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Η φωτογραφία μου
Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com, https://plus.google.com/communities/115462130054650919641?sqinv=VFJWaER0c2NCRl9ERzRjZWhxQmhzY09kVV84cjRn , ,https://plus.google.com/u/0/+AlexandrosGSfakianakis , https://www.youtube.com/channel/UCQH21WX8Qn5YSTKrlJ3OrmQ , https://www.youtube.com/channel/UCTREJHxB6yt4Gaqs4-mLzDA , https://twitter.com/g_orl?lang=el, https://www.instagram.com/alexandrossfakianakis/,

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Παρασκευή, 19 Μαΐου 2017

Association of fibrinogen level with early neurological deterioration among acute ischemic stroke patients with diabetes

Abstract

Background

Diabetes mellitus (DM) is a risk factor for early neurological deterioration (END) in acute ischemic stroke. The prothrombotic protein fibrinogen is frequently elevated in patients with diabetes, and may be associated with poorer prognoses. We evaluated whether fibrinogen is associated with END in patients with diabetes after acute ischemic stroke.

Methods

We included 3814 patients from a single hospital database admitted within 72 h of onset of ischemic stroke. END was defined as an increase in the National Institutes of Health Stroke Scale (NIHSS) ≥2 within 7 days post-admission. In the total population (END, n = 661; non-END, n = 3153), univariate and multivariate analyses were performed to assess fibrinogen as an independent predictor for END. We then performed propensity score matching and univariate analyses for DM (END, n = 261; non-END, n = 522) and non-DM populations (END, n = 399; non-END, n = 798). Multiple logistic analyses were performed after matching for fibrinogen as a risk factor in each subgroup.

Results

Fibrinogen levels were higher in the END group than in the non-END group (367 ± 156 mg/dL vs. 347 ± 122 mg/dL, p = 0.002), though they were not associated with END in logistic regression analyses. Fibrinogen levels were found to be an independent predictor for END, but only in the DM population (fibrinogen levels 300–599 mg/dL, odds ratio: 1.618, 95% confidence interval: 1.037–2.525, p = 0.034, fibrinogen levels ≥600 mg/dL, 2.575, 1.018–6.514, p = 0.046; non-DM population, p = 0.393). The diabetes-fibrinogen interaction for the entire cohort was p = 0.101.

Conclusions

Elevated fibrinogen is dose-dependently associated with END in patients with diabetes following acute ischemic stroke.



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Thromboembolic and bleeding complications during oral anticoagulation therapy in cancer patients with atrial fibrillation: a Danish nationwide population-based cohort study

Abstract

Coexisting cancer in patients with atrial fibrillation (AF) has been associated with thromboembolism and bleeding. We used Danish population-based medical databases to conduct a population-based cohort study that included all AF patients who redeemed a prescription for vitamin K antagonists (VKA) or non-VKA oral anticoagulant (NOAC) between July 2004 and December 2013. We characterized these patients according to the presence (N = 11,855) or absence (N = 56,264) of a cancer diagnosis before redemption of their oral anticoagulant prescription, and then examined their 1-year risk of thromboembolic or bleeding complications or death. We next used Cox regression to compare the hazard ratios for complications among VKA- or NOAC-treated AF patients with versus without a cancer diagnosis, after adjusting for sex, age, and CHA2DS2 VASc score. One-year risks of thromboembolic complications in AF patients who redeemed a VKA prescription were similar in those with (6.5%) and without (5.8%) cancer [hazard ratio (HR) 1.0 (95% confidence interval (CI): 0.93, 1.1)]. This also was found for bleeding complications (5.4% vs. 4.3%, HR 1.1 [95% CI: 1.0, 1.2]). For AF patients with cancer who redeemed a NOAC prescription, risks were also similar for thromboembolic complications (4.9% of cancer patients vs. 5.1% of noncancer patients, HR 0.80 [95% CI: 0.61, 1.1]), and for bleeding complications (4.4% vs. 3.1%, HR 1.2 [95% CI: 0.92, 1.7]). The absolute risks of thromboembolic or bleeding complications were nearly the same in patients with and without cancer who redeemed prescription for VKAs or NOACs.

Thumbnail image of graphical abstract

Since both atrial fibrillation and cancer are common, any increased risk of complications among patients treated with vitamin K antagonists (VKAs) or non-VKA oral anticoagulants (NOACs) may have major public health implications. This study found that the absolute risks of thromboembolic or bleeding complications were nearly the same in patients with and without cancer who redeemed prescriptions for VKAs or NOACs.



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Are public-private partnerships the solution to tackle neglected tropical diseases? A systematic review of the literature

Publication date: Available online 19 May 2017
Source:Health Policy
Author(s): Céline Aerts, Temmy Sunyoto, Fabrizio Tediosi, Elisa Sicuri
Pharmaceutical companies are reluctant to invest in research and development (R&D) of products for neglected tropical diseases (NTDs) mainly due to the low ability-to-pay of health insurance systems and of potential consumers. The available preventive and curative interventions for NTDs mostly rely on old technologies and products that are often not adequate. Moreover, NTDs mostly affect populations living in remote rural areas and conflict zones, thereby hampering access to healthcare. The challenges posed by NTDs have led to the proliferation of a variety of public-private partnerships (PPPs) in the last decades. We conducted a systematic review to assess the functioning and impact of these partnerships on the development of and access to better technologies for NTDs. Our systematic review revealed a clear lack of empirical assessment of PPPs: no impact evaluation analyses could be found, which are crucial to realize the full potential of PPPs and to progress further towards NTDs elimination.



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UNDERSTANDING STAKEHOLDERS’ PERSPECTIVES AND EXPERIENCES OF GENERAL PRACTICE ACCREDITATION

Publication date: Available online 19 May 2017
Source:Health Policy
Author(s): Deborah Debono, David Greenfield, Luke Testa, Virginia Mumford, Anne Hogden, Marjorie Pawsey, Johanna Westbrook, Jeffrey Braithwaite
ObjectiveTo examine general practice accreditation stakeholders’ perspectives and experiences to identify program strengths and areas for improvements.Design, setting and participantsIndividual (n=2) and group (n=9) interviews were conducted between September 2011–March 2012 with 52 stakeholders involved in accreditation in Australian general practices. Interviews were recorded, transcribed and thematically analysed. Member checking activities in April 2016 assessed the credibility and currency of the findings in light of current reforms.ResultsOverall, participants endorsed the accreditation program but identified several areas of concern. Noted strengths of the program included: program ownership, peer review and collaborative learning; access to Practice Incentives Program payments; and, improvements in safety and quality. Noted limitations in these and other aspects of the program offer potential for improvement: evidence for the impact of accreditation; resource demands; clearer outcome measures; and, specific experiences of accreditation.ConclusionsThe effectiveness of accreditation as a strategy to improve safety and quality was shaped by the attitudes and experience of stakeholders. Strengths and weaknesses in the accreditation program influence, and are influenced by, stakeholder engagement and disengagement. After several accreditation cycles, the sector has the opportunity to reflect on, review and improve the process. This will be important if the continued or extended engagement of practices is to be realised to assure the continuation and effectiveness of the accreditation program.



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Exploding head syndrome

Exploding head syndrome: an unusual form of parasomnia (type of sleep disturbance) in which a person perceives loud noises (such as a gunshot, explosion, or crash) when awakening or falling asleep. Some estimates suggest that up to 10% of the population may have experienced this phenomenon. The perception of noise is often associated with fear, racing heartbeat, palpitations, and confusion. There is no associated pain. The cause of exploding head syndrome is poorly understood.



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Impact of Muscarinic M 3 Receptor Antagonism on the Risk of Type 2 Diabetes in Antidepressant-Treated Patients: A Case-Controlled Study

Abstract

Background

M3 muscarinic receptor antagonism has been associated with glucose intolerance and disturbance of insulin secretion.

Objective

Our objective was to examine the risk of type 2 diabetes mellitus (T2DM) in patients using antidepressants with and without M3 muscarinic receptor antagonism (AD_antaM3 and AD_nonantaM3, respectively).

Methods

We designed a case–control study using a pharmacy prescription database. We selected a cohort of patients who initiated antidepressant use between the ages of 20 and 40 years and who did not receive any anti-diabetic prescriptions at baseline. Cases were defined as those who developed T2DM [i.e., receiving oral anti-diabetic medication, Anatomical Therapeutic Chemical (ATC) code A10B] during the follow-up period (1994–2014), and ten random controls were picked for each case from the cohort of patients who did not develop T2DM.

Results

A total of 530 cases with incident T2DM and 5300 controls were included. Compared with no use of antidepressants during the previous 2 years, recent (within the last 6 months) exposure to AD_antaM3 was associated with a moderately increased risk of T2DM: adjusted odds ratio 1.55 (95% confidence interval 1.18–2.02). In the stratified analyses, this association was dose dependent (>365 defined daily doses) and significant for patients who were in the younger age group (<45 years at the end of follow-up), were female and had no co-morbidity. On the other hand, recent exposure to AD_nonantaM3 was not associated with a risk for T2DM in any of our analyses.

Conclusion

Our results suggest that exposure to AD_antaM3 was associated with the development of T2DM among antidepressant users.



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Mutual interference between adult females of Galendromus flumenis (Acari: Phytoseiidae) feeding on eggs of Banks grass mite decreases predation efficiency and increases emigration rate

Abstract

The Banks grass mite, Oligonychus pratensis (Banks) (Acari: Tetranychidae) causes significant damage to dates in California (USA), if not controlled. Studies are underway to develop biological control strategies against this pest in dates using the predatory mite Galendromus flumenis (Chant) (Acari: Phytoseiidae). In California date gardens, this predator is found in low numbers that are insufficient for the economic suppression of Banks grass mites, and our research aims to understand why it fails to keep up with prey densities. The hypothesis that prey density and predator interference interactively determine the predation efficiency of G. flumenis was tested. In addition, the effect of arena size and prey and predator density manipulations on the emigration rate of the predator was investigated. Our results indicate that the per capita predation rate of G. flumenis decreases steeply with increasing predator density due to mutual interference. Analysis of emigration data considering the arena size and predator numbers showed that the emigration rate of G. flumenis was higher from small arenas, and increased with increasing predator numbers. When emigration data were analyzed using prey and predator densities as independent variables, only the effect of predator density was significant, suggesting that higher predator density increases the emigration rate of G. flumenis. These results contribute to our understanding of the predator–prey interactions, and help in designing strategies for more efficient augmentative releases of G. flumenis.



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The sialate O-acetylesterase EstA from gut Bacteroidetes species enables sialidase-mediated cross-species foraging of 9-O-acetylated sialoglycans [Microbiology]

The gut harbors many symbiotic, commensal, and pathogenic microbes that engage in the breakdown and metabolism of host carbohydrates. Sialic acids are prominent outermost carbohydrates on mucins and protect underlying glycan chains from enzymatic degradation. Sialidases produced by some members of the colonic microbiota have been shown to promote the expansion of several potential pathogens (e.g. Clostridium difficile, Salmonella, Escherichia coli) that do not produce sialidases. O-acetyl ester modifications of sialic acids help resist the action of many sialidases and are found at high levels in the mammalian colon. However, some gut bacteria, in turn, produce sialylate-O-acetyl esterases to remove them. Here we investigated O-acetylation as a shield against the release of sialic acids by Bacteroidetes sialidases and the subsequent utilization of host sialic acids by commensal and pathogenic strains of E. coli. In vitro foraging studies demonstrated that sialidase-dependent E. coli outgrowth on mucin is enabled by Bacteroides EstA, which acts on glycosidically-linked sialylate-O-acety-esterase substrates, particularly at neutral pH. Biochemical studies suggest that spontaneous migration of O-acetyl esters on the side chain of sialic acid, which can occur at colonic pH, may serve as a switch controlling EstA-assisted sialic acid liberation. Specifically, EstA does not act on O-acetyl esters in their initial 7-position. But, following migration to the 9-position, glycans with O-acetyl esters become susceptible to the sequential enzyme action of bacterial esterases and sialidases. Thus, EstA specifically unlocks the nutritive potential of 9-O-acetylated mucus sialic acids for foraging by bacteria that otherwise lack the means to access this potential carbon source.

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Functional regions of the peroxin Pex19 necessary for peroxisome biogenesis [Membrane Biology]

The peroxins Pex19 and Pex3 play an indispensable role in peroxisomal membrane protein (PMP) biogenesis, peroxisome division and inheritance. Pex19 plays multiple roles in these processes, but how these functions relate to the structural organization of the Pex19 domains is unresolved. To this end, using deletion mutants, we mapped the Pex19 regions required for peroxisome biogenesis in the yeast Pichia pastoris. Surprisingly, import-competent peroxisomes still formed when Pex19 domains previously believed to be required for biogenesis were deleted, although the peroxisome size was larger than that in wild-type cells. Moreover, these mutants exhibited a delay of 14-24 h in peroxisome biogenesis. The shortest functional N-terminal (NTCs) and C-terminal constructs (CTCs) were Pex19 (aa 1-150) and Pex19 (aa 89-300), respectively. Deletions of the N-terminal Pex3-binding site disrupted direct interactions of Pex19 with Pex3, but preserved interactions with a membrane peroxisomal targeting signal (mPTS)-binding PMP, Pex10. In contrast, deletion of the C-terminal mPTS-binding domain of Pex19 disrupted its interaction with Pex10, while leaving the Pex19-Pex3 interactions intact. However, Pex11 and Pex25 retained their interactions with both N- and C-terminal deletion mutants. NTC-CTC co-expression improved growth and reverted the larger-than-normal peroxisome size observed with the single deletions. Pex25 was critical for peroxisome formation with the CTC variants, and its overexpression enhanced their interactions with Pex3 and aided the growth of both NTC and CTC Pex19 variants. In conclusion, physical segregation of the Pex3 and PMP-binding domains of Pex19 has provided novel insights into the modular architecture of Pex19. We define the minimum region of Pex19 required for peroxisome biogenesis and a unique role for Pex25 in this process.

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Identification and Characterisation of Nanobodies targeting the EphA4 receptor [Neurobiology]

The ephrin receptor A4 (EphA4) is one of the receptors in the ephrin system that plays a pivotal role in a variety of cell-cell interactions, mostly studied during development. In addition, EphA4 has been found to play a role in cancer biology as well as in the pathogenesis of several neurological disorders such as stroke, spinal cord injury, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and Alzheimer′s disease (AD). Pharmacological blocking of EphA4 has been suggested to be a therapeutic strategy for these disorders. Therefore, the aim of our study was to generate potent and selective Nanobodies against the ligand-binding domain of the human EphA4 receptor. We identified two Nanobodies, Nb 39 and Nb 53, that bind EphA4 with affinities in the nanomolar range. These Nanobodies were most selective for EphA4, with residual binding to EphA7 only. Using Alphascreen technology, we found that both Nanobodies displaced all known EphA4-binding ephrins from the receptor. Furthermore, Nb 39 and Nb 53 inhibited ephrin-induced phosphorylation of the EphA4 protein in a cell-based assay. Finally, in a cortical neuron primary culture, both Nanobodies were able to inhibit endogenous EphA4-mediated growth cone collapse induced by ephrin-B3. Our results demonstrate the potential of Nanobodies to target the ligand-binding domain of EphA4. These Nanobodies may deserve further evaluation as potential therapeutics in disorders in which EphA4-mediated signalling plays a role.

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Region-specific proteolysis differentially regulates type 1 inositol 1,4,5-trisphosphate receptor activity [Membrane Biology]

The inositol 1,4,5 trisphosphate receptor (IP3R) is an intracellular Ca2+ release channel expressed predominately on the membranes of the endoplasmic reticulum. IP3R1 can be cleaved by caspase or calpain into at least two receptor fragments. However, the functional consequences of receptor fragmentation are poorly understood. Our previous work has demonstrated that IP3R1 channels, formed following either enzymatic fragmentation or expression of the corresponding complementary polypeptide chains, retain tetrameric architecture and are still activated by IP3 binding, despite the loss of peptide continuity. In the current study, we demonstrate that region specific receptor fragmentation modifies channel regulation. Specifically, the agonist-evoked temporal Ca2+ release profile and protein kinase A modulation of Ca2+ release is markedly altered. Moreover, we also demonstrate that activation of fragmented IP3R1 can result in a distinct functional outcome. Our work suggests that proteolysis of IP3R1 may represent a novel form of modulation of IP3R1 channel function and increases the repertoire of Ca2+ signals achievable through this channel.

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The origin and evolution of human glutaminases and their atypical C-terminal ankyrin repeats [Enzymology]

On the basis of tissue-specific enzyme activity and inhibition by catalytic products, Hans Krebs first demonstrated the existence of multiple glutaminases in mammals. Currently, two human genes are known to encode at least four glutaminase isoforms. However, the phylogeny of these medically relevant enzymes remains unclear, prompting us to investigate their origin and evolution. Using prokaryotic and eukaryotic glutaminase sequences, we built a phylogenetic tree whose topology suggested that the multidomain architecture was inherited from bacterial ancestors, probably simultaneously with the hosting of the proto-mitochondrion endosymbiont. We propose an evolutionary model wherein the appearance of the most active enzyme isoform, glutaminase C (GAC), which is expressed in many cancers, was a late retrotransposition event that occurred in fishes from the Chondrichthyes class. The ankyrin (ANK) repeats in the glutaminases were acquired early in their evolution. To obtain information on ANK folding, we solved two high-resolution structures of the ANK repeat-containing C-termini of both kidney-type glutaminase (KGA) and GLS2 isoforms (glutaminase B and liver-type glutaminase). We found that the glutaminase ANK repeats form unique intramolecular contacts through two highly conserved motifs; curiously, this arrangement occludes a region usually involved in ANK-mediated protein-protein interactions. We also solved the crystal structure of full-length KGA and present a small-angle X-ray scattering model for full-length GLS2. These structures explain these proteins' compromised ability to assemble into catalytically active supra-tetrameric filaments, as previously shown for GAC. Collectively, these results provide information about glutaminases that may aid in the design of isoform-specific glutaminase inhibitors.

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Water Concentration Analysis of the Surgical Margin—Response



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Water Concentration Analysis of the Surgical Margin—Letter



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TAM Receptor Tyrosine Kinases in Cancer Drug Resistance

Receptor tyrosine kinases (RTK) are major regulators of key biological processes, including cell growth, survival, and differentiation, and were established early on as proto-oncogenes, with aberrant expression linked to tumor progression in many cancers. Therefore, RTKs have emerged as major targets for selective therapy with small-molecule inhibitors. However, despite improvements in survival rates, it is now apparent that the targeting of RTKs with selective inhibitors is only transiently effective, as the majority of patients eventually become resistant to therapy. As chemoresistance is the leading cause of cancer spread, progression, and mortality, there is an increasing need for understanding the mechanisms by which cancer cells can evade therapy-induced cell death. The TAM (Tyro3, Axl, Mer) subfamily of RTKs in particular feature in a variety of cancer types that have developed resistance to a broad range of therapeutic agents, including both targeted as well as conventional chemotherapeutics. This article reviews the roles of TAMs as tumor drivers and as mediators of chemoresistance, and the potential effectiveness of targeting them as part of therapeutic strategies to delay or combat resistance. Cancer Res; 77(11); 1–4. ©2017 AACR.

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Therapeutic IgE Antibodies: Harnessing a Macrophage-Mediated Immune Surveillance Mechanism against Cancer

IgG monoclonal antibodies have made significant contributions to cancer therapy, but suffer from several limitations that restrict their effectiveness in unleashing host immune system components against tumors. The development of monoclonal antibodies of an alternative class, namely IgE, may offer enhanced immune surveillance and superior effector cell potency against cancer cells. In our recent article, we elaborate our proof-of-concept studies of a mouse/human chimeric IgE antibody (MOv18 IgE), which is specific for the cancer-associated antigen folate receptor alpha. We demonstrate superior antitumor efficacy for IgE compared with an otherwise identical IgG in a syngeneic immunocompetent animal, and we identify TNFα/MCP-1 signaling as an IgE-mediated mechanism of monocyte and macrophage activation and recruitment to tumors. These findings draw parallels with powerful macrophage-activating functions employed by IgE against parasites, rather than allergic IgE mechanisms. The potential clinical application of IgE-derived drugs in clinical oncology is clear if the antitumor activity of MOv18 IgE in these preclinical experiments can be replicated in patients. In particular, different IgE antibodies with specificity for many other antigens already validated as targets for IgG suggest a wide potential for development of a novel class of antibody therapy. Cancer Res; 77(11); 1–5. ©2017 AACR.

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Molecular Confirmation of Intraspecific Tomato ( Solanum lycopersicum) Hybrids and Their Evaluation Against Late Blight and Cucumber Mosaic Virus

Abstract

Tomato is one of the most consumed vegetables in the world. Diseases are the number one concern in the development of high-yield and disease-resistant tomato hybrids which is the foremost priority of breeders. Present study was conducted (1) to develop DNA-based markers for genetic confirmation of tomato F1 hybrids, (2) to utilize sequenced characterized amplified region (SCAR) marker linked to the Ph-3 gene for Phytophthora infestans resistance in tomato and (3) to evaluate male and female parental genotypes and their F1 hybrids against late blight (LB) and cucumber mosaic virus (CMV). For molecular studies, 58 previously reported markers including RAPDs (10), SCAR (01), EST-SSR (01) and SSR (46) were applied. The SCAR marker clearly differentiated the LB3 and LB4 from Roma and T-1359 and provided evidence for Ph-3 gene. The SCAR marker was able to confirm the Ph-3 gene in the hybrids Roma × LB4, Roma × LB3, Riogrande × LB2, Riogrande × LB3 and Roma × LB7. Out of several tested primers, SSR-22 proved useful for genetic confirmation of F1 hybrid TMS1 × Money Maker (MM). For LB, tested hybrids/genotypes were ranked as susceptible to highly susceptible with different infection percentage (IP). However, the pace of symptom development was slower in hybrid Rio × LB2, 45% IP after 10 days of inoculation compared with 85% disease in one of the parent genotypes (Riogrande). None of the tested genotypes was found resistant; however, TMS1 responded as tolerant against CMV using mechanical inoculation. Under natural field conditions, TMS1 was found resistant while hybrids TMS1 × Naqeeb and TMS1 × MM were tolerant where as others were found to be susceptible. In conclusion, all tomato hybrids were genetically confirmed using DNA-based markers. SCAR marker was useful for marker-assisted confirmation of the Ph-3 gene in parental lines and hybrids; however, this gene was unable to provide protection against the local population of P. infestans.



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Standards of practice in interventional neuroradiology

Abstract

The growing importance of INR has resulted in the need to define and promote professional standards of clinical practice. Several professional organizations have published guidelines recently for the neurointerventional treatment of cerebrovascular diseases, including technical and personal recommendations, but detailed definitions of technical and organizational conditions needed for the safe and effective performance of such treatments are lacking. To fill this gap ESNR, ESMINT and the UEMS Division for Neuroradiology established a working group, to develop a consensus paper on "Standards of Practice in Interventional Neuroradiology". This document is the result of the Consensus Working Group and has following review gained approval by the Executive Boards of ESNR and ESMINT and by the members of the UEMS Division for Neuroradiology in 2017.



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Homozygous TCF3 mutation is associated with severe hypogammaglobulinemia and B-cell acute lymphoblastic leukemia

The identification of a homozygous TCF3 gene mutation in a patient presenting with severe hypogammaglobulinemia and acute lymphoblastic leukemia supports the crucial role of this transcription factor in normal B-lymphocyte development.

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Flexible IgE epitope containing domains of Phl p 5 cause high allergenic activity

This is the first study determining the three-dimensional structure of Phl p 5a which reveals a novel mechanism for high allergenic activity based on flexibly connected IgE-reactive domains which cross-link effector cell-bound IgE more efficiently than isolated rigid globular proteins. These findings may also form a basis for specific immunotherapy strategies.

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The IL-33/ST2 axis is crucial in type 2 airway responses induced by the Staphylococcus aureus protease SplD

S.aureus protein SplD acts as an allergen and an adjuvant inducing asthma features via inducing IL-33 production by airway epithelial cells. Soluble IL-33 receptor is a promising treatment option as it interferes with SplD-induced inflammation.

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Mechanistic Link between Diesel Exhaust Particles and Respiratory Reflexes

These findings provide the first mechanistic insights into how exposure to urban air pollution leads to the activation of human sensory nerves which are responsible for respiratory symptoms.

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“Is it possible to calculate surface areas of intraoral structures from preoperative CT scan?”

Microsurgical reconstruction of intraoral structures requires accurate planning of flap shape and dimensions. The goal of this study is to describe a method that allows to calculate surfaces of oral structures from preoperative CT-scan in order to determine a precise flap design before the surgery. We created casts of the human mouth from cadavers with a head and neck CT-scan available using an impression material. We digitalized the mouth casts and unwrapped the surfaces of the different structures of the mouth in a bi-dimensional plane in order to measure the area.

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Decreased contralateral breast volume after mastectomy, adjuvant chemotherapy, and anti-estrogen therapy, in particular in breasts with high density

Adjuvant chemotherapy and anti-estrogenic therapy can result in decreased volume of the contralateral breast, following mastectomy for the treatment of breast cancer. However, no data on the effect of adjuvant therapy on contralateral breast volume have previously been reported. We aimed to evaluate the extent to which adjuvant therapy and differences in breast density contribute to decreased breast volume.We conducted a prospective cohort study, selecting 40 nonconsecutive patients who underwent immediate breast reconstruction with mastectomy and expander insertion followed by expander replacement.

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A Direct Comparison of Porcine (Strattice™) and Bovine (Surgimend™) Acellular Dermal Matrices in Implant-Based Immediate Breast Reconstruction

Acellular dermal matrix (ADM) assisted implant-based breast reconstruction (IBBR) has grown in popularity over traditional submuscular techniques. Numerous human, bovine or porcine derived ADMs are available with the type used varying considerably worldwide. Yet, comparative evidence for the efficacy of different ADMs particularly xenogenic is limited. This study directly compares early outcomes of porcine (StratticeTM) and bovine (SurgimendTM) ADMs in IBBR.

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Detection of Merkel Cell Polyoma Virus and Beta Human Papillomavirus in Multiple Eccrine Poromas in a Patient With Acute Leukemia Treated With Stem Cell Transplant

imageNo abstract available

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Depletion of Epidermal Langerhans Cells in the Skin Lesions of Pellagra Patients

imageAbstract: Pellagra is a nutrient deficiency disease caused by insufficient niacin levels. Recent studies have shown that numbers of epidermal Langerhans cells decreased in other diseases caused by nutritional deficiencies, including necrolytic migratory erythema and acrodermatitis enteropathica. Epidermal Langerhans cells are capable of modulating or even halting the inflammatory reaction. The aim of this study was to examine changes in the number of Langerhans cells and other dendritic cells, and maturation of epidermal Langerhans cells in the lesional and adjacent non-lesional skin in pellagra patients. Seven pellagra patients and 10 healthy individuals who served as controls were included. The number and distribution of dendritic cells and other cutaneous cells were examined by immunohistochemistry. Epidermal Langerhans cells decreased considerably in the skin lesions of pellagra patients, whereas other dendritic cells did not change. The decrease in the number of Langerhans cells was positively correlated with the histological severity of skin lesions. As the number of Langerhans cells was not reduced in the undisturbed neighboring skin, the depletion of epidermal Langerhans cells did not precede skin damage but was a cause of prolonged severe inflammation.

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Bullous Pyoderma Gangrenosum With Subungual Involvement Associated With Ulcerative Colitis

imageAbstract: Pyoderma gangrenosum (PG) is a rare inflammatory and ulcerative skin disease of unknown etiology characterized by neutrophilic infiltration of the dermis, mainly affecting the lower extremities. Bullous PG is a rare variant of this disease, usually associated with hematologic disorders. Here, we report a case of pathergy-positive bullous PG with subungual involvement associated with ulcerative colitis.

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Clonal Seborrheic Keratosis Versus Pagetoid Bowen Disease: Histopathology and Role of Adjunctive Markers

imageAbstract: Clonal seborrheic keratosis (CSK) and pagetoid Bowen disease (squamous cell carcinoma in situ) (PBD) share similar histological features making it sometimes difficult to differentiate the 2. The study group included 29 and 13 cases of CSK and PBD, respectively. Both groups were examined histopathologically (suprabasal mitotic figures, broad rete ridges, crowding of nuclei, nuclear pleomorphism, necrotic keratinocytes, parakeratosis, and dermal inflammation) and immunohistochemically (CK10, Ki-67, and p16). P values for all parameters were calculated using Fisher exact test, 2 tailed. Significant differences were seen regarding mitosis, crowding, nuclear pleomorphism (more common in PBD), and broad rete ridges (more common in CSK). Significant differences were also noted with Ki-67, CK10, and p16 antibodies. Increased Ki-67-positive cells and the presence of >75% positive p16 cells were commonly seen in PBD, whereas CK10-negative cells were a common finding in CSK. A spectrum of staining patterns was observed with CK10 and p16. There is no single reliable criterion to distinguish CSK from PBD. A panel of markers comprising CK10, Ki-67, and p16 seems to be useful in the context of relevant histology.

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Cutaneous Apocrine Carcinoma With an In Situ Component and Histiocytoid and Signet-Ring Cells

imageAbstract: We present a case of cutaneous apocrine carcinoma arising in the axilla of a 71-year-old man. The tumor had a significant component of histiocytoid and signet-ring cells as well as in situ carcinoma within the apocrine glands. The cells expressed GATA3, gross cystic disease fluid protein 15, androgen receptor, and E-cadherin. Estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 were negative. Clinical correlation was required to rule out a metastasis from the breast or the gastrointestinal tract. Although most cutaneous apocrine carcinomas do not behave aggressively, our patient developed bone metastases and eventually died of his disease. It is debated whether histiocytoid and signet-ring cell cutaneous carcinomas should be classified as apocrine neoplasm. The presence of in situ carcinoma associated with this kind of tumor has been reported only once in the literature. This characteristic and the immunohistochemical profile are in favor of apocrine differentiation.

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Epidermolytic Ichthyosis Sine Epidermolysis

imageAbstract: Epidermolytic ichthyosis (EI) is a rare disorder of cornification caused by mutations in KRT1 and KRT10, encoding two suprabasal epidermal keratins. Because of the variable clinical features and severity of the disease, histopathology is often required to correctly direct the molecular analysis. EI is characterized by hyperkeratosis and vacuolar degeneration of the upper epidermis, also known as epidermolytic hyperkeratosis, hence the name of the disease. In the current report, the authors describe members of 2 families presenting with clinical features consistent with EI. The patients were shown to carry classical mutations in KRT1 or KRT10, but did not display epidermolytic changes on histology. These observations underscore the need to remain aware of the limitations of pathological features when considering a diagnosis of EI.

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Counterfeit Pennies: Distinguishing Chromoblastomycosis From Phaeohyphomycotic Infections

imageNo abstract available

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Beta Human Papillomavirus Infection Is Prevalent in Elephantiasis and Exhibits a Productive Phenotype: A Case-Control Study

imageAbstract: Elephantiasis is considered a cutaneous region of immune deficiency with cobblestone-like surface caused by a wart-like eruption. Verrucosis is a diffuse human papillomavirus (HPV) infection linked to immunodeficiency disorders. The objective of this study was to examine the prevalence of HPV infection in lymphedema and its pathogenic role in elephantiasis. A retrospective case-control study was performed examining lymphedematous skin and controls of peritumoral normal skin. HPV infection was evaluated at the DNA, protein, and histopathologic levels by polymerase chain reaction, immunohistochemistry, and light microscopy, respectively. Overall, 540 HPV DNAs were detected in 120 of 122 cutaneous samples (median 4 HPV DNAs per sample, range 0–9). Compared with controls, no differences existed in type or number of HPVs identified. Instead, a diverse spectrum of HPV-related histopathologies were evident, likely reflecting the multiplicity of HPV genotypes detected. Most notably, increasing histopathologic lymphedema stage significantly correlated with markers of productive HPV infection such as altered keratohyaline granules and HPV L1 capsid expression. Limitations of this study are the absence of normal skin controls not associated with neoplasia or subclinical lymphedema, and lack of assessment of HPV copy number per keratinocyte infected. In conclusion, productive HPV infection, not HPV type or numbers detected, distinguished lymphedematous skin from controls. These findings support the theory that lymphedema creates a region of depressed immunity that permits productive HPV infection, manifested clinically by diffuse papillomatosis, characteristic of elephantiasis.

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Pseudoxanthoma Elasticum-Like Papular Eruption

No abstract available

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A Rapidly Growing Facial Mass: Challenge

imageNo abstract available

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Diagnostic Criteria in Intraepithelial Pagetoid Neoplasms: A Histopathologic Study and Evaluation of Select Features in Paget Disease, Bowen Disease, and Melanoma In Situ

imageBackground: Paget disease, Bowen disease, and malignant melanoma in situ are intraepidermal neoplasms, characterized by the presence of pagetoid scatter of atypical cells in the epidermis. This study reviewed the frequency of select histologic criteria to validate their usefulness in the histologic distinction between these entities. Methods: One hundred forty-four specimens with the diagnosis of Bowen disease, 144 specimens with Paget disease (mammary and extramammary), and 144 specimens with malignant melanoma in situ were examined microscopically to define frequencies of select histologic criteria present in each disease. Results: Comparison between mammary Paget and extramammary Paget disease showed no significant differences in the features studied. Crushing of basal keratinocytes, presence of atypical cells in the corneum, and presence of large cells with amphophilic cytoplasm were significantly noted in Paget disease. Transition between the atypical clear cells and surrounding keratinocytes was absent in all cases of melanoma in situ and in 87 (60.4%) cases of Paget disease, but it was significantly associated with Bowen disease (98.6%). Dyskeratotic cells were significantly associated with Bowen disease cases. Conclusion: Our study demonstrated a practical histologic approach to differentiate between intraepidermal pagetoid neoplasms. Careful histologic study of the proposed criteria may reduce reliance on immunohistochemical stains.

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A Pseudoxanthoma Elasticum–Like Papular Eruption: Challenge

imageNo abstract available

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Chronic Localized Fibrosing Leukocytoclastic Vasculitis Associated With Lymphedema, Intralymphatic and Intravascular Lymphocytosis, and Chronic Myelogenous Leukemia: A Case Report of Unilateral Erythema Elevatum Diutinum

imageAbstract: One of the pathogenic causes of cutaneous inflammatory pseudotumors is chronic localized fibrosing leukocytoclastic vasculitis (CLFLCV), a vasculitic reaction pattern seen in granuloma faciale (GF), a localized vasculitis, and erythema elevatum diutinum (EED), a generalized vasculitis. Patients with myelodysplastic syndromes (MDSs) are at risk for a diverse spectrum of cutaneous neutrophilic dermatoses such as EED. Herein, we report a 74-year-old man who presented with a large ulcerative, fungating tumor affecting the right flexor ankle caused by CLFLCV. During his workup and management, MDS and Philadelphia chromosome-negative chronic myeloid leukemia was diagnosed. Surgical excision of the inflammatory mass promptly triggered tumor recurrence, whereas antineutrophil therapy (dapsone coupled with hydroxyurea, and prednisone) lead to tumor regression. Histopathologic examination revealed an eosinophilic-rich small-vessel neutrophilic vasculitis associated with storiform and angiocentric fibrosis (GF-like). In the regions of fibrosis, dilated lymphatic and vascular spaces were numerous, some of which were congested with small CD3+-positive lymphocytes (intralymphatic and intravascular lymphocytosis). These findings indicate coexisting localized lymphedema. By direct immunofluorescence, IgM and C4d vessel deposits were detected. The pathogenesis of the fibrotic nodules and plaques of CLFLCV is suspected to be due to recurring bouts of immune-complex vasculitis, creating a cycle of vessel damage followed by reparative granulation tissue. Poor lymphatic drainage may be the underlying factor initiating and maintaining recurrent, localized episodes of immune-complex vasculitis and progressive fibrosis. Although his tumor histopathology resembled GF—eosinophilic rich CLFLCV—the clinical context points to a solitary and paraneoplastic case of EED.

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Asymptomatic Annular Plaques in a 67-Year-Old Man: Challenge

imageNo abstract available

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Necrotizing Thrombophlebitis Secondary to Mycobacterium Chelonae in a Hemodialyzed Patient

imageNo abstract available

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Congenital Infantile Fibrosarcoma Associated With a Lipofibromatosis-Like Component: One Train May Be Hiding Another

imageAbstract: Congenital infantile fibrosarcoma (CIFS) is a soft tissue sarcoma of infants mainly involving lower extremities and usually developing during the first year of life. At another end of the spectrum of pediatric fibroblastic lesions, lipofibromatosis is a rare benign infiltrative soft tissue tumor that affects children. The authors report in this study a particular presentation with a CIFS surrounded by lipofibromatosis-like areas. The presence of a surrounding benign tumor confused and delayed CIFS diagnosis.

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A Rapidly Growing Facial Mass: Answer

No abstract available

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How does supplementary feeding affect endoparasite infection in wild boar?

Abstract

Supplementary feeding is widely used in game management but may aid the transmission of parasites. Firstly, feeding sites attract animals and may be regarded as high-risk areas for parasite transmission. Secondly, high host population densities resulting from and supported by supplementary feeding, as well as accumulation of parasites in the environment, may increase parasite prevalence. Our aim was to investigate whether host density or the number of feeding sites drives endoparasite infection in an Estonian wild boar (Sus scrofa) population. For this, we collected wild boar faeces from forests, and soil samples from supplementary feeding sites in central and south-eastern Estonia. The role of host density and number of feeding sites on both the risk and mean abundance of endoparasite infection was modelled using generalized linear models (GLM). The presence of biohelminths in faecal samples was associated with both wild boar and feeding site density, whereas the presence of Eimeria sp. oocysts in faecal samples was only associated with wild boar density. Helminth eggs were found more often from the soil of active and abandoned feeding sites than from control areas. This could reflect parasitic contamination or indicate that supplementary feeding sites are suitable habitat for soil-dwelling nematodes. These results suggest that the effects of supplementary feeding on parasite prevalence in wild boar are mediated by the characteristics of parasite life cycles.



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Immunoproapoptotic molecule scFv-Fdt-tBid modified mesenchymal stem cells for prostate cancer dual-targeted therapy

Highly efficient target therapy is urgently needed for prostate cancer with overexpression of γ-seminoprotein (γ-SM). Recent studies indicated that mesenchymal stem cells (MSCs) are attractive candidate for cell-based, targeted therapy due to their tumor tropism. Here we designed a dual-target therapeutic system in which MSCs were engineered to produce and deliver scFv-Fdt-tBid, a novel γ-SM-targeted immunoproapoptotic molecule. Such engineered MSCs (MSC.scFv-Fdt-tBid) would home to tumor sites and release the fusion protein to induce the apoptosis of prostate cancer cells.

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Cochlear implantation in patients with otosclerosis of the otic capsule

To evaluate outcomes of cochlear implantation of patients with otosclerosis of the otic capsule.

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The impact of pre-injury direct oral anticoagulants compared to warfarin in geriatric G-60 trauma patients

Abstract

Purpose

Pre-injury oral anticoagulants are associated with worse outcomes in geriatric (G-60) trauma patients, but there are limited data comparing warfarin with direct oral anticoagulants (DOAC). We sought to compare outcomes in G-60 trauma patients taking pre-injury DOACs vs. warfarin.

Methods

All trauma patients, age ≥60 who were admitted to the hospital and taking an oral anticoagulant pre-injury were retrospectively identified. Patients were excluded if their reason for admission was a suicide attempt or penetrating extremity injury. Outcome measures included blood transfusions, hospital LOS, and mortality. A second analysis was performed, whereby patients were matched using ISS and age.

Results

There were 3,941 patients identified; 331 had documentation of anticoagulant use, pre-injury (warfarin, n = 237; DOAC, n = 94). Demographics were similar, but ISS [9 (4–13) vs. 8 (4–9), p = .027], initial INR [2.2 (1.8–2.9) vs. 1.2 (1.1–1.5), p < .001], and the use of pharmacologic reversal agents (48 vs. 14%, p < .001) were higher in the warfarin group. There was no difference in the use of blood transfusions (24 vs. 17%, p = .164) or mortality (5.9 vs. 4.3%, p = .789) between warfarin and DOAC groups, respectively. However, LOS was longer in the warfarin group [5 (3–7.5) vs. 4 (2–6.3) days, p = .02]. Matched analysis showed no difference in blood transfusions (23 vs. 17%, p = .276), mortality (2.1 vs. 4.3%, p = .682) or LOS [5 (3–7) vs. 4 (2–6.3) days, p = .158] between warfarin and DOAC groups, respectively.

Conclusion

Pre-injury DOACs are not associated with worse clinical outcomes compared to warfarin in G-60 trauma patients. Higher use of pharmacologic reversal agents with warfarin may be related to differences in mechanism of action and effect on INR.



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Overweight boys at greater risk of colon cancer as adults, but losing weight may modify risk

New research presented at this year’s European Congress on Obesity in Porto, suggests that overweight boys may be at greater risk of colon cancer when they grow up than their slimmer friends

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Erratum to: Endoscopic management of post-laparoscopic sleeve gastrectomy stenosis



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Prediction of surgical outcomes of laparoscopic liver resections for hepatocellular carcinoma by defining surgical difficulty

Abstract

Background

Several classification systems for assessing the surgical difficulty of laparoscopic liver resection (LLR) have been proposed. We evaluated three current classification systems, including traditional Major/Minor Classification, Complexity Classification, and the Difficulty Scoring System for predicting the surgical outcomes after LLR.

Methods

We reviewed the clinical data of 301 patients who underwent LLR for hepatocellular carcinoma between March 1, 2004 and June 30, 2015. We compared the intraoperative, pathologic, and postoperative outcomes according to the three classifications. We also compared the prognostic value of the three classifications using receiver operating characteristic (ROC) curves.

Results

The Major/Minor Classification, Complexity Classification, and the Difficulty Scoring System efficiently differentiated surgical difficulty in terms of blood loss (P = 0.001, P = 0.009, and P < 0.001, respectively) and operation time (all P < 0.001). Regarding intraoperative outcomes, the Difficulty Scoring System and Complexity Classification successfully differentiated the transfusion rate (P = 0.001 and P < 0.001, respectively). However, only the Complexity Classification adequately predicted severe postoperative complications (P = 0.032), the severity of complications (P < 0.001), and the length of hospital stay (P = 0.005). In ROC curve analysis, the Complexity Classification (area under the curve [AUC] = 0.611) outperformed the Major/Minor Classification (AUC = 0.544) and the Difficulty Scoring System (AUC = 0.530) for predicting severe postoperative complications. None of the classification systems predicted recurrence or patient survival.

Conclusion

The Complexity Classification was superior to the other methods for assessing surgical difficulty and predicting complications after LLR for hepatocellular carcinoma.



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Simultaneous conversion of gastric band to sleeve gastrectomy is associated with increased postoperative complications: an analysis of the American College of Surgeons National Surgical Quality Improvement Program

Abstract

Background

Laparoscopic sleeve gastrectomy (LSG) has gained popularity for the treatment of morbid obesity as gastric banding (BAND) has fallen out of favor. As a result, simultaneous conversion (CONV) of BAND to LSG is commonly performed. We hypothesized that CONV is associated with higher 30-day risk-adjusted serious morbidity.

Methods

Preoperative characteristics and 30-day outcomes from the American College of Surgeons National Surgical Quality Improvement Program Participant Use Files 2010–2014 were selected for patients who underwent LSG. Patients undergoing CONV were identified. Descriptive comparisons were performed using Chi-square and Wilcoxon rank-sum tests as appropriate. Multivariate logistic regression was performed to assess the association between CONV and a composite measure of 30-day serious morbidity and mortality.

Results

Overall, 35,307 patients met criteria for inclusion, of which 943 (2.7%) underwent CONV. The median age of patients undergoing CONV was higher (46 vs 44 years, p < 0.001) and a greater percentage of CONV patients was female (84.8 vs 77.9%, p < 0.001) than LSG patients. CONV patients had lower rates of common comorbidities, including diabetes (14.9 vs 23.1%, p < 0.001), hypertension (41.9 vs 48.6%, p < 0.001), and tobacco use (7.2 vs 9.8%, p < 0.001), as well as lower median BMI (41 vs 44, p < 0.001). Individual unadjusted outcomes of serious 30-day complications were similar between both groups, as was a composite measure of serious morbidity (CONV 4.3% vs LSG 3.6%, p = 0.1). However, after controlling for demographics, comorbidities, and concurrent band removal, CONV was associated with increased odds of serious 30-day morbidity (1.44, 95% CI 1.03–1.97) (c-statistic: 0.60).

Conclusions

Serious morbidity following LSG is uncommon; however, CONV is associated with a modest increase in risk-adjusted adverse 30-day outcomes. Patients being evaluated for CONV should be counseled about the added risks versus LSG alone. Further research is warranted to identify whether the incremental risks of CONV may be modifiable.



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Lip reconstruction using a functioning serratus anterior free flap: preliminary study

Publication date: Available online 19 May 2017
Source:International Journal of Oral and Maxillofacial Surgery
Author(s): A.O. Gundeslioglu, E.C. Karadag, I. Inan, L. Jasharllari, M.N. Selimoglu, F. Guney, B. Yuruten, M. Bekerecioglu
Reconstructive surgery to the lips requires the replacement of defective tissues with similarly functioning tissues. While non-dynamic free tissue transfers provide adequate lower lip reconstruction, improved benefits may be obtained with innervated free muscle flaps. This study reports the use of innervated serratus anterior muscle free flaps for lip reconstruction in five patients. All patients had squamous cell carcinoma of either the upper or lower lip. After resection of the tumours, the resultant defects comprised two-thirds of the lips. The innervated serratus anterior muscle free flap was transferred to the lip and an end-to-end vascular anastomosis on the facial artery was performed. The marginal mandibular branch of the facial nerve was preferred for nerve coaptation. The inner and outer surfaces of the flaps were grafted with a split-thickness skin graft. Concentric needle electromyography of the orbicularis oris and frontal muscles was performed for all patients in the preoperative, postoperative, and follow-up periods. All patients survived the surgical operation. Three patients achieved perfect oral sphincter function without drooling. Electromyography at 1 year postoperative demonstrated the successful reinnervation of the serratus anterior muscle. This study demonstrates that lip reconstruction using an innervated serratus anterior muscle free flap is a reliable method, providing a functional lower lip.



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Second Thoughts on Whether Self-Knowledge Is Overrated

Intellectuals continue to debate the value of deep inquiry into the human condition.

-- Read more on ScientificAmerican.com
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Three Novel Xenorhabdus – Steinernema Associations and Evidence of Strains of X. khoisanae Switching Between Different Clades

Abstract

Xenorhabdus species are normally closely associated with entomopathogenic nematodes of the family Steinernematidae. Strain F2, isolated from Steinernema nguyeni, was identified as Xenorhabdus bovienii and strains J194 and SB10, isolated from Steinernema jeffreyense and Steinernema sacchari as Xenorhabdus khoisanae, based on phenotypic characteristics and sequencing of 16S rRNA and housekeeping genes dnaN, gltX, gyrB, infB and recA. All three strains produced antimicrobial compounds that inhibited the growth of Gram-positive and Gram-negative bacteria. This is the first report of associations between strains of the symbiotic bacteria X. bovienii with S. nguyeni, and X. khoisanae with S. jeffreyense and S. sacchari. This provides evidence that strains of Xenorhabdus spp. may switch between nematode species within the same clade and between different clades.



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Exercise Science Principles and the Vocal Warm-up: Implications for Singing Voice Pedagogy

Principles from exercise science literature were applied to singing warm-up pedagogy as a method for examining parallels between athletic and voice training. Analysis of the use of exercise principles in vocal warm-up should illuminate aspects of voice training that may be further developed in the future.

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Transcutaneous Electrical Nerve Stimulation (TENS) and Laryngeal Manual Therapy (LMT): Immediate Effects in Women With Dysphonia

This study aimed to verify the immediate effect of low-frequency transcutaneous electrical nerve stimulation (TENS) and laryngeal manual therapy (LMT) in musculoskeletal pain, voice quality, and self-reported signs in women with dysphonia.

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Prevalence of hearing-loss among HAART-treated children in the Horn of Africa

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Publication date: July 2017
Source:International Journal of Pediatric Otorhinolaryngology, Volume 98
Author(s): Alden F. Smith, David C. Ianacone, Robbert J.H. Ensink, Abebe Melaku, Margaretha L. Casselbrant, Glenn Isaacson
ObjectivesThe prevalence of hearing loss (HL) in children infected with HIV/AIDS is not well studied. Even fewer studies focus on stable HIV-infected children treated with high-effective antiretroviral therapy (HAART). We aim to compare the prevalence of ear disease and HL in HAART-treated, HIV + children in Addis Ababa, Ethiopia with a well, similarly-aged elementary school population with unknown HIV status (HIVU).MethodsChildren underwent standard head and neck examination and cerumen removal by board certified otolaryngologists. Next, certified audiologists performed hearing screening with pure-tone audiometry using a circumaural headset but without an ambient noise reducing environment. Children failing audiometric screening underwent full behavioral audiometry including air and bone testing. The primary outcome parameter was HL > 25 dB with the audiologist accounting for background noise. A second endpoint was PTA >40 dB (500, 1000, 2000 Hz) without assessment of background noise.Results107 HIV+ and 147 HIVU children met inclusion criteria. In the HIV + cohort 17.8% had evidence of TM perforations and 8.4% had otorrhea. In the HIVU group 2.7% had a TM perforation and 0% had otorrhea. Hearing was significantly worse in HIV + children. (Audiologist determination: 38.3% HL HIV+, 12.2% HIVU, Fisher's-Exact-Test OR: 4.5, 95% CI 2.4–8.3, p-value <0.0001; Worse-hearing-ear PTA > 40 dB: 19.6% HL HIV+, 6.1% HIVU, OR: 3.7, 95% CI 1.7–8.4, p-value <0.001).ConclusionsChronic OM, conductive and mixed hearing losses are significantly more common in HAART-treated HIV + children than in well, similarly-aged controls. Rates of SNHL are similar.



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Interplay Between SIRT-3, Metabolism and Its Tumor Suppressor Role in Hepatocellular Carcinoma

Abstract

Sirtuins (SIRT), first described as nicotinamide adenine dinucleotide (NAD+)-dependent type III histone deacetylases, are produced by cells to support in the defense against chronic stress conditions such as metabolic syndromes, neurodegeneration, and cancer. SIRT-3 is one of the most studied members of the mitochondrial sirtuins family. In particular, its involvement in metabolic diseases and its dual role in cancer have been described. In the present review, based on the evidence of SIRT-3 involvement in metabolic dysfunctions, we aimed to provide an insight into the multifaceted role of SIRT-3 in many solid and hematological tumors with a particular focus on hepatocellular carcinoma (HCC). SIRT-3 regulatory effect and involvement in metabolism dysfunctions may have strong implications in HCC development and treatment. Research literature widely reports the relationship between metabolic disorders and HCC development. This evidence suggests a putative bridge role of SIRT-3 between metabolic diseases and HCC. However, further studies are necessary to demonstrate such interconnection.



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Gefäßnotfälle im Kindesalter

Abstract

Die vorliegende Arbeit gibt zum einen eine Übersicht über die Möglichkeiten der Schaffung eines Gefäßzugangs im Kindesalter. Zum anderen soll der Artikel über die Inzidenz, Therapie und Langzeitkomplikationen einer Gefäßverletzung im Kindesalter informieren.



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Hochauflösungsmanometrie der pharyngealen Schluckdynamik

Zusammenfassung

Hintergrund

Zum Transport eines Speisebolus aus der Mundhöhle in den Magen ist eine regelrechte Kontraktion der Pharynxmuskulatur und eine koordinierte Funktion des oberen Ösophagussphinkters (oÖS) notwendig. Der durch die Muskelkontraktion erzeugte intraluminale Druck treibt den Bolus kontinuierlich voran. Im Gegensatz zu bildgebenden ermöglichen manometrische Verfahren eine Abschätzung des Druckaufbaus und damit der Muskelfunktion. Sie wurden zunächst für den Ösophagus und seit 7–8 Jahren auch vermehrt im Pharynx angewendet. Die pharyngeale Hochauflösungsmanometrie (pHRM) ermöglicht Druckmessungen in hoher räumlicher und zeitlicher Auflösung und so eine Beurteilung der pharyngealen Schluckmotorik.

Ziel der Arbeit

Es wird eine aktuelle Übersicht über die Durchführung, Auswertung und Interpretation der pHRM und den derzeitigen Forschungsstand gegeben.

Material und Methoden

Eine Recherche in PubMed und Scopus wurde nach den Stichworten „high-resolution manometry“ und „pharynx“ oder „upper esophageal sphincter“ durchgeführt. Arbeiten, die originäre Daten für pHRM beinhalten, sowie Übersichtsarbeiten und Buchbeiträge wurden berücksichtigt.

Ergebnisse

Mit der pHRM können die während des Schluckens auftretenden Druckverhältnisse im Pharynx und oÖS beurteilt werden. Einen Überblick über Veränderungen der pharyngealen Schluckmotorik bietet der Druckkonturplot. Die Bestimmung von Schluckparametern ermöglicht eine differenzierte Bewertung einzelner Komponenten des Schluckvorgangs. Ein Vergleich mit Normwerten erlaubt die Abgrenzung von Störungen im Schluckablauf.

Schlussfolgerung

Auch wenn einzelne Schluckparameter für die klinische Routine noch weiter evaluiert werden müssen, sollte bereits jetzt zur vollständigen Beurteilung des Schluckvorgangs immer eine pHRM durchgeführt werden.



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Patient needs and preferences for herb-drug-disease interaction alerts: a structured interview study

While complementary and alternative medicine (CAM) is commonly used in the United States and elsewhere, and hazardous interactions with prescription drugs can occur, patients do not regularly communicate with ...

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The effects of Kanizsa contours on temporal integration and attention in rapid serial visual presentation

Abstract

Performance in rapid serial visual presentation tasks has been shown to depend on the temporal integration of target stimuli when they are presented in direct succession. Temporal target integration produces a single, combined representation of visually compatible stimuli, which is comparatively easy to identify. It is currently unknown to what extent target compatibility affects this perceptual behavior, because it has not been studied systematically to date. In the present study, the effects of compatibility on temporal integration and attention were investigated by manipulating the Gestalt properties of target features. Of particular interest were configurations in which a global illusory shape was formed when all stimulus features were present; a Kanizsa stimulus, which was expected to have a unifying effect on the perception of the successive targets. The results showed that although the presence of a Kanizsa shape can indeed enhance temporal integration, this also was observed for other good Gestalts, such as due to common fate and closure. Identification accuracy seemed to vary, possibly as a result of masking strength, but this did not seem associated with attentional processing per se. Implications for theories of Gestalt processing and temporal integration are discussed.



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A Review of the Hemodynamic Factors Believed to Contribute to Vascular Access Dysfunction

Abstract

A vascular access (VA) is used to facilitate hemodialysis in patients that suffer from end-stage renal disease. However, they suffer from high failure rates due to non-maturation and venous stenosis, with intimal hyperplasia (IH) the underlying cause of both conditions. Abnormal hemodynamic profiles, which arise following VA creation, are believed to lead to the development of IH. However, the exact physiological response that initiates this process is unknown. This review evaluates the different hemodynamic parameters that are hypothesised to correlate with the development of IH. Review studies that examine the correlation between hemodynamic parameters and the onset of IH using computational fluid dynamics. These studies are divided into groups depending on the type of analysis conducted; longitudinal studies, patient specific arteriovenous fistula (AVF) studies, arteriovenous graft studies, idealised AVF studies and studies that analyse the bulk flow. Studies that conduct longitudinal analysis identify an overall reduction in wall shear stress (WSS) as the VA matures. This is further associated with outward remodelling and the successful maturation of the VA. The majority of studies that conduct a transversal analysis find that low/oscillating shear is associated with the development of IH. However, a number of studies find a link between high shear and high spatial and temporal WSS gradients and the onset of IH. This review highlights the lack of unanimity between studies and emphasises the fact that the exact physiological response that leads to the development of IH remains unknown. This accentuates the need for a single, precise hypothesis capable of accurately predicting the onset of IH. If computational modelling is to assist in this process, the number of longitudinal studies conducted must increase. This will provide a better understanding of the effect that hemodynamic parameters have on the remodelling process and potentially identify a single/group of parameter/s that can accurately predict the onset of IH.



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Methylone and MDPV activate autophagy in human dopaminergic SH-SY5Y cells: a new insight into the context of β-keto amphetamines-related neurotoxicity

Abstract

Autophagy has an essential role in neuronal homeostasis and its dysregulation has been recently linked to neurotoxic effects of a growing list of psychoactive drugs, including amphetamines. However, the role of autophagy in β-keto amphetamine (β-KA) designer drugs-induced neurotoxicity has hitherto not been investigated. In the present study, we show that two commonly abused cathinone derivatives, 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxypyrovalerone (MDPV), elicit morphological changes consistent with autophagy and neurodegeneration, including formation of autophagic vacuoles and neurite retraction in dopaminergic SH-SY5Y cells. Methylone and MDPV prompted the formation of acidic vesicular organelles (AVOs) and lead to increased expression of the autophagy-associated protein LC3-II in a concentration- and time-dependent manner. Electron microscopy confirmed the presence of autophagosomes with typical double membranes and autolysosomes in cells exposed to both β-KA. The autophagic flux was further confirmed using bafilomycin A1, a known inhibitor of the late phase of autophagy. Moreover, we showed that autophagy markers were activated before the triggering of cell death and caspase 3 activation, suggesting that β-KA-induced autophagy precedes apoptotic cell death. To address the role of oxidative stress in autophagy induction, we also investigated the effects of antioxidant treatment with N-acetyl-l-cysteine (NAC) on autophagy and apoptotic markers altered by these drugs. NAC significantly attenuated methylone- and MDPV-induced cell death by completely inhibiting the generation of reactive oxygen and nitrogen species, and hampering both apoptotic and autophagic activity, suggesting that oxidative stress plays an important role in mediating autophagy and apoptosis elicited by these drugs.



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Emerging Trends in Micro- and Nanoscale Technologies in Medicine: From Basic Discoveries to Translation

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.7b01493
ancac3?d=yIl2AUoC8zA


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A neural network based model to analyze rice parboiling process with small dataset

Abstract

In this study, milling recovery, head rice yield, degree of milling and whiteness were utilized to characterize the milling quality of Tarom parboiled rice variety. The parboiled rice was prepared with three soaking temperatures and steaming times. Then the samples were dried to three levels of final moisture contents [8, 10 and 12% (w.b)]. Modeling of process and validating of the results with small dataset are always challenging. So, the aim of this study was to develop models based on the milling quality data in parboiling process by means of multivariate regression and artificial neural network. In order to validate the neural network model with a little dataset, K-fold cross validation method was applied. The ANN structure with one hidden layer and Tansig transfer function by 18 neurons in the hidden layer was selected as the best model in this study. The results indicated that the neural network could model the parboiling process with higher degree of accuracy. This method was a promising procedure to create accuracy and can be used as a reliable model to select the best parameters for the parboiling process with little experiment dataset.



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The effect of mechanical processing on avenanthramide and phenol levels in two organically grown Italian oat cultivars

Abstract

Avenanthramides (AVNs), free and bound phenols and their antioxidant capacities (ORAC) were evaluated in two Avena sativa L. cultivars, Donata and Flavia. The cultivars (cvs.) were grown in loamy and medium texture soils and assessed after industrial dehulling and milling. Total dietary fiber, β-glucan, starch and proteins were also evaluated. Cv. Donata showed 2.8 fold higher AVN storage as compared to cv. Flavia, which was linked with genotype. The accumulation of AVN content was also influenced by the texture of the soil. Dehulling resulted in a 75 and 37% AVN decrease in cv. Donata and Flavia, respectively. The dehulled grains of cv. Donata showed 40% reduction in free phenolic content, whereas the dehulled grains of both cvs. showed 67% reduction in bound phenols. Milling affected the bound phenolics and their antioxidant capacity. Cv. Flavia showed 1.3 fold higher β-glucan than that of cv. Donata. Total dietary fiber was reduced by 50 and 12% after dehulling and milling, respectively, while marginal changes in proteins were observed after milling. The results suggest that the choice of genotype and the kind of dehulling processes that are employed are essential considerations in the production of oat-based products with high AVN content and extra health benefits.



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Comparison of echocardiographic parameters to assess right ventricular function in pulmonary hypertension

Abstract

Although measurement of right ventricular ejection fraction (RVEF) may be relevant for evaluation of therapeutic efficacy and/or prognosis in patients with pulmonary hypertension, RVEF obtained by echocardiography has limited accuracy. In contrast, radionuclide and/or magnetic resonance imaging can measure RVEF more reliably. In this study, we investigated the relationship between RVEF measured by radionuclide angiography and the echocardiographic parameters that are recommended by the American Society of Echocardiography as representative of right heart function. There were 23 study participants with pulmonary hypertension who underwent radionuclide angiography and 2-dimensional and Doppler echocardiography (n = 30 measurements). RVEF measured by radionuclide angiography correlated with right ventricular Tei index (RV Tei index) measured by Doppler echocardiography (r = −0.601, P < 0.0005). Receiver operating characteristic curve analysis showed that an RV Tei index cut-off value of 0.371 was the best of predictor of RVEF ≤35% (area under the curve = 0.768, sensitivity = 0.857, selectivity = 0.667). Multiple regression analysis showed that RVEF was correlated with the RV Tei index, and this association was independent of other echocardiographic right ventricular function parameters (r = −0.644, P < 0.005). The RV Tei index measured by Doppler echocardiography may be an acceptable surrogate marker of RVEF in patients with pulmonary hypertension.



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Finite element method simulating temperature distribution in skin induced by 980-nm pulsed laser based on pain stimulation

Abstract

For predicting the temperature distribution within skin tissue in 980-nm laser-evoked potentials (LEPs) experiments, a five-layer finite element model (FEM-5) was constructed based on Pennes bio-heat conduction equation and the Lambert-Beer law. The prediction results of the FEM-5 model were verified by ex vivo pig skin and in vivo rat experiments. Thirty ex vivo pig skin samples were used to verify the temperature distribution predicted by the model. The output energy of the laser was 1.8, 3, and 4.4 J. The laser spot radius was 1 mm. The experiment time was 30 s. The laser stimulated the surface of the ex vivo pig skin beginning at 10 s and lasted for 40 ms. A thermocouple thermometer was used to measure the temperature of the surface and internal layers of the ex vivo pig skin, and the sampling frequency was set to 60 Hz. For the in vivo experiments, nine adult male Wistar rats weighing 180 ± 10 g were used to verify the prediction results of the model by tail-flick latency. The output energy of the laser was 1.4 and 2.08 J. The pulsed width was 40 ms. The laser spot radius was 1 mm. The Pearson product-moment correlation and Kruskal-Wallis test were used to analyze the correlation and the difference of data. The results of all experiments showed that the measured and predicted data had no significant difference (P > 0.05) and good correlation (r > 0.9). The safe laser output energy range (1.8–3 J) was also predicted. Using the FEM-5 model prediction, the effective pain depth could be accurately controlled, and the nociceptors could be selectively activated. The FEM-5 model can be extended to guide experimental research and clinical applications for humans.



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Preface



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A multiomics approach to study the microbiome response to phytoplankton blooms

Abstract

Phytoplankton blooms are predictable features of marine and freshwater habitats. Despite a good knowledge base of the environmental factors controlling blooms, complex interactions between the bacterial and archaeal communities and phytoplankton bloom taxa are only now emerging. Here, the current research on bacterial community's structural and functional response to phytoplankton blooms is reviewed and discussed and further research is proposed. More attention should be paid on structure and function of autotrophic bacteria and archaea during phytoplankton blooms. A multiomics integration approach is needed to investigate bacterial and archaeal communities' diversity, metabolic diversity, and biogeochemical functions of microbial interactions during phytoplankton blooms.



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Rubisco mutants of Chlamydomonas reinhardtii display divergent photosynthetic parameters and lipid allocation

Abstract

Photosynthesis and lipid allocation were investigated in Rubisco small subunit mutants of the microalga Chlamydomonas reinhardtii. Comparative analyses were undertaken with cells grown photoheterotrophically under sulphur-replete or sulphur-depleted conditions. The Y67A Rubisco mutant, which has previously demonstrated a pronounced reduction in Rubisco levels and higher hydrogen production rates than the wild type, also shows the following divergences in photosynthetic phenotype and lipid allocation: (i) low Fv/Fm (maximum photochemical efficiency), (ii) low effective quantum yield of photosystem II (ΦPSII), (iii) low effectiveness at protection against high light intensities, (iv) a higher level of total lipids per pigment and (v) changes in the relative proportions of different fatty acids, with a marked decrease in unsaturated fatty acids (FAs). The most abundant thylakoid membrane lipid, monogalactosyldiacylglycerol, decreased in amount, while the neutral lipid/polar lipid ratio increased in the mutant. The low amount and activity of the mutated Rubisco Y67A enzyme seems to have an adverse effect on photosynthesis and causes changes in carbon allocation in terms of membrane fatty acid composition and storage lipid accumulation. Our results suggest that Rubisco mutants of Chlamydomonas might be useful in biodiesel production.



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Hybrid peripheral nerve sheath tumors: report of five cases and detailed review of literature

Hybrid peripheral nerve sheath tumors (PNSTs) have been recognized recently and were first included in the 4th edition of World Health Organization (WHO) Classification of Tumors of Soft tissue and Bone, publi...

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Venous thromboembolism in hospitalized patients receiving chemotherapy for malignancies at Japanese community hospital: prospective observational study

Although Asian population was recognized to have a lower risk of venous thromboembolism (VTE), its increasing prevalence and incidence remain unclear in patients with malignancies. We attempted to predict VTE ...

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Multiple sclerosis antibody shrinks tumours in preclinical models

While studying the underpinnings of multiple sclerosis, investigators at Brigham and Women's Hospital came across important clues for how to treat a very different disease: cancer. In a paper published in Science Immunology, a group of researchers led by...

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Forces applied during classical touch assays for Caenorhabditis elegans

by Adam L. Nekimken, Eileen A. Mazzochette, Miriam B. Goodman, Beth L. Pruitt

For decades, Caenorhabditis elegans roundworms have been used to study the sense of touch, and this work has been facilitated by a simple behavioral assay for touch sensation. To perform this classical assay, an experimenter uses an eyebrow hair to gently touch a moving worm and observes whether or not the worm reverses direction. We used two experimental approaches to determine the manner and moment of contact between the eyebrow hair tool and freely moving animals and the forces delivered by the classical assay. Using high-speed video (2500 frames/second), we found that typical stimulus delivery events include a brief moment when the hair is contact with the worm’s body and not the agar substrate. To measure the applied forces, we measured forces generated by volunteers mimicking the classical touch assay by touching a calibrated microcantilever. The mean (61 μN) and median forces (26 μN) were more than ten times higher than the 2-μN force known to saturate the probability of evoking a reversal in adult C. elegans. We also considered the eyebrow hairs as an additional source of variation. The stiffness of the sampled eyebrow hairs varied between 0.07 and 0.41 N/m and was correlated with the free length of hair. Collectively, this work establishes that the classical touch assay applies enough force to saturate the probability of evoking reversals in adult C. elegans in spite of its variability among trials and experimenters and that increasing the free length of the hair can decrease the applied force.

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Genomic and transcriptomic analyses reveal adaptation mechanisms of an Acidithiobacillus ferrivorans strain YL15 to alpine acid mine drainage

by Tangjian Peng, Liyuan Ma, Xue Feng, Jiemeng Tao, Meihua Nan, Yuandong Liu, Jiaokun Li, Li Shen, Xueling Wu, Runlan Yu, Xueduan Liu, Guanzhou Qiu, Weimin Zeng

Acidithiobacillus ferrivorans is an acidophile that often occurs in low temperature acid mine drainage, e.g., that located at high altitude. Being able to inhabit the extreme environment, the bacterium must possess strategies to copy with the survival stress. Nonetheless, information on the strategies is in demand. Here, genomic and transcriptomic assays were performed to illuminate the adaptation mechanisms of an A. ferrivorans strain YL15, to the alpine acid mine drainage environment in Yulong copper mine in southwest China. Genomic analysis revealed that strain has a gene repertoire for metal-resistance, e.g., genes coding for the mer operon and a variety of transporters/efflux proteins, and for low pH adaptation, such as genes for hopanoid-synthesis and the sodium:proton antiporter. Genes for various DNA repair enzymes and synthesis of UV-absorbing mycosporine-like amino acids precursor indicated hypothetical UV radiation—resistance mechanisms in strain YL15. In addition, it has two types of the acquired immune system–type III-B and type I-F CRISPR/Cas modules against invasion of foreign genetic elements. RNA-seq based analysis uncovered that strain YL15 uses a set of mechanisms to adapt to low temperature. Genes involved in protein synthesis, transmembrane transport, energy metabolism and chemotaxis showed increased levels of RNA transcripts. Furthermore, a bacterioferritin Dps gene had higher RNA transcript counts at 6°C, possibly implicated in protecting DNA against oxidative stress at low temperature. The study represents the first to comprehensively unveil the adaptation mechanisms of an acidophilic bacterium to the acid mine drainage in alpine regions.

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Chemically induced disseminated pythiosis in BALB/c mice: A new experimental model for Pythium insidiosum infection

by Juliana S. M. Tondolo, Érico S. Loreto, Pauline C. Ledur, Francielli P. K. Jesus, Taiara M. Silva, Glaucia D. Kommers, Sydney H. Alves, Janio M. Santurio

Pythiosis is a severe and life-threatening disease that affects humans and various animal species. We report a model of vascular/disseminated pythiosis occurring after subcutaneous inoculation of 2 x 104Pythium insidiosum zoospores/mL in immunocompromised BALB/c mice. For this model, we carried out two rounds of experiments. First, we evaluated two protocols of immunosuppression before inoculation: cyclophosphamide at 150 mg/kg (CYP group) and cyclophosphamide 200 mg/kg plus hydrocortisone acetate at 250 mg/kg (CYP+HCA group). It was not possible to obtain mortality in the CYP group; however, the combination of CYP+HCA altered disease outcomes, with mortality rates reaching 60%. Second, we used the CYP+HCA immunosuppression protocol to analyze the histological and immunological statuses triggered by disease. When we inoculated immunocompetent mice with P. insidiosum zoospores, self-healing occurred via increased levels of IL-2, IFN-γ and IL-17A, which are characteristic of the Th1/Th17 cytokine response. For infected and immunosuppressed mice, the cytokine profiles showed high levels of IL-10, IL-6 and TNF-α. Increased IL-10 values are related to fungal infection susceptibility and led us to speculate that infection may be established through suppression of the host immune response. In addition, histopathological evaluation of the kidneys and liver demonstrated the presence of hyphae and the cellular findings suggested an acute vascular inflammation that mimics vascular/disseminated pythiosis in humans. This is the first murine model for pythiosis that is useful both for understanding the pathogenesis of this disease and for evaluating new treatment approaches.

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Disease-related gene module detection based on a multi-label propagation clustering algorithm

by Xue Jiang, Han Zhang, Xiongwen Quan, Zhandong Liu, Yanbin Yin

Detecting disease-related gene modules by analyzing gene expression data is of great significance. It is helpful for exploratory analysis of the interaction mechanisms of genes under complex disease phenotypes. The multi-label propagation algorithm (MLPA) has been widely used in module detection for its fast and easy implementation. The accuracy of MLPA greatly depends on the connections between nodes, and most existing research focuses on measuring the similarity between nodes. However, MLPA does not perform well with loose connections between disease-related genes. Moreover, the biological significance of modules obtained by MLPA has not been demonstrated. To solve these problems, we designed a double label propagation clustering algorithm (DLPCA) based on MLPA to study Huntington’s disease. In DLPCA, in addition to category labels, we introduced pathogenic labels to supervise the process of multi-label propagation clustering. The pathogenic labels contain pathogenic information about disease genes and the hierarchical structure of gene expression data. Experimental results demonstrated the superior performance of DLPCA compared with other conventional gene-clustering algorithms.

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Granulocyte colony-stimulating factor blockade enables dexamethasone to inhibit lipopolysaccharide-induced murine lung neutrophils

by Jesus Banuelos, Yun Cao, Soon Cheon Shin, Bruce S. Bochner, Pedro Avila, Shihong Li, Xin Jiang, Mark W. Lingen, Robert P. Schleimer, Nick Z. Lu

Glucocorticoids promote neutrophilic inflammation, the mechanisms of which are poorly characterized. Using a lipopolysaccharide (LPS)-induced acute murine lung injury model, we determined the role of granulocyte colony-stimulating factor (G-CSF) in mouse lung neutrophil numbers in the absence and presence of dexamethasone, a potent glucocorticoid. G-CSF was blocked using a neutralizing antibody. Airway neutrophil numbers, cytokine levels, and lung injury parameters were measured. Glucocorticoid treatment maintained LPS-induced airway G-CSF while suppressing TNF and IL-6. The addition of anti-G-CSF antibodies enabled dexamethasone to decrease airway G-CSF, neutrophils, and lung injury scores. In LPS-challenged murine lungs, structural cells and infiltrating leukocytes produced G-CSF. In vitro using BEAS 2B bronchial epithelial cells, A549 lung epithelial cells, human monocyte-derived macrophages, and human neutrophils, we found that dexamethasone and proinflammatory cytokines synergistically induced G-CSF. Blocking G-CSF production in BEAS 2B cells using shRNAs diminished the ability of BEAS 2B cells to protect neutrophils from undergoing spontaneous apoptosis. These data support that G-CSF plays a role in upregulation of airway neutrophil numbers by dexamethasone in the LPS-induced acute lung injury model.

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A Rho-associated coiled-coil containing kinases (ROCK) inhibitor, Y-27632, enhances adhesion, viability and differentiation of human term placenta-derived trophoblasts in vitro

by Kenichiro Motomura, Naoko Okada, Hideaki Morita, Mariko Hara, Masato Tamari, Keisuke Orimo, Go Matsuda, Ken-Ichi Imadome, Akio Matsuda, Takeshi Nagamatsu, Mikiya Fujieda, Haruhiko Sago, Hirohisa Saito, Kenji Matsumoto

Although human term placenta-derived primary cytotrophoblasts (pCTBs) represent a good human syncytiotrophoblast (STB) model, in vitro culture of pCTBs is not always easily accomplished. Y-27632, a specific inhibitor of Rho-associated coiled-coil containing kinases (ROCK), reportedly prevented apoptosis and improved cell-to-substrate adhesion and culture stability of dissociated cultured human embryonic stem cells and human corneal endothelial cells. The Rho kinase pathway regulates various kinds of cell behavior, some of which are involved in pCTB adhesion and differentiation. In this study, we examined Y-27632’s potential for enhancing pCTB adhesion, viability and differentiation. pCTBs were isolated from term, uncomplicated placentas by trypsin–DNase I–Dispase II treatment and purified by HLA class I-positive cell depletion. Purified pCTBs were cultured on uncoated plates in the presence of epidermal growth factor (10 ng/ml) and various concentrations of Y-27632. pCTB adhesion to the plates was evaluated by phase-contrast imaging, viability was measured by WST-8 assay, and differentiation was evaluated by immunofluorescence staining, expression of fusogenic genes and hCG-β production. Ras-related C3 botulinum toxin substrate 1 (Rac1; one of the effector proteins of the Rho family) and protein kinase A (PKA) involvement was evaluated by using their specific inhibitors, NSC-23766 and H-89. We found that Y-27632 treatment significantly enhanced pCTB adhesion to plates, viability, cell-to-cell fusion and hCG-β production, but showed no effects on pCTB proliferation or apoptosis. Furthermore, NSC-23766 and H-89 each blocked the effects of Y-27632, suggesting that Y-27632 significantly enhanced pCTB differentiation via Rac1 and PKA activation. Our findings suggest that Rac1 and PKA may be interactively involved in CTB differentiation, and addition of Y-27632 to cultures may be an effective method for creating a stable culture model for studying CTB and STB biology in vitro.

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Evaluations of the setup discrepancy between BrainLAB 6D ExacTrac and cone-beam computed tomography used with the imaging guidance system Novalis-Tx for intracranial stereotactic radiosurgery

by Se An Oh, Jae Won Park, Ji Woon Yea, Sung Kyu Kim

The objective of this study was to evaluate the setup discrepancy between BrainLAB 6 degree-of-freedom (6D) ExacTrac and cone-beam computed tomography (CBCT) used with the imaging guidance system Novalis Tx for intracranial stereotactic radiosurgery. We included 107 consecutive patients for whom white stereotactic head frame masks (R408; Clarity Medical Products, Newark, OH) were used to fix the head during intracranial stereotactic radiosurgery, between August 2012 and July 2016. The patients were immobilized in the same state for both the verification image using 6D ExacTrac and online 3D CBCT. In addition, after radiation treatment, registration between the computed tomography simulation images and the CBCT images was performed with offline 6D fusion in an offline review. The root-mean-square of the difference in the translational dimensions between the ExacTrac system and CBCT was

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First report of a Japanese family with spinocerebellar ataxia type 10: The second report from Asia after a report from China

by Hiroyuki Naito, Tetsuya Takahashi, Masaki Kamada, Hiroyuki Morino, Hiroyo Yoshino, Nobutaka Hattori, Hirofumi Maruyama, Hideshi Kawakami, Masayasu Matsumoto

Spinocerebellar ataxia type 10 (SCA10) is an autosomal-dominant cerebellar ataxia that is variably accompanied by epilepsy and other neurological disorders. It is caused by an expansion of the ATTCT pentanucleotide repeat in intron 9 of the ATXN10 gene. Until now, SCA10 was almost exclusively found in the American continents, while no cases had been identified in Japan. Here, we report the first case of an SCA10 family from Japan. The clinical manifestations in our cases were cerebellar ataxia accompanied by epilepsy, hyperreflexia and cognitive impairment. Although the primary pathology in SCA10 in humans is reportedly the loss of Purkinje cells, brain MRI revealed frontal lobe atrophy with white matter lesions. This pathology might be associated with cognitive dysfunction, indicating that the pathological process is not limited to the cerebellum. Examination of the SNPs surrounding the SCA10 locus in the proband showed the “C-expansion-G-G-C” haplotype, which is consistent with previously reported SCA10-positive individuals. This result was consistent with the findings that the SCA10 mutation may have occurred before the migration of Amerindians from East Asia to North America and the subsequent spread of their descendants throughout North and South America.

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T0001, a variant of TNFR2-Fc fusion protein, exhibits improved Fc effector functions through increased binding to membrane-bound TNFα

by Yijun Shen, Gang Li, Chunying Gu, Ben Chen, Aihua Chen, Hua Li, Bei Gao, Chencai Liang, Jingsong Wu, Tong Yang, Li Jin, Yong Su

T0001 is a recombinant human TNFR-Fc fusion protein mutant; it exhibits higher affinity to TNFα than etanercept and is now being tested in a Phase 1 study in China (ClinicalTrials.gov Identifier: NCT02481180). T0001 can inhibit the binding of soluble TNFα (sTNFα) or membrane-bound TNFα (mTNFα) to TNF receptors. When bound to mTNFα, the Fc-bearing TNFα antagonists have the potential to induce Fc-mediated effects, such as antibody-dependent cellular cytotoxicity (ADCC) and complement-mediated cytotoxicity (CDC) as well as outside-to-inside signals (apoptosis mainly). Recent studies have shown that ADCC may also play an important role in Crohn's disease (CD) and ulcerative colitis (UC). In this study, T0001 presented a higher binding activity on mTNFα than etanercept and similar binding activity with adalimumab and infliximab. Upon the addition of sTNFα, adalimumab and infliximab showed significantly increased binding to FcγRIIIa and C1q than T0001 and etanercept. T0001 exhibited significantly higher ADCC and CDC activity than etanercept, and the potency and the reporter response of T0001 were very close to adalimumab and infliximab in ADCC reporter gene assays. And the similar potency of T0001 was also corroborated by PMBC-based ADCC assay. T0001, but not etanercept could induce apoptosis, while adalimumab and infliximab were more effective. These results suggest that T0001 may not only exert improved efficacy in treating rheumatoid arthritis (RA) because of its high affinity to sTNFα but also has a therapeutic potential in CD and UC due to its increased binding to mTNFα with resultant Fc-associated functions (ADCC, in particular) and improved apoptosis.

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A link between thrifty phenotype and maternal care across two generations of intercrossed mice

by Bruno Sauce, Carolina P. Goes, Isabela Forti, Bruno Gabriel O. do Monte, Isabela M. Watanabe, Joao Cunha, Andrea C. Peripato

Maternal effects are causal influences from mother to offspring beyond genetic information, and have lifelong consequences for multiple traits. Previously, we reported that mice whose mothers did not nurse properly had low birth weight followed by rapid fat accumulation and disturbed development of some organs. That pattern resembles metabolic syndromes known collectively as the thrifty phenotype, which is believed to be an adaptation to a stressful environment which prepares offspring for reduced nutrient supply. The potential link between maternal care, stress reactivity, and the thrifty phenotype, however, has been poorly explored in the human and animal literature: only a couple of studies even mention (much less, test) these concepts under a cohesive framework. Here, we explored this link using mice of the parental inbred strains SM/J and LG/J–who differ dramatically in their maternal care–and the intercrossed generations F1 and F2. We measured individual differences in 15 phenotypes and used structural equation modeling to test our hypotheses. We found a remarkable relationship between thrifty phenotype and lower quality of maternal behaviors, including nest building, pup retrieval, grooming/licking, and nursing. To our knowledge, this is the first study to show, in any mammal, a clear connection between the natural variation in thrifty phenotype and maternal care. Both traits in the mother also had a substantial effect on survival rate in the F3 offspring. To our surprise, however, stress reactivity seemed to play no role in our models. Furthermore, the strain of maternal grandmother, but not of paternal grandmother, affected the variation of maternal care in F2 mice, and this effect was mediated by thrifty phenotype in F2. Since F1 animals were all genetically identical, this finding suggests that maternal effects pass down both maternal care and thrifty phenotype in these mice across generations via epigenetic transmission.

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