Τρίτη, 22 Ιανουαρίου 2019

Unknown primary (CUP) of the head and neck : No advantages of bilateral radiotherapy, the strategy of ipsilateral radiotherapy can be recommended for the adjuvant treatment

Bilateral vs ipsilateral adjuvant radiotherapy in patients with cancer of unknown primary of the head and neck: An analysis of the clinical outcome and radiation‐induced side effects
Nguyen‐Son Le  Stefan Janik MD, PhD  Helmut Simmel MD  Boban M. Erovic MD, PD, MBA
First published: 19 January 2019 https://doi.org/10.1002/hed.25637
This work was presented at the 61st Annual Meeting of the Austrian Society of Oto‐Rhino‐Laryngology – Head and Neck Surgery, Vienna, Austria

Abstract
Background
The purpose of this study was to analyze and compare ipsilateral and bilateral adjuvant radiotherapy in patients with cancer of unknown primary (CUP) of the head and neck.

Methods
Overall survival, recurrence‐free survival, and radiation‐induced side effects were assessed in 76 patients with CUP who underwent ipsilateral (n = 29) or bilateral (n = 47) radiotherapy.

Results
At a median follow‐up of 41 months, the 5‐year overall survival and recurrence‐free rate were 67.9% and 71.5%, respectively. No statistically significant difference between ipsilateral and bilateral radiotherapy could be found regarding 5‐year overall survival, recurrence‐free survival, occurrence of a primary tumor, and distant metastasis. The analysis of radiation‐induced acute side effects showed a significant benefit of ipsilateral radiotherapy.

Conclusion
As the main parameters of the study regarding the outcome and radiation‐induced side effects showed no advantages of bilateral radiotherapy, the strategy of ipsilateral radiotherapy can be recommended for the adjuvant treatment of CUP patients.

Acanthosis Nigricans & Metabolic Syndrome : Metabolic syndrome refers to a clustering of metabolic risk factors including central obesity, glucose intolerance, hyperinsulinemia, low HDL cholesterol, high triglycerides and hypertension. High prevalence of Acanthosis Nigricans (AN) in subjects with metabolic syndrome. Also there was a positive correlation between severity of Acanthosis Nigricans (AN) and Metabolic syndrome.

Acanthosis nigricans: A cutaneous marker for metabolic syndrome p. 16
Nirali Girish Shah, Swapna S Khatu, Neeta R Gokhale, Yuvraj E More, Deepak Khismatrao
DOI:10.4103/mjdrdypu.mjdrdypu_44_18  
Background: Acanthosis Nigricans (AN) is an easily identifiable dermatoses characterized by thickened, hyperpigmented plaques. Metabolic syndrome refers to a clustering of metabolic risk factors including central obesity, glucose intolerance, hyperinsulinemia, low HDL cholesterol, high triglycerides and hypertension. AN is a skin marker associated with this syndrome. Aims and Objectives: This study aimed to determine the relationship between AN and metabolic syndrome by studying its clinico-epidemiological features and also the relation of severity of AN over neck with metabolic syndrome. Methodology: This is a case-control study. One hundred consecutive patients of AN attending dermatology OPD of a tertiary care hospital were included in this study. They were evaluated for AN and severity of AN over neck was assessed. Age and sex matched 100 controls were included in the study. Epidemiological, clinical and anthropometric characteristics (height, weight, waist circumference) were measured of all the cases and controls. Body Mass Index (BMI) was calculated. Fasting Blood Sugar, High Density Lipoprotein and Serum Triglyceride levels were estimated. Result: The average age of the patients was 32.4 years and females (62%) were more than the males (38%). Neck was involved in all the patients. There was statistically significant correlation of increasing severity of AN with each component of Metabolic syndrome. On comparing between cases and controls, each component of metabolic syndrome was raised in cases as compared to the controls. 70% cases had Metabolic syndrome which was statistically significant. Conclusion: There was a high prevalence of AN in subjects with metabolic syndrome. Also there was a positive correlation between severity of AN and Metabolic syndrome.

Auxin-Inducible Depletion of the Essentialome Suggests Inhibition of TORC1 by Auxins and Inhibition of Vrg4 by SDZ 90-215, a Natural Antifungal Cyclopeptide

Gene knockout and knockdown strategies have been immensely successful probes of gene function, but small molecule inhibitors (SMIs) of gene products allow much greater time resolution and are particularly useful when the targets are essential for cell replication or survival. SMIs also serve as lead compounds for drug discovery. However, discovery of selective SMIs is costly and inefficient. The action of SMIs can be modeled simply by tagging gene products with an auxin-inducible degron (AID) that triggers rapid ubiquitylation and proteasomal degradation of the tagged protein upon exposure of live cells to auxin. To determine if this approach is broadly effective, we AID-tagged over 750 essential proteins in Saccharomyces cerevisiae and observed growth inhibition by low concentrations of auxin in over 66% of cases. Polytopic transmembrane proteins in the plasma membrane, Golgi complex, and endoplasmic reticulum were efficiently depleted if the AID-tag was exposed to cytoplasmic OsTIR1 ubiquitin ligase. The auxin analog 1-napthylacetic acid (NAA) was as potent as auxin on AID-tags, but surprisingly NAA was more potent than auxin at inhibiting target of rapamycin complex 1 (TORC1) function. Auxin also synergized with known SMIs when acting on the same essential protein, indicating that AID-tagged strains can be useful for SMI screening. Auxin synergy, resistance mutations, and cellular assays together suggest the essential GMP/GDP-mannose exchanger in the Golgi complex (Vrg4) as the target of a natural cyclic peptide of unknown function (SDZ 90-215). These findings indicate that AID-tagging can efficiently model the action of SMIs before they are discovered and can facilitate SMI discovery.



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Genome-Wide Studies of Rho5-Interacting Proteins That Are Involved in Oxidant-Induced Cell Death in Budding Yeast

Rho GTPases play critical roles in cell proliferation and cell death in many species. As in animal cells, cells of the budding yeast Saccharomyces cerevisiae undergo regulated cell death under various physiological conditions and upon exposure to external stress. The Rho5 GTPase is necessary for oxidant-induced cell death, and cells expressing a constitutively active GTP-locked Rho5 are hypersensitive to oxidants. Yet how Rho5 regulates yeast cell death has been poorly understood. To identify genes that are involved in the Rho5-mediated cell death program, we performed two complementary genome-wide screens: one screen for oxidant-resistant deletion mutants and another screen for Rho5-associated proteins. Functional enrichment and interaction network analysis revealed enrichment for genes in pathways related to metabolism, transport, and plasma membrane organization. In particular, we find that ATG21, which is known to be involved in the CVT (Cytoplasm-to-Vacuole Targeting) pathway and mitophagy, is necessary for cell death induced by oxidants. Cells lacking Atg21 exhibit little cell death upon exposure to oxidants even when the GTP-locked Rho5 is expressed. Moreover, Atg21 interacts with Rho5 preferentially in its GTP-bound state, suggesting that Atg21 is a downstream target of Rho5 in oxidant-induced cell death. Given the high degree of conservation of Rho GTPases and autophagy from yeast to human, this study may provide insight into regulated cell death in eukaryotes in general.



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Development of a Novel Mule Deer Genomic Assembly and Species-Diagnostic SNP Panel for Assessing Introgression in Mule Deer, White-Tailed Deer, and Their Interspecific Hybrids

Mule deer (Odocoileus hemionus) are endemic to a wide variety of habitats in western North America, many of which are shared in sympatry with their closely related sister-species white-tailed deer (Odocoileus virginianus), whom they hybridize with in wild populations. Although mule deer meet many ideal conditions for a molecular ecological research species, such as high abundance, ecological importance, and broad dispersal and gene flow, conservation genetic studies have been limited by a relative lack of existing genomic resources and inherent difficulties caused by introgression with white-tailed deer. Many molecular tools currently available for the study of cervids were designed using reference assemblies of divergent model species, specifically cattle (Bos taurus). Bovidae and Cervidae diverged approximately 28 million years ago, therefore, we sought to ameliorate the available resources by contributing the first mule deer whole genome sequence draft assembly with an average genome-wide read depth of 25X, using the white-tailed genome assembly (Ovir.te_1.0) as a reference. Comparing the two assemblies, we identified ~33 million single nucleotide polymorphisms (SNPs) and insertion/deletion variants. We then verified fixed SNP differences between the two species and developed a 40-loci SNP assay capable of identifying pure mule deer, white-tailed deer, and interspecific hybrids. Assignment capacity of the panel, which was tested on simulated datasets, is reliable up to and including the third backcross hybrid generation. Identification of post-F1 hybrids will be necessary for hybrid zone population studies going forward, and the new mule deer assembly will be a valuable resource for genetic and comparative genomics studies.



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Transcriptional Basis of Copper-Induced Olfactory Impairment in the Sea Lamprey, a Primitive Invasive Fish

Olfaction mediates behaviours necessary for survival and reproduction in fishes. Anthropogenic inputs of contaminants into aquatic environments, specifically copper, are known to disrupt a broad range of olfactory-mediated behaviours and can cause long-lasting damage even at low concentrations that have profound impacts on the biology of aquatic organisms. The sea lamprey (Petromyzon marinus) is a primitive fish species invasive to the North American Great Lakes that relies on olfaction to navigate during natal homing and in mate choice during reproduction. To investigate effects of copper on sea lamprey olfaction and the potential for maintenance of olfactory function during copper exposure, we exposed juvenile sea lamprey to environmentally ecologically relevant copper concentrations (0, 5, 10 and 30 µg/L) for 24 hours and characterized gene transcription response in olfactory tissue (i.e. peripheral olfactory organ and olfactory bulb) and forebrain using whole transcriptome sequencing. Copper exposure induced a pattern of positive dose-dependent transcriptional response. Expression changes primarily reflected up-regulation of genes involved in apoptosis and wound healing. Unlike higher vertebrates, genes specifically related to the olfactory senses of the sea lamprey, e.g. olfactory receptors, exhibited little transcriptional response to copper exposure, suggesting the mechanism of copper-induced olfactory impairment is through necrosis of the olfactory bulb and not copper-selective inhibition of olfactory receptors. Fully two-thirds of the differentially expressed genes at higher doses of copper have no known function and thus represent important candidates for further study of the responses to copper-induced olfactory injury. Our results shed light on the evolution of vertebrate olfactory repair mechanisms and have important implications for the conservation and management of both invasive and native populations of lamprey.



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Aegilops tauschii Genome Sequence: A Framework for Meta-analysis of Wheat QTLs

Numerous quantitative trait loci (QTLs) have been mapped in tetraploid and hexaploid wheat and wheat relatives, mostly with simple sequence repeat (SSR) or single nucleotide polymorphism (SNP) markers. To conduct meta-analysis of QTLs requires projecting them onto a common genomic framework, either a consensus genetic map or genomic sequence. The latter strategy is pursued here. Of 774 QTLs mapped in wheat and wheat relatives found in the literature, 585 (75.6%) were successfully projected onto the Aegilops tauschii pseudomolecules. QTLs mapped with SNP markers were more successfully projected (92.2%) than those mapped with SSR markers (66.2%). The QTLs were not distributed homogeneously along chromosome arms. Their frequencies increased in the proximal-to-distal direction but declined in the most distal regions and were weakly correlated with recombination rates along the chromosome arms. Databases for projected SSR markers and QTLs were constructed and incorporated into the Ae. tauschii JBrowse. To facilitate meta-QTL analysis, eight clusters of QTLs were used to estimate standard deviations (ô) of independently mapped QTLs projected onto the Ae. tauschii genome sequence. The standard deviations ô were modeled as an exponential decay function of recombination rates along the Ae. tauschii chromosomes. We implemented four hypothesis tests for determining the membership of query QTLs. The hypothesis tests and estimation procedure for were implemented in a web portal for meta-analysis of projected QTLs. Twenty-one QTLs for fusarium head blight resistance mapped on wheat chromosomes 3A, 3B, and 3D were analyzed to illustrate the use of the portal for meta-QTL analyses.



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PharmGKB summary: Ondansetron and tropisetron pathways, pharmacokinetics and pharmacodynamics

No abstract available

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DNA methylation is associated with improvement in lung function on inhaled corticosteroids in pediatric asthmatics

Asthma is the most common chronic disease in children. Inhaled corticosteroids (ICS) are the first-line treatment for asthma control, but up to one-third of children have a poor treatment response. The mechanism of ICS resistance is poorly understood, and the role of DNA methylation in ICS treatment response is not known. We examined the association between peripheral blood DNA methylation and ICS treatment response in 152 pediatric persistent asthmatics from the Childhood Asthma Management Program. Response to ICS was measured by the percentage change in forced expiratory volume in 1 s (FEV1) 8 weeks after treatment initiation. The top CpG sites with a nominal P value less than 0.001 were correlated with gene expression using Pearson's and partial correlations. In 152 participants, mean±SD age was 9.8±2.0 years and median change in FEV1 after ICS initiation was 4.6% (interquartile range: 10.4%). A total of 545 CpG sites were differentially methylated (nominal P

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Won't You Write Me a Letter?

"Write Me a Letter." Do a quick internet search of this sentence. You'll discover many songs with this title. Aerosmith, the American rock band, recorded this song written by the dynamic and frenetic Steven Tyler. There are lesser known examples. A group called BZN recorded a song by this title, included in their album "Reflections." The Blossoms recorded a different song by the same title in 1961. A more contemporary group called Rusty Cage recorded their song, "Write Me a Letter" on their Gangstalkers album, released in 2018.

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The Size of Well Differentiated Pancreatic Neuroendocrine Tumors Correlates with Ki67 Proliferative Index and is not Associated with Age

Concerns exist about a conservative management of well-differentiated nonfunctioning small pancreatic neuroendocrine tumors (NF-PanNET) in young patients and when preoperative Ki67 proliferative index is ≥3%.

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Comparison of EUS-guided versus percutaneous and transjugular approaches for the performance of liver biopsies

Liver biopsy through endoscopic ultrasound (EUS) has become a novel approach for tissue acquisition. We aim to evaluate the adequacy of EUS-guided liver biopsies in comparison to those obtained through interventional radiology (IR) techniques.

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Correlation between endoscopic and histological validated scoring indices in Crohn's disease

It is of crucial importance to evaluate disease activity by means of endoscopy and histopathology in Crohn's disease (CD). Nonetheless, correlation between endoscopic and histological validated indices has not been verified.

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Intensivist staffing and outcome in the ICU: daytime, nighttime, 24/7?

Purpose of review Many hospitals, particularly large academic centers, have begun to provide 24-h in-house intensive care attending coverage. Proposed advantages for this model include improved patient care, greater provider, nursing and patient satisfaction, better communication, and greater cost-effectiveness. This review will evaluate current evidence with respect to 24/7 coverage, including patient outcomes, cost-effectiveness, and impact on training/education. Recent findings Evidence surrounding 24-h intensivist staffing has been mixed. Although a subset of studies suggest a possible benefit to 24-h intensivist coverage, recent prospective studies have shown no difference in major patient outcomes, including mortality and ICU length of stay between patients in ICUs with and those without 24-h intensivist coverage. Summary Although some studies cite increased caregiver and patient satisfaction, outcome studies find no consistent effect on patient-centered outcomes such as mortality or length of stay. Downsides to in-house nighttime attending staffing include physician burnout, adverse effects on physician health, decreased trainee autonomy, and effects on trainee specialty choices because of undesirable lifestyle considerations. Tele-ICU and other novel approaches may allow for attending supervision without physical presence. Correspondence to Avery Tung, MD, 5841 S Maryland Ave MC 4028, Chicago, IL 60637, USA. Tel: +1 (773) 834 7937; E-mail: atung@dacc.uchicago.edu Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Helicopter air ambulance services

Purpose of review Helicopter air ambulances are an integral component of modern trauma care, and are able to transport patients to facilities with greater capabilities, extract injured patients from hostile terrain, and speed transport to a trauma center. Recent findings HAA transport does not reduce the total time required to transport a patient, but it does reduce the time that the patient is between healthcare facilities. Factors that have been suggested to improve outcomes for trauma patients include the availability of advanced interventions, skilled personnel, speed, and trauma center access. Despite their potential benefits to the patient, HAA operations carry significant risks. HAA operations are among the most dangerous professions for both pilot and crew with a mortality rate greater than commercial fishing, loggers, and steelworkers. The US Federal Aviation Administration (FAA) has identified that the four most common causes of HAA accidents as inadvertent flight into instrument meteorological conditions, loss of control, controlled flight into terrain, and night conditions. Summary HAA operations are well tolerated and can improve patient care, but additional research is needed to improve our understanding of HAA operations and their effect on outcomes. Correspondence to Keith J. Ruskin, MD, FAsMA, FRAeS, Professor of Anesthesia and Critical Care and Biological Sciences Collegiate Division, Department of Anesthesia and Critical Care, University of Chicago, 5841 S. Maryland Avenue MC4028, Chicago, IL 60637, USA. Tel: +1 773 834 2369; e-mail: ruskin@uchicago.edu Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Burn injury and blood transfusion

Purpose of review Blood transfusion is ubiquitous in major burn injury. The present article describes recent research findings directly impacting blood transfusion strategies in major burn injury both in the operating room and the ICU. Recent findings Transfusion strategies have been the focus of recent burn investigations. First, a randomized prospective trial encompassing both the ICU and operating room reported that a restrictive red blood cell transfusion threshold (7 g/dl) had equivalent outcomes to a traditional threshold (10 g/dl) for burns more than 20% in terms of mortality, infection, length of stay, duration of mechanical ventilation, and wound healing despite receiving significantly fewer transfusions. The second burn transfusion advance addresses coagulation. Although burn patients initially have elevated fibrinogen, thrombocytopenia and other coagulation disorders develop during excision. Blood product repletion should be based on measurements such as thromboelastography in addition to traditional tests. Finally, a recent randomized trial suggests that fresh-frozen plasma and platelets during burn excision more than 20% may decrease transfusion requirements. Summary A restrictive transfusion practice during burn excision and grafting is well tolerated and effective in reducing the number of transfusions without increasing complications. Repletion of coagulation products should focus on measured deficits of platelets, fibrinogen, and factors. Correspondence to Tina L. Palmieri, 2425 Stockton Blvd, Suite 718, Sacramento, CA 95817, USA. Tel: +1-916-453-2050; fax: +1-916-453-2373; e-mail: tlpalmieri@ucdavis.edu Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Resuscitative endovascular balloon occlusion of the aorta: an option for noncompressible torso hemorrhage?

Purpose of review Hemorrhage is the major cause of early death in severely injured patients. In civilian emergency medical services, the majority of life-threatening bleedings are found in noncompressible body regions (e.g. abdomen and pelvis). Resuscitative endovascular balloon occlusion of the aorta (REBOA) has therefore been discussed in recent years as a possible lifesaving procedure and numerous studies, meta-analyses and guidelines have been published. In this review, the data situation of REBOA in the management of bleeding trauma patients is discussed and practical implementation is depicted. Recent findings The typical indication for REBOA is a traumatic life-threatening hemorrhage below the diaphragm in patients unresponsive or only transiently responsive to the usual conservative therapeutic measures. REBOA appears to be a safe and effective procedure to reduce blood loss and stabilize the patient's hemodynamic status. However, surgical hemostasis has to be achieved within 30–60 min after occlusion of the aorta. Data on clear advantages of REBOA over resuscitative thoracostomy are inconclusive. Summary REBOA could play an important role in the management of the severely bleeding patient in the future. Together with transfusion and therapy of coagulation disorders, REBOA may be an additional tool in the anesthetist's hands for trauma management in interprofessional care concepts. Correspondence to Dr Jürgen Knapp, Department of Anaesthesiology and Pain Medicine, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse, 3010 Bern, Switzerland. Tel: +41 31 632 04 96; e-mail: juergen.knapp@insel.ch Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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The use of new procoagulants in blunt and penetrating trauma

Purpose of review Uncontrolled bleeding in trauma secondary to a combination of surgical bleeding and trauma-induced complex coagulopathy is a leading cause of death. Prothrombin complex concentrates (PCCs), recombinant activated factor seven (rFVIIa) and recombinant human prothrombin act as procoagulants by increasing thrombin generation and fibrinogen concentrate aids stable clot formation. This review summarizes current evidence for procoagulant use in the management of bleeding in trauma, and data and evidence gaps for routine clinical use. Recent findings Retrospective and prospective studies of PCCs (±fibrinogen concentrate) have demonstrated a decreased time to correction of trauma coagulopathy and decreased red cell transfusion with no obvious effect on mortality or thromboembolic outcomes. PCCs in a porcine model of dilutional coagulopathy demonstrated a sustained increase in thrombin generation, unlike recombinant human prothrombin which showed a transient increase and has been studied only in animals. In other retrospective studies, there is a suggestion that lower doses of PCCs may be effective in the setting of acquired coagulopathy. Summary There is increasing evidence that early correction of coagulopathy has survival benefits, and the use of procoagulants as first-line therapy has the potential benefit of rapid access and timely treatment. This requires confirmation in prospective studies. Correspondence to Pratima Chowdary, Consultant Haematologist, KD Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London, UK;. e-mails: p.chowdary@nhs.net, p.chowdary@ucl.ac.uk Copyright © 2019 YEAR Wolters Kluwer Health, Inc. All rights reserved.

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Dysfunction of GRAP, encoding the GRB2-related adaptor protein, is linked to sensorineural hearing loss [Genetics]

We have identified a GRAP variant (c.311A>T; p.Gln104Leu) cosegregating with autosomal recessive nonsyndromic deafness in two unrelated families. GRAP encodes a member of the highly conserved growth factor receptor-bound protein 2 (GRB2)/Sem-5/drk family of proteins, which are involved in Ras signaling; however, the function of the growth factor receptor-bound protein...

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Disruption of RPGR protein interaction network is the common feature of RPGR missense variations that cause XLRP [Genetics]

Retinitis pigmentosa (RP) is an inherited retinal degenerative disease with severe vision impairment leading to blindness. About 10–15% of RP cases are caused by mutations in the RPGR gene, with RPGR mutations accounting for 70% of X-linked RP cases. The mechanism by which RPGR mutations cause photoreceptor cell dysfunction is...

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The harmonic mean p-value for combining dependent tests [Genetics]

Analysis of "big data" frequently involves statistical comparison of millions of competing hypotheses to discover hidden processes underlying observed patterns of data, for example, in the search for genetic determinants of disease in genome-wide association studies (GWAS). Controlling the familywise error rate (FWER) is considered the strongest protection against false...

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Letter to the Editor regarding Paganoni S: Evidence-based physiatry; managing low back pain wisely.: Am J Phys Med Rehabil: 2018;97:85

No abstract available

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Possible contributions of ipsilateral pathways from the contralesional motor cortex to the voluntary contraction of the spastic elbow flexors in stroke survivors: a TMS study

Objective The contribution of the contralesional motor cortex to the impaired limbs is still controversial. The purpose of this study was to investigate the role of descending projections from the contralesional hemisphere during voluntary elbow flexion on the paretic side. Design Eleven healthy and 10 stroke subjects performed unilateral isometric elbow flexion tasks at various submaximal levels. Transcranial magnetic stimulation (TMS) was delivered to the hot spot of biceps muscles ipsilateral to the target side (paretic side in stroke subjects or right side in controls) at rest and during elbow flexion tasks. Motor evoked potential (MEP) amplitudes of the contralateral resting biceps muscles, TMS-induced ipsilateral force increment, and reflex torque and weakness of spastic elbow flexors were quantified. Results The normalized MEP amplitude increased with force level in both healthy and stroke subjects. However, stroke subjects exhibited significantly higher force increment compared with healthy subjects only at low level of elbow flexion, but similar at moderate to high levels. The greater force increment significantly correlated with reflex torque of the spastic elbow flexors, but not weakness. Conclusion These results provide novel evidence that ipsilateral projections are not likely to contribute to strength, but are correlated to spasticity of spastic-paretic elbow flexors after stroke. Correspondence: Sheng Li, MD, PhD, 1333 Moursund, Houston, TX 77030, Tel: 713-797-7125, E-mail: sheng.li@uth.tmc.edu Author Disclosures: Include an explanation of the following. Competing Interests: None. Funding or grants or equipment provided for the project from any source: This study was supported in part by NIH NICHD/NCMRR R21HD087128, R21HD090453. Financial benefits to the authors: None Details of any previous presentation of the research, manuscript, or abstract in any form: The study was selected for the Best Paper Award in the Fellow category, and was present at AAP 2018 annual meeting in Atlanta, GA on 2/15/2018. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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Reply to Letter to the Editor regarding Paganoni S: Evidence-based physiatry; managing low back pain wisely. Am J Phys Med Rehabil 2018;97: 85

No abstract available

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Human protein mutagens found via bacteria

Human protein mutagens found via bacteria

Human protein mutagens found via bacteria, Published online: 22 January 2019; doi:10.1038/s41576-019-0096-4

A new study published in Cell uses bacterial genetic screens to identify mutagenic proteins. Overexpression of homologues of these proteins in human cells has similar mutagenic effects and potential prognostic value in cancer.

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Publisher Correction: Challenges in unsupervised clustering of single-cell RNA-seq data

Publisher Correction: Challenges in unsupervised clustering of single-cell RNA-seq data

Publisher Correction: Challenges in unsupervised clustering of single-cell RNA-seq data, Published online: 22 January 2019; doi:10.1038/s41576-019-0095-5

Publisher Correction: Challenges in unsupervised clustering of single-cell RNA-seq data

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Contents

Publication date: February 2019

Source: Clinical Neurophysiology, Volume 130, Issue 2

Author(s):



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Editorial Board

Publication date: February 2019

Source: Clinical Neurophysiology, Volume 130, Issue 2

Author(s):



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Simpson–Golabi–Behmel syndrome with 46,XY disorders of sex development: A case report

Abstract

We present a case of a Chinese child with X‐linked Simpson–Golabi–Behmel syndrome (SGBS). To the best of our knowledge, this is the first report of 46,XY disorders of sex development (ambiguous genitalia, cryptorchidism, and uterus in the pelvis) in surviving SGBS patients. Other external anomalies included characteristic facial anomalies, overgrowth, macrocephaly, organomegaly, pectus excavatum, and cryptorchidism. It could be that the GPC3 gene mutation caused Leydig cell dysfunction in our patient. Disorders of sex development can be included as part of the clinical spectrum of SGBS.



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Bladder overactivity and afferent hyperexcitability induced by prostate‐to‐bladder cross‐sensitization in rats with prostatic inflammation

Key points

There is clinical evidence showing that prostatic inflammation contributes to overactive bladder symptoms in male patients; however, little is known about the underlying mechanisms. In this study, we investigated the mechanism that prostatic inflammation causes detrusor overactivity by using a rat model of chemically induced prostatic inflammation. We observed a significant number of dorsal root ganglion neurons with dichotomized afferents innervating both prostate and bladder. We also found that prostatic inflammation induces bladder overactivity and urothelial NGF overexpression in the bladder, which are dependent on activation of the pelvic nerve, as well as changes in ion channel expression and hyperexcitability of bladder afferent neurons. These results indicate that the prostate‐to‐bladder cross‐sensitization through primary afferent pathways in the pelvic nerve, which contain dichotomized afferents, would be an important mechanism contributing to bladder overactivity and afferent hyperexcitability induced by prostatic inflammation.

Abstract

Prostatic inflammation is reportedly an important factor inducing lower urinary tract symptoms (LUTS) including urinary frequency, urgency and incontinence in patients with benign prostatic hyperplasia (BPH). However, the underlying mechanisms inducing bladder dysfunction after prostatic inflammation are not well clarified. We therefore investigated the effects of prostatic inflammation on bladder activity and afferent function using a rat model of non‐bacterial prostatic inflammation. We here demonstrated that bladder overactivity, evident as decreased voided volume and shorter intercontraction intervals in cystometry, was observed in rats with prostatic inflammation versus controls. Tissue inflammation, evident as increased myeloperoxidase activity, IL‐1α, IL‐1β, and IL‐6 levels inside the prostate, but not in the bladder, induced an increase NGF expression in the bladder urothelium, which depended on activation of the pelvic nerve, in rats with prostatic inflammation. A significant proportion (18‐19%) of dorsal root ganglion neurons was double labelled by dye tracers injected to either bladder or prostate. In rats with prostatic inflammation, TRPV1, TRPA1 and P2 × 2 were increased, Kv1.4, a potassium channel α‐subunit that can form A‐type potassium (KA) channels, was decreased at mRNA levels in bladder afferent and double‐labelled neurons vs. non‐labelled neurons, and slow KA current density was decreased in association with hyperexcitability of these neurons. Collectively, non‐bacterial inflammation localized in the prostate induces bladder overactivity and enhances bladder afferent function. Thus, prostate‐to‐bladder afferent cross‐sensitization through primary afferents in the pelvic nerve, which contain dichotomized afferents, could underlie storage LUTS in symptomatic BPH with prostatic inflammation.

This article is protected by copyright. All rights reserved



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Publisher Correction: Challenges in unsupervised clustering of single-cell RNA-seq data



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Saving Sevoflurane: Automated gas control can reduce consumption of anesthetic vapor by one third in pediatric anesthesia

Abstract

Background

Many modern anesthetic machines offer automated control of anesthetic vapor. The user simply sets a desired end‐tidal concentration and the machine will manipulate the vaporizer and gas flow rates to obtain and maintain the pre set target. The aim of this software is to allow greater efficiency, and more accurate delivery of anesthetic vapor during anesthesia. These benefits have been documented across multiple machines within the adult setting(1,2,3,4) however there is little evidence for their use in children.

Aim

To compare the consumption of sevoflurane using the Maquet Flow‐i anesthesia machine (Maquet, Solna, Sweden) in automatic gas control (AGC) mode versus manual mode in pediatric anesthesia. The primary outcome measure is rate of sevoflurane use.

Method

Data logs were collected from our three Maquet Flow‐i anesthesia machines over a four‐week period. We compared the rate of sevoflurane use when in manual mode versus cases where AGC mode was used. We also examined each AGC case to determine whether percentage of anesthesia time in this mode correlated significantly with average rate of sevoflurane consumption.

Results

Sevoflurane was the primary anesthetic used in 220 cases, comprising over 230 hours of anesthesia time. Of these, 36 cases were identified as AGC cases and 184 as manual cases.

Consumption of sevoflurane liquid in ml/min was significantly lower in AGC cases (median 0.46, IQR 0.32 to 0.72 ml/min for AGC; median 0.82, IQR 0.62 to 1.17 ml/min for manual; p<0.001 by Wilcoxon Rank Sum test). For a case of median duration (49minutes), average rate of sevoflurane liquid consumption was 0.54 ml/min for AGC cases versus 0.81 ml/min for manual cases, a reduction of 33% (bootstrapped 95%CI 0.21 to 0.61 ml/min, p<0.001).

We also identified an inverse correlation between the rate of sevoflurane consumption and the percentage of the anesthesia time for which AGC mode was utilized, increasing the use of automatic gas control from 30% to 90% of anesthetic time was associated with a fall in rate of sevoflurane liquid consumption from 0.73 ml/min to 0.35 ml/min, a reduction of 52% (bootstrapped 95%CI 0.17 to 0.66 ml/min, p<0.001 for the trend).

Conclusion

Maquet's Flow‐i automatic gas control mode reduced use of sevoflurane an average of one third in a pediatric anesthesia setting.

This article is protected by copyright. All rights reserved.



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Hemodynamic monitoring in children with heart disease: Overview of newer technologies

Abstract

Every day, hundreds of children around the world undergo some form of heart surgery. Safely seeing a patient through the complexities of paediatric cardiac surgery requires a range of skills, many of which are based on use and interpretation of standard clinical monitoring. However, these monitors are unable to tell us about absolute cardiac output, or whether the current cardiovascular state is adequate to the patient's needs.

This article is protected by copyright. All rights reserved.



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Sex differences in interleukin‐6 stress responses in people with Type 2 diabetes

Abstract

People with Type 2 diabetes (T2D) show dysregulated inflammatory responses to acute stress, but the effect of sex on inflammatory responses in T2D remains unclear. The purpose of this study was to investigate differences in interleukin (IL)‐6 stress responses between older men and women with T2D. One hundred and twenty‐one people (76 men; mean age = 64.09, SD = 7.35, 45 women; mean age = 63.20, SD = 6.70) with doctor‐verified T2D took part in this laboratory‐based stress testing study. Participants carried out acute mental stress tasks, and blood was sampled at baseline, immediately poststress, 45 min poststress, and 75 min poststress to detect plasma IL‐6 concentrations. IL‐6 change scores were computed as the difference between the baseline measurement and the three time points poststress. Main effects and interactions were tested using mixed model analysis of covariance. We found a significant main effect of time on IL‐6 levels, and a significant Sex × Time interaction. In adjusted analyses including the three change scores and all the covariates, the significant Sex × Time interaction was maintained; IL‐6 responses were greater in women at 45 and 75 min poststress compared with men, adjusting for age, body mass index, smoking, household income, glycated hemoglobin, oral antidiabetic medication, insulin/other injectable antidiabetic medication, depressive symptoms, and time of day of testing. Different inflammatory stress response pathways are present in men and women with T2D, with women producing larger IL‐6 increases. The long‐term implications of these differences need to be elucidated in future studies.



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Leveraging linkage evidence to identify low-frequency and rare variants on 16p13 associated with blood pressure using TOPMed whole genome sequencing data

Abstract

In this study, we investigated low-frequency and rare variants associated with blood pressure (BP) by focusing on a linkage region on chromosome 16p13. We used whole genome sequencing (WGS) data obtained through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program on 395 Cleveland Family Study (CFS) European Americans (CFS-EA). By analyzing functional coding variants and non-coding rare variants with CADD score > 10 residing within the chromosomal region in families with linkage evidence, we observed 25 genes with nominal statistical evidence (burden or SKAT p < 0.05). One of the genes is RBFOX1, an evolutionarily conserved RNA-binding protein that regulates tissue-specific alternative splicing that we previously reported to be associated with BP using exome array data in CFS. After follow-up analysis of the 25 genes in ten independent TOPMed studies with individuals of European, African, and East Asian ancestry, and Hispanics (N = 29,988), we identified variants in SLX4 (p = 2.19 × 10−4) to be significantly associated with BP traits when accounting for multiple testing. We also replicated the associations previously reported for RBFOX1 (p = 0.007). Follow-up analysis with GTEx eQTL data shows SLX4 variants are associated with gene expression in coronary artery, multiple brain tissues, and right atrial appendage of the heart. Our study demonstrates that linkage analysis of family data can provide an efficient approach for detecting rare variants associated with complex traits in WGS data.



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Translating cancer genomics into precision medicine with artificial intelligence: applications, challenges and future perspectives

Abstract

In the field of cancer genomics, the broad availability of genetic information offered by next-generation sequencing technologies and rapid growth in biomedical publication has led to the advent of the big-data era. Integration of artificial intelligence (AI) approaches such as machine learning, deep learning, and natural language processing (NLP) to tackle the challenges of scalability and high dimensionality of data and to transform big data into clinically actionable knowledge is expanding and becoming the foundation of precision medicine. In this paper, we review the current status and future directions of AI application in cancer genomics within the context of workflows to integrate genomic analysis for precision cancer care. The existing solutions of AI and their limitations in cancer genetic testing and diagnostics such as variant calling and interpretation are critically analyzed. Publicly available tools or algorithms for key NLP technologies in the literature mining for evidence-based clinical recommendations are reviewed and compared. In addition, the present paper highlights the challenges to AI adoption in digital healthcare with regard to data requirements, algorithmic transparency, reproducibility, and real-world assessment, and discusses the importance of preparing patients and physicians for modern digitized healthcare. We believe that AI will remain the main driver to healthcare transformation toward precision medicine, yet the unprecedented challenges posed should be addressed to ensure safety and beneficial impact to healthcare.



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Human protein mutagens found via bacteria



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Food-First Approach to Enhance the Regulation of Post-exercise Skeletal Muscle Protein Synthesis and Remodeling

Abstract

Protein recommendations are provided on a daily basis as defined by the recommended dietary allowance (RDA) at 0.80 g protein/kg/day. However, meal-based, as opposed to daily, dietary protein recommendations are likely more informative given the role of the daily protein distribution pattern in modulating the post-exercise muscle protein synthetic response. Current protein meal recommendations to plateau post-exercise muscle protein synthesis rates are based on the ingestion of isolated protein sources, and not protein-rich whole foods. It is generally more common to eat whole food sources of dietary protein within a normal eating pattern to meet dietary protein requirements. Yet, there is a need to define how dietary protein action on muscle protein synthesis rates can be modulated by other nutrients within a food matrix to achieve protein requirements for optimal muscle adaptations. Recent developments suggest that the identification of an "optimal" protein source should likely consider the characteristics of the protein and the food matrix in which it is consumed. This review aims to discuss recent concepts related to protein quality, and the potential interactive effects of the food matrix, to achieve optimal protein requirements and elicit a robust postprandial muscle protein synthetic response with an emphasis on the post-exercise recovery window.



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Exit Gluten-Free and Enter Low FODMAPs: A Novel Dietary Strategy to Reduce Gastrointestinal Symptoms in Athletes

Abstract

Exercise-associated physiological disturbances alter gastrointestinal function and integrity. These alterations may increase susceptibility to dietary triggers, namely gluten and a family of short-chain carbohydrates known as FODMAPs (fermentable oligo-, di-, monosaccharides and polyols). A recent surge in the popularity of gluten-free diets (GFDs) among athletes without celiac disease has been exacerbated by unsubstantiated commercial health claims and high-profile athletes citing this diet to be the secret to their success. Up to 41% of athletes at least partially adhere to a GFD diet, with the belief that gluten avoidance improves exercise performance and parameters influencing performance, particularly gastrointestinal symptoms (GIS). In contrast to these beliefs, seminal work investigating the effects of a GFD in athletes without celiac disease has demonstrated no beneficial effect of a GFD versus a gluten-containing diet on performance, gastrointestinal health, inflammation, or perceptual wellbeing. Interestingly, the subsequent reduction in FODMAPs concurrent with the elimination of gluten-containing grains may actually be the factors affecting GIS improvement, not gluten. Pre-existent in the gastrointestinal tract or ingested during exercise, the osmotic and gas-producing effects of variably absorbed FODMAPs may trigger or increase the magnitude of exercise-associated GIS. Research using FODMAP reduction to address gastrointestinal issues in clinically healthy athletes is emerging as a promising strategy to reduce exercise-associated GIS. Applied research and practitioners merging clinical and sports nutrition methods will be essential for the effective use of a low FODMAP approach to tackle the multifactorial nature of gastrointestinal disturbances in athletes.



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Fruit-Derived Polyphenol Supplementation for Athlete Recovery and Performance

Abstract

Polyphenols are characterised structurally by two or more hydroxyl groups attached to one or more benzene rings, and provide the taste and colour characteristics of fruits and vegetables. They are radical scavengers and metal chelators, but due to their low concentration in biological fluids in vivo their antioxidant properties seem to be related to enhanced endogenous antioxidant capacity induced via signalling through the Nrf2 pathway. Polyphenols also seem to possess anti-inflammatory properties and have been shown to enhance vascular function via nitric oxide-mediated mechanisms. As a consequence, there is a rationale for supplementation with fruit-derived polyphenols both to enhance exercise performance, since excess reactive oxygen species generation has been implicated in fatigue development, and to enhance recovery from muscle damage induced by intensive exercise due to the involvement of inflammation and oxidative damage within muscle. Current evidence would suggest that acute supplementation with ~ 300 mg polyphenols 1–2 h prior to exercise may enhance exercise capacity and/or performance during endurance and repeated sprint exercise via antioxidant and vascular mechanisms. However, only a small number of studies have been performed to date, some with methodological limitations, and more research is needed to confirm these findings. A larger body of evidence suggests that supplementation with > 1000 mg polyphenols per day for 3 or more days prior to and following exercise will enhance recovery following muscle damage via antioxidant and anti-inflammatory mechanisms. The many remaining unanswered questions within the field of polyphenol research and exercise performance and recovery are highlighted within this review article.



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From Paper to Podium: Quantifying the Translational Potential of Performance Nutrition Research

Abstract

Sport nutrition is one of the fastest growing and evolving disciplines of sport and exercise science, demonstrated by a 4-fold increase in the number of research papers between 2012 and 2018. Indeed, the scope of contemporary nutrition-related research could range from discovery of novel nutrient-sensitive cell-signalling pathways to the assessment of the effects of sports drinks on exercise performance. For the sport nutrition practitioner, the goal is to translate innovations in research to develop and administer practical interventions that contribute to the delivery of winning performances. Accordingly, step one in the translation of research to practice should always be a well-structured critique of the translational potential of the existing scientific evidence. To this end, we present an operational framework (the "Paper-2-Podium Matrix") that provides a checklist of criteria for which to prompt the critical evaluation of performance nutrition-related research papers. In considering the (1) research context, (2) participant characteristics, (3) research design, (4) dietary and exercise controls, (5) validity and reliability of exercise performance tests, (6) data analytics, (7) feasibility of application, (8) risk/reward and (9) timing of the intervention, we aimed to provide a time-efficient framework to aid practitioners in their scientific appraisal of research. Ultimately, it is the combination of boldness of reform (i.e. innovations in research) and quality of execution (i.e. ease of administration of practical solutions) that is most likely to deliver the transition from paper to podium.



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Phytochemicals for Improving Aspects of Cognitive Function and Psychological State Potentially Relevant to Sports Performance

Abstract

Subjective alertness and optimal cognitive function, including in terms of attention, spatial/working memory and executive function, are intrinsic to peak performance in many sports. Consumption of a number of plant-derived 'secondary metabolite' phytochemicals can modulate these psychological parameters, although there is a paucity of evidence collected in a sporting context. The structural groups into which these phytochemicals fall—phenolics, terpenes and alkaloids—vary in terms of the ecological roles they play for the plant, their toxicity and the extent to which they exert direct effects on brain function. The phenolics, including polyphenols, play protective roles in the plant, and represent a natural, benign component of the human diet. Increased consumption has been shown to improve cardiovascular function and is associated with long-term brain health. However, whilst short-term supplementation with polyphenols has been shown to consistently modulate cerebral blood-flow parameters, evidence of direct effects on cognitive function and alertness/arousal is currently comparatively weak. Terpenes play both attractant and deterrent roles in the plant, and typically occur less frequently in the diet. Single doses of volatile monoterpenes derived from edible herbs such as sage (Salvia officinalis/lavandulaefolia) and peppermint (Mentha piperita), diterpene-rich Ginkgo biloba extracts and triterpene-containing extracts from plants such as ginseng (Panax ginseng/quinquefolius) and Bacopa monnieri have all been shown to enhance relevant aspects of cognitive function and alertness. The alkaloids play toxic defensive roles in the plant, including via interference with herbivore brain function. Whilst most alkaloids are inappropriate in a sporting context due to toxicity and legal status, evidence suggests that single doses of nicotine and caffeine may be able to enhance relevant aspects of cognitive function and/or alertness. However, their benefits may be confounded by habituation and withdrawal effects in the longer term. The efficacy of volatile terpenes, triterpene-rich extracts and products combining low doses of caffeine with other phytochemicals deserves more research attention.



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Heat, Hydration and the Human Brain, Heart and Skeletal Muscles

Abstract

People undertaking prolonged vigorous exercise experience substantial bodily fluid losses due to thermoregulatory sweating. If these fluid losses are not replaced, endurance capacity may be impaired in association with a myriad of alterations in physiological function, including hyperthermia, hyperventilation, cardiovascular strain with reductions in brain, skeletal muscle and skin blood perfusion, greater reliance on muscle glycogen and cellular metabolism, alterations in neural activity and, in some conditions, compromised muscle metabolism and aerobic capacity. The physiological strain accompanying progressive exercise-induced dehydration to a level of ~ 4% of body mass loss can be attenuated or even prevented by: (1) ingesting fluids during exercise, (2) exercising in cold environments, and/or (3) working at intensities that require a small fraction of the overall body functional capacity. The impact of dehydration upon physiological function therefore depends on the functional demand evoked by exercise and environmental stress, as cardiac output, limb blood perfusion and muscle metabolism are stable or increase during small muscle mass exercise or resting conditions, but are impaired during whole-body moderate to intense exercise. Progressive dehydration is also associated with an accelerated drop in perfusion and oxygen supply to the human brain during submaximal and maximal endurance exercise. Yet their consequences on aerobic metabolism are greater in the exercising muscles because of the much smaller functional oxygen extraction reserve. This review describes how dehydration differentially impacts physiological function during exercise requiring low compared to high functional demand, with an emphasis on the responses of the human brain, heart and skeletal muscles.



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Reflecting on Eliud Kipchoge’s Marathon World Record: An Update to Our Model of Cooperative Drafting and Its Potential for a Sub-2-Hour Performance



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