCR and in 68 pairs of GC tissues at protein level by immunohistochemistry. We established stable TIPE2 knockdown SGC7901 and BGC823 cell lines and performed CCK-8 and EdU proliferation assays under the stimulation of LPS. And then we analyzed AKT, IκBα and ERK phosphorylation levels, as well as cycle related proteins CDK4 and CyclinD3 in the stable TIPE2 knockdown SGC7901 and BGC823 cells.

Results

Our present studies indicated that the expression of TIPE2 was significantly decreased in tumor tissues compared to distant mucosa tissues in human GC patients. TIPE2 inhibited proliferation stimulated by LPS in SGC7901 and BGC823 cells. Silencing of TIPE2 significantly decreased cell G₀/G₁ phase ratio and increased G₂/M phase. TIPE2 knockdown SGC7901 and BGC823 cells declined AKT and IκBα phosphorylation. TIPE2's action on GC cell cycle was.

Conclusions

Our results demonstrated that TIPE2 is a novel tumor suppressor gene that inhibits GC growth may mediated via AKT and IκBα phosphorylated activation. We revealed that TIPE2 may effectively interdict neoplasm development, which has potential clinical application values for GC targeted therapies.

https://ift.tt/2omNGg0