JAZF1 Inhibits Adipose Tissue Macrophages and Adipose Tissue Inflammation in Diet-Induced Diabetic Mice

Background. Juxtaposed with another zinc finger gene 1 (JAZF1) affects gluconeogenesis, insulin sensitivity, lipid metabolism, and inflammation, but its exact role in chronic inflammation remains unclear. This study aimed to examine JAZF1 overexpression in vivo on adipose tissue macrophages (ATMs). Methods. Mouse models of high-fat diet- (HFD-) induced insulin resistance were induced using C57BL/6J and JAZF1-overexpressing (JAZF1-OX) mice. The mice were randomized (8–10/group) to C57BL/6J mice fed regular diet (RD) (NC group), C57BL/6J mice fed HFD (HF group), JAZF1-OX mice fed RD (NJ group), and JAZF1-OX mice fed HFD (HJ group). Adipose tissue was harvested 12 weeks later. ATMs were evaluated by flow cytometry. Inflammatory markers were evaluated by ELISA. Results. JAZF1-OX mice had lower blood lipids, blood glucose, body weight, fat weight, and inflammatory markers compared with HF mice (all ). JAZF1 overexpression decreased ATM number and secretion of proinflammatory cytokines. JAZF1 overexpression decreased total CD4+ T cells, active T cells, and memory T cells and increased Treg cells. JAZF1 overexpression downregulated IFN-γ and IL-17 levels and upregulated IL-4 levels. JAZF1 overexpression decreased MHCII, CD40, and CD86 in total ATM, CD11c+ ATM, and CD206+ ATM. Conclusions. JAZF1 limits adipose tissue inflammation by limiting macrophage populations and restricting their antigen presentation function.

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Sialendoscopic Approach in Management of Juvenile Recurrent Parotitis.

Related Articles

Sialendoscopic Approach in Management of Juvenile Recurrent Parotitis.

Indian J Otolaryngol Head Neck Surg. 2017 Dec;69(4):453-458

Authors: Singh PP, Goyal M, Goyal A

Abstract
To assess the role of sialendoscopy as a diagnostic and therapeutic modality in juvenile recurrent parotitis. Juvenile recurrent parotitis (JRP) is the second most frequent salivary gland disease in childhood and is characterized by recurrent non suppurative and non obstructive parotid inflammation. These attacks influence the quality of life and can even lead to gland destruction, and there are no definitive treatment to avoid them. Sialendoscopic dilatation is emerging as the new treatment modality in this aspect.
STUDY DESIGN:  retrospective study.
STUDY SETTING: Department of Otorhinolaryngology in tertiary care hospital. 17 cases of juvenile recurrent parotitis (i.e. children of age group 3-11 years presenting with complaints of recurrent parotid region swelling and pain, sometimes associated with fever) were included in the study during October 2012-September 2015. All cases underwent sialendoscopy under general anaesthesia. Diagnostic (classifying the ductal lesion) and interventional sialendoscopic procedure (dilatation with instillation of steroid) were carried out in single sitting. Follow up was done for a minimum of 6 months (range 6-36 months). 17 patients with mean age of 5.6 years and gender distribution of 47:53 (boys:girls) underwent sialendoscopy for JRP. 8 patients presented with unilateral parotitis and 9 with bilateral. The mean number of attacks in previous 1 year were 9.2. Average time for procedure was 20 min. All cases had ductal stenosis and ductal mucosa was pale in 15 cases on endoscopy. 1 patient underwent repeat endoscopy after 2 years. 50% had complete resolution of symptoms and 6 patients had one mild (swelling not associated with fever which subsided on its own) attack after treatment. Follow up period ranged from 6 months to 3 years. No complications were observed. Sialendoscopy has emerged as a viable option for assessment and treatment of JRP. Dilatation of the parotid duct and steroid instillation has significantly reduced the morbidity of this condition.

PMID: 29238673 [PubMed]

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The event-related potential component P3a is diminished by identical deviance repetition, but not by non-identical repetitions

Abstract

Mismatch negativity (MMN) represents an event-related potential (ERP) component which is elicited by deviant sound events in an otherwise regular, repetitive stimulation. The MMN amplitude typically decreases when two identical deviants are presented in direct succession, but it remains stable when the two deviants vary from the standard in different features. Less is known about such repetition effects on another ERP component, the P3a, which usually follows the MMN. In the current study, we investigated how the P3a was affected by identical and non-identical repetitions of sound deviants. The ERP analysis revealed that the P3a amplitudes were strongly diminished when the repeated deviants were identical, but the P3a remained stable when the repeated deviants varied. The findings suggest that not only the deviance detection system, as reflected in the MMN, but also subsequent attention switch systems, as reflected in the P3a, operate independently across different sound features.

http://ift.tt/2GaAg17

Stability of steady hand force production explored across spaces and methods of analysis

Abstract

We used the framework of the uncontrolled manifold (UCM) hypothesis and explored the reliability of several outcome variables across different spaces of analysis during a very simple four-finger accurate force production task. Fourteen healthy, young adults performed the accurate force production task with each hand on 3 days. Small spatial finger perturbations were generated by the "inverse piano" device three times per trial (lifting the fingers 1 cm/0.5 s and lowering them). The data were analyzed using the following main methods: (1) computation of indices of the structure of inter-trial variance and motor equivalence in the space of finger forces and finger modes, and (2) analysis of referent coordinates and apparent stiffness values for the hand. Maximal voluntary force and the index of enslaving (unintentional finger force production) showed good to excellent reliability. Strong synergies stabilizing total force were reflected in both structure of variance and motor equivalence indices. Variance within the UCM and the index of motor equivalent motion dropped over the trial duration and showed good to excellent reliability. Variance orthogonal to the UCM and the index of non-motor equivalent motion dropped over the 3 days and showed poor to moderate reliability. Referent coordinate and apparent stiffness indices co-varied strongly and both showed good reliability. In contrast, the computed index of force stabilization showed poor reliability. The findings are interpreted within the scheme of neural control with referent coordinates involving the hierarchy of two basic commands, the r-command and c-command. The data suggest natural drifts in the finger force space, particularly within the UCM. We interpret these drifts as reflections of a trade-off between stability and optimization of action. The implications of these findings for the UCM framework and future clinical applications are explored in the discussion. Indices of the structure of variance and motor equivalence show good reliability and can be recommended for applied studies.

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Cold Shock as a Screen for Genes Involved in Cold Acclimatization in Neurospora crassa

When subjected to rapid drops of temperature (cold shock), Neurospora responds with a temporary shift in its morphology. This report is the first to examine this response genetically. We report here the results of a screen of selected mutants from the Neurospora knockout library for alterations in their morphological response to cold shock. Three groups of knockouts were selected to be subject to this screen: genes previously suspected to be involved in hyphal development as well as knockouts resulting in morphological changes; transcription factors; and genes homologous to E. coli genes known to alter their expression in response to cold shock. A total of 344 knockout strains were subjected to cold shock. Of those, 118 strains were identified with altered responses. We report here the cold shock morphologies and GO categorizations of strains subjected to this screen. Of strains with knockouts in genes associated with hyphal growth or morphology, 33 of 131 tested (25%) showed an altered response to cold shock. Of strains with knockouts in transcription factor genes, 30 of 145 (20%) showed an altered response to cold shock. Of strains with knockouts in genes homologous to E. coli genes which display altered levels of transcription in response to cold shock, a total of 55 of 68 tested (81%) showed an altered cold shock response. This suggests that the response to cold shock in these two organisms is largely shared in common.

http://ift.tt/2FSePCC

Site-Specific Fat-1 Knock-in Enables Significant Decrease of n-6PUFAs/n-3PUFAs Ratio in Pigs

The fat-1 gene from Caenorhabditis elegans encodes a fatty acid desaturase which was widely studied due to its beneficial function of converting n-6 polyunsaturated fatty acids (n-6PUFAs) to n-3 polyunsaturated fatty acids (n-3PUFAs). To date, many fat-1 transgenic animals have been generated to study disease pathogenesis or improve meat quality. However, all of them were generated using a random integration method with variable transgene expression levels and the introduction of selectable marker genes often raise biosafety concern. To this end, we aimed to generate marker-free fat-1 transgenic pigs in a site-specific manner. The Rosa26 locus, first found in mouse embryonic stem cells, has become one of the most common sites for inserting transgenes due to its safe and ubiquitous expression. In our study, the fat-1 gene was inserted into porcine Rosa 26 (pRosa26) locus via Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated 9 (Cas9) system. The Southern blot analysis of our knock-in pigs indicated a single copy of the fat-1 gene at the pRosa26 locus. Furthermore, this single-copy fat-1 gene supported satisfactory expression in a variety of tissues in F1 generation pigs. Importantly, the gas chromatography analysis indicated that these fat-1 knock-in pigs exhibited a significant increase in the level of n-3PUFAs, leading to an obvious decrease in the n-6PUFAs/n-3PUFAs ratio from 9.36 to 2.12 (***P<0.0001). Altogether, our fat-1 knock-in pigs hold great promise for improving the nutritional value of pork and serving as an animal model to investigate therapeutic effects of n-3PUFAs on various diseases.

http://ift.tt/2HQLuFd

Comparison of the Relative Potential for Epigenetic and Genetic Variation To Contribute to Trait Stability

The theoretical ability of epigenetic variation to influence the heritable variation of complex traits is gaining traction in the study of adaptation. This theory posits that epigenetic marks can control adaptive phenotypes but the relative potential of epigenetic variation in comparison to genetic variation in these traits is not presently understood. To compare the potential of epigenetic and genetic variation in adaptive traits, we analyzed the influence of DNA methylation variation on the accumulation of chemical defense compounds glucosinolates from the order Brassicales. Several decades of work on glucosinolates has generated extensive knowledge about their synthesis, regulation, genetic variation and contribution to fitness establishing this pathway as a model pathway for complex adaptive traits. Using high-throughput phenotyping with a randomized block design of ddm1 derived Arabidopsis thaliana epigenetic Recombinant Inbred Lines, we measured the correlation between DNA methylation variation and mean glucosinolate variation and within line stochastic variation. Using this information, we identified epigenetic Quantitative Trait Loci that contained specific Differentially Methylated Regions associated with glucosinolate traits. This showed that variation in DNA methylation correlates both with levels and variance of glucosinolates and flowering time with trait-specific loci. By conducting a meta-analysis comparing the results to different genetically variable populations, we conclude that the influence of DNA methylation variation on these adaptive traits is much lower than the corresponding impact of standing genetic variation. As such, selective pressure on these traits should mainly affect standing genetic variation to lead to adaptation.

http://ift.tt/2FTgQ1v

Inter-replicon Gene Flow Contributes to Transcriptional Integration in the Sinorhizobium meliloti Multipartite Genome

Integration of newly acquired genes into existing regulatory networks is necessary for successful horizontal gene transfer (HGT). Ten percent of bacterial species contain at least two DNA replicons over 300 kilobases in size, with the secondary replicons derived predominately through HGT. The Sinorhizobium meliloti genome is split between a 3.7 Mb chromosome, a 1.7 Mb chromid consisting largely of genes acquired through ancient HGT, and a 1.4 Mb megaplasmid consisting primarily of recently acquired genes. Here, RNA-sequencing is used to examine the transcriptional consequences of massive, synthetic genome reduction produced through the removal of the megaplasmid and/or the chromid. Removal of the megaplasmid influenced the transcription of only six genes. In contrast, removal of the chromid influenced expression of ~ 8% of chromosomal genes and ~ 4% of megaplasmid genes. This was mediated in part by the loss of the ETR DNA region whose presence on pSymB is due to a translocation from the chromosome. No obvious functional bias among the up-regulated genes was detected, although genes with putative homologs on the chromid were enriched. Down-regulated genes were enriched in motility and sensory transduction pathways. Four transcripts were examined further, and in each case the transcriptional change could be traced to loss of specific pSymB regions. In particularly, a chromosomal transporter was induced due to deletion of bdhA likely mediated through 3-hydroxybutyrate accumulation. These data provide new insights into the evolution of the multipartite bacterial genome, and more generally into the integration of horizontally acquired genes into the transcriptome.

http://ift.tt/2u8mOWF

Occult cardiac lymphoma and sudden death

Abstract

A 56-year-old man with no previous medical history collapsed and was not able to be resuscitated. The major findings at autopsy were enlargement of the heart (weight = 527 g) which contained an infiltrating firm, homogeneous tumor in an epicardial location adjacent to the left anterior descending and right coronary arteries, with further extension into the right ventricular outflow tract, the interventricular septum and left ventricular free wall. Sections showed sheets of small lymphoid cells with scattered large lymphocytes amounting to a low-grade follicular non-Hodgkin lymphoma, as tumor cells were CD20, CD10, Bcl 2 and LMO 2 positive. This case demonstrates a very rare cause of sudden and unexpected death that resulted from a low-grade follicular lymphoma in an asymptomatic, immunocompetent individual.

http://ift.tt/2FTowAL

Reply to `Comment on `Clinical significance of BRAF non-V600E mutations on the therapeutic effects of anti-EGFR monoclonal antibody treatment in patients with pretreated metastatic colorectal cancer: the Biomarker Research for anti-EGFR monoclonal Antibodies by Comprehensive Cancer genomics (BREAC) study''

Reply to `Comment on `Clinical significance of BRAF non-V600E mutations on the therapeutic effects of anti-EGFR monoclonal antibody treatment in patients with pretreated metastatic colorectal cancer: the Biomarker Research for anti-EGFR monoclonal Antibodies by Comprehensive Cancer genomics (BREAC) study''

Reply to `Comment on `Clinical significance of BRAF non-V600E mutations on the therapeutic effects of anti-EGFR monoclonal antibody treatment in patients with pretreated metastatic colorectal cancer: the Biomarker Research for anti-EGFR monoclonal Antibodies by Comprehensive Cancer genomics (BREAC) study'', Published online: 22 March 2018; doi:10.1038/s41416-018-0040-y

Reply to `Comment on `Clinical significance of BRAF non-V600E mutations on the therapeutic effects of anti-EGFR monoclonal antibody treatment in patients with pretreated metastatic colorectal cancer: the Biomarker Research for anti-EGFR monoclonal Antibodies by Comprehensive Cancer genomics (BREAC) study''

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Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma

Sunitinib, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, is a standard of care for first-line treatment of advanced renal-cell carcinoma. In a large, randomized, phase 3 trial involving previously untreated patients, the median progression-free survival with sunitinib was…

http://ift.tt/2FT0uWF

In breast cancer subtypes steroid sulfatase (STS) is associated with less aggressive tumour characteristics

In breast cancer subtypes steroid sulfatase (STS) is associated with less aggressive tumour characteristics

In breast cancer subtypes steroid sulfatase (STS) is associated with less aggressive tumour characteristics, Published online: 22 March 2018; doi:10.1038/s41416-018-0034-9

In breast cancer subtypes steroid sulfatase (STS) is associated with less aggressive tumour characteristics

http://ift.tt/2DLwFkJ

Trends and projections in adenocarcinoma and squamous cell carcinoma of the oesophagus in England from 1971 to 2037

Trends and projections in adenocarcinoma and squamous cell carcinoma of the oesophagus in England from 1971 to 2037

Trends and projections in adenocarcinoma and squamous cell carcinoma of the oesophagus in England from 1971 to 2037, Published online: 22 March 2018; doi:10.1038/s41416-018-0047-4

Trends and projections in adenocarcinoma and squamous cell carcinoma of the oesophagus in England from 1971 to 2037

http://ift.tt/2GONZIE

A multicentre, open-label, phase-I/randomised phase-II study to evaluate safety, pharmacokinetics, and efficacy of nintedanib vs. sorafenib in European patients with advanced hepatocellular carcinoma

A multicentre, open-label, phase-I/randomised phase-II study to evaluate safety, pharmacokinetics, and efficacy of nintedanib vs. sorafenib in European patients with advanced hepatocellular carcinoma

A multicentre, open-label, phase-I/randomised phase-II study to evaluate safety, pharmacokinetics, and efficacy of nintedanib vs. sorafenib in European patients with advanced hepatocellular carcinoma, Published online: 22 March 2018; doi:10.1038/s41416-018-0051-8

A multicentre, open-label, phase-I/randomised phase-II study to evaluate safety, pharmacokinetics, and efficacy of nintedanib vs. sorafenib in European patients with advanced hepatocellular carcinoma

http://ift.tt/2DJ0ORO

The tyrosine-kinase inhibitor sunitinib targets vascular endothelial (VE)-cadherin: a marker of response to antitumoural treatment in metastatic renal cell carcinoma

The tyrosine-kinase inhibitor sunitinib targets vascular endothelial (VE)-cadherin: a marker of response to antitumoural treatment in metastatic renal cell carcinoma

The tyrosine-kinase inhibitor sunitinib targets vascular endothelial (VE)-cadherin: a marker of response to antitumoural treatment in metastatic renal cell carcinoma, Published online: 22 March 2018; doi:10.1038/s41416-018-0054-5

The tyrosine-kinase inhibitor sunitinib targets vascular endothelial (VE)-cadherin: a marker of response to antitumoural treatment in metastatic renal cell carcinoma

http://ift.tt/2HShZmh

Fasting blood glucose, glycaemic control and prostate cancer risk in the Finnish Randomized Study of Screening for Prostate Cancer

Fasting blood glucose, glycaemic control and prostate cancer risk in the Finnish Randomized Study of Screening for Prostate Cancer

Fasting blood glucose, glycaemic control and prostate cancer risk in the Finnish Randomized Study of Screening for Prostate Cancer, Published online: 22 March 2018; doi:10.1038/s41416-018-0055-4

Fasting blood glucose, glycaemic control and prostate cancer risk in the Finnish Randomized Study of Screening for Prostate Cancer

http://ift.tt/2GONVZq

Chimeric Antigen Receptor T Cell-Mediated Neurotoxicity in Non-Human Primates [Research Articles]

Chimeric Antigen Receptor (CAR) T cell immunotherapy has revolutionised the treatment of refractory leukemias and lymphomas, but is associated with significant toxicities, namely cytokine release syndrome (CRS) and neurotoxicity. A major barrier to developing therapeutics to prevent CAR T cell-mediated neurotoxicity is the lack of clinically relevant models. Accordingly, we developed a rhesus macaque (RM) model of neurotoxicity via adoptive transfer of autologous CD20-specific CAR T cells. Following cyclophosphamide lymphodepletion, CD20 CAR T cells expand to 272-4450 cells/µl after 7-8 days and elicit CRS and neurotoxicity. Toxicities are associated with elevated serum IL-6, IL-8, IL-1RA, MIG and I-TAC levels, and disproportionately high cerebrospinal fluid (CSF) IL-6, IL-2, GM-CSF and VEGF levels. During neurotoxicity, both CD20 CAR and non-CAR T cells accumulate in the CSF and in the brain parenchyma. This RM model demonstrates that CAR T cell-mediated neurotoxicity is associated with pro-inflammatory CSF cytokines and a pan-T cell encephalitis.

http://ift.tt/2IHDXJS

Identification of CRKII, CFL1, CNTN1, NME2, and TKT as Novel and Frequent T-cell Targets in Human IDH-Mutant Glioma

Purpose: Successful immunotherapies for IDH mut gliomas require better knowledge of T-cell target antigens. Here, we elucidated their antigen repertoire recognized by spontaneous T-cell responses using an unbiased proteomic approach. Experimental Design: Protein fractionations of tissue lysates from IDH mut gliomas (n=4) were performed. Fractions were tested by IFN-E; ELISpot assay for recognition through patient's T-cells. Proteins of immunogenic fractions were identified by mass spectrometry and validated by in silico-predicted synthetic long-peptides in patients of origin, additional IDH mut glioma patients (n=16), and healthy donors (n=13). mRNA and protein expression of immunogenic antigens was analyzed in tumor tissues and IDH mut glioma stem-like cells (GSCs). HLA-A*02-restricted T-cell epitopes were functionally determined by short peptides and numbers of antigen-specific T-cells by HLA-peptide tetramer analysis. Results: 2,897 proteins were identified in immunogenic tumor fractions. Based on a thorough filter process 79 proteins were selected as potential T-cell antigens. 26 of these were recognized by the patients' T-cells and five of them (CRKII, CFL1, CNTN1, NME2, and TKT) in up to 56% unrelated IDH mut glioma patients. Most immunogenic tumor-associated antigens (TAAs) were expressed in IDH mut gliomas and GSCs, while being almost absent in normal brain tissues. Finally, we identified HLA-A*02-restricted epitopes for CRKII, NME2, and TKT that were recognized by up to 2.82% of antigen-specific peripheral cytotoxic T-cells in IDH mut glioma patients. Conclusion: By analyzing the repertoire of T-cell target antigens in IDH mut glioma patients, we identified five novel immunogenic TAAs and confirmed their expression on IDH mut tumors and GSCs.

http://ift.tt/2FSfPXm

Induction of Telomere Dysfunction Prolongs Disease Control of Therapy-Resistant Melanoma

Purpose: Telomerase promoter mutations are highly prevalent in human tumors including melanoma. A subset of patients with metastatic melanoma often fail multiple therapies and there is an unmet and urgent need to prolong disease control for those patients. Experimental Design: Numerous pre-clinical therapy-resistant models of human and mouse melanoma were used to test the efficacy of a telomerase-directed nucleoside, 6-thio-2'-deoxyguanosine (6-thio-dG). Integrated transcriptomics and proteomics approaches were used to identify genes and proteins that were significantly down-regulated by 6-thio-dG.  Results: We demonstrated the superior efficacy of 6-thio-dG both in vitro and in vivo that results in telomere dysfunction, leading to apoptosis and cell death in various pre-clinical models of therapy-resistant melanoma cells. 6-thio-dG concomitantly induces telomere dysfunction and inhibits the expression level of AXL. Conclusions: In summary, this study shows that indirectly targeting aberrant telomerase in melanoma cells with 6-thio-dG is a viable therapeutic approach in prolonging disease control and overcoming therapy resistance.

http://ift.tt/2HWIlUu

A new approach to predict progression-free survival in stage IV EGFR-mutant NSCLC patients with EGFR-TKI therapy

Purpose: We established a computed tomography (CT)-derived approach to achieve accurate progression-free survival (PFS) prediction to EGFR tyrosine kinase inhibitors (TKIs) therapy in multicenter, stage IV EGFR-mutated non-small-cell lung cancer (NSCLC) patients. Experimental Design: 1032 CT-based phenotypic characteristics were extracted according to the intensity, shape and texture of NSCLC pre-therapy images. Based on these CT features extracted from 117 stage IV EGFR-mutant NSCLC patients, a CT-based phenotypic signature was proposed using a Cox regression model with LASSO penalty for the survival risk stratification of EGFR-TKI therapy. The signature was validated using two independent cohorts (101 and 96 patients, respectively). The benefit of EGFR-TKIs in stratified patients was then compared with another stage-IV EGFR-mutant NSCLC cohort only treated with standard chemotherapy (56 patients). Furthermore, an individualized prediction model incorporating the phenotypic signature and clinicopathologic risk characteristics was proposed for PFS prediction, and also validated by multicenter cohorts. Results: The signature consisted of 12 CT features demonstrated good accuracy for discriminating patients with rapid- and slow-progression to EGFR-TKI therapy in three cohorts (hazard ratio: 3.61, 3.77 and 3.67, respectively). Rapid-progression patients received EGFR TKIs did not show significant difference with patients underwent chemotherapy for progression-free survival benefit (p = 0.682). Decision curve analysis revealed that the proposed model significantly improved the clinical benefit compared with the clinicopathologic-based characteristics model (p < 0.0001). Conclusions:The proposed CT-based predictive strategy can achieve individualized prediction of PFS probability to EGFR-TKI therapy in NSCLCs, which holds promise of improving the pre-therapy personalized management of TKIs.

http://ift.tt/2Gcnpvj

The pattern of Mesenchymal stem cell expression is an independent marker of outcome in multiple myeloma.

Purpose: Mesenchymal stem cells (MSCs) are an essential component of the bone marrow (BM) microenvironment and have shown to support cancer evolution in multiple myeloma (MM). Despite the increasing evidence that MM MSCs differ from their healthy counterparts, little knowledge exists as to whether MSCs independently influence disease outcome. The aim of the present study was to determine the importance of MSCs in disease progression and outcome in MM. Experimental Design: To determine the impact of MSCs on MM outcome in an in vivo system, we first identified genes from cultured MSCs that were specific to MSC expression and were not or minimally expressed in PCs or other cells present in BM aspirates. We then applied this MSC gene signature to whole BM biopsies of MM patients compared to healthy controls and determined MSC expression scores specific to MM and predictive of outcome. Results: We show that MM MSC gene expression signatures are able to differentiate MM from monoclonal gammopathy (MGUS) and smoldering MM (SMM) as well as from healthy controls and treated MM patients that have achieved a complete remission (CR). We identified a prognostic gene score based on three MSC specific genes COL4A1, NPR3 and ITGBL1, that was able to predict progression free survival (PFS) in MM patients and progression into MM from SMM. Conclusions: Our findings show that progression of MM and of SMM into MM not solely relies on intrinsic PC factors, but is independently impacted by the biology of the surrounding microenvironment.

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Ensartinib (X-396) in ALK-positive Non-Small Cell Lung Cancer: Results from a First-in-Human Phase I/II, Multicenter Study

Purpose:Evaluate safety and determine the recommended phase II dose (RP2D) of ensartinib (X-396), a potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), and evaluate preliminary pharmacokinetics and antitumor activity in a first-in-human, phase I/II clinical trial primarily in patients with non-small cell lung cancer (NSCLC). Experimental Design: In dose escalation, ensartinib was administered at doses of 25–250 mg once daily in patients with advanced solid tumors; in dose expansion, patients with advanced ALK-positive NSCLC were administered 225 mg once daily. Patients who had received prior ALK TKI(s) and patients with brain metastases were allowed. Results: Thirty-seven patients enrolled in dose escalation, and 60 enrolled in dose expansion. The most common treatment-related toxicities were rash (56%), nausea (36%), pruritus (28%), vomiting (26%), and fatigue (22%); 23% of patients experienced a treatment-related Grade 3-4 toxicity (primarily rash and pruritus). The maximum tolerated dose was not reached, but the RP2D was chosen as 225 mg based on the frequency of rash observed at 250 mg without improvement in activity. Among the ALK-positive efficacy evaluable patients treated at ≥200 mg, the response rate (RR) was 60% and median progression-free survival (PFS) was 9.2 months. RR in ALK TKI naïve patients was 80% and median PFS was 26.2 months. In patients with prior crizotinib only, the RR was 69% and median PFS was 9.0 months. Responses were also observed in the central nervous system, with an intracranial RR of 64%. Conclusions: Ensartinib was active and generally well tolerated in patients with ALK-positive NSCLC.

http://ift.tt/2FSfIuU

Saline Shortages — Many Causes, No Simple Solution

Severe and long-standing prescription-drug shortages have become a major threat to public health and patient safety. Despite increased awareness and mitigation strategies, the United States has experienced shortages of many lifesaving drugs and other supplies essential to patient care. There was…

http://ift.tt/2uc00W9

Facing the Shortage of IV Fluids — A Hospital-Based Oral Rehydration Strategy

Puerto Rico produces 44% of the intravenous (IV) fluid bags used in the United States. On September 20, 2017, Hurricane Maria struck the island, causing a humanitarian crisis and widespread devastation that escalated a critical shortage of IV fluids throughout the United States. Initially,…

http://ift.tt/2puRv3E

Facing the Shortage of IV Fluids — A Hospital-Based Oral Rehydration Strategy

Puerto Rico produces 44% of the intravenous (IV) fluid bags used in the United States. On September 20, 2017, Hurricane Maria struck the island, causing a humanitarian crisis and widespread devastation that escalated a critical shortage of IV fluids throughout the United States. Initially,…

http://ift.tt/2puRv3E

Saline Shortages — Many Causes, No Simple Solution

Severe and long-standing prescription-drug shortages have become a major threat to public health and patient safety. Despite increased awareness and mitigation strategies, the United States has experienced shortages of many lifesaving drugs and other supplies essential to patient care. There was…

http://ift.tt/2uc00W9

Saline Shortages — Many Causes, No Simple Solution

Severe and long-standing prescription-drug shortages have become a major threat to public health and patient safety. Despite increased awareness and mitigation strategies, the United States has experienced shortages of many lifesaving drugs and other supplies essential to patient care. There was…

http://ift.tt/2uc00W9

Facing the Shortage of IV Fluids — A Hospital-Based Oral Rehydration Strategy

Puerto Rico produces 44% of the intravenous (IV) fluid bags used in the United States. On September 20, 2017, Hurricane Maria struck the island, causing a humanitarian crisis and widespread devastation that escalated a critical shortage of IV fluids throughout the United States. Initially,…

http://ift.tt/2puRv3E

Long non-coding RNA CASC2 inhibits tumorigenesis via the miR-181a/PLXNC1 axis in melanoma

Abstract

Melanoma is the most malignant and aggressive form of skin carcinoma originating in the pigment-producing melanocytes. In this study, to further investigate the molecular mechanisms of the development and progression of melanoma, we explored the impacts of long non-coding RNA (lncRNA) CASC2 on melanoma cell functions. Microarray analysis was carried out to identify the expression of lncRNA CASC2 in melanoma cells. MiR-181a was predicted as a sponging target of CASC2 by miRcode, while the 3′-UTR of Plexin C1 (PLXNC1) was a potential target of miR-181a according to the TargetScan database. The correlation among CASC2, miR-181a, and PLXNC1 was verified by dual luciferase reporter assay and qRT-PCR. After manipulation of CASC2, miR-181a and PLXNC1 expression with transfection in A375 and M14 cells, cell viability, apoptosis, and invasive ability were evaluated using CCK-8, flow cytometry and Transwell assays, respectively. A low expression of CASC2 was detected in melanoma tissues and cells. Dual luciferase reporting assay confirmed that miR-181a targeted the 3′-UTR of PLXNC1. Furthermore, CASC2 could efficiently sponge miR-181a, thereby facilitating the expression of PLXNC1. Up-regulation of CASC2 suppressed the cell proliferation and invasion, but induced the apoptosis of melanoma cells. Our results demonstrated that lncRNA CASC2 can promote PLXNC1 expression by sponging miR-181a, thereby inhibiting the proliferation and invasion of melanoma cells, indicating that lncRNA CASC2 functions via the miR-181a/PLXNC1 axis in melanoma.

http://ift.tt/2HVJ9bR

A multicentre, open-label, phase-I/randomised phase-II study to evaluate safety, pharmacokinetics, and efficacy of nintedanib vs. sorafenib in European patients with advanced hepatocellular carcinoma

http://ift.tt/2u7AGAD

Trends and projections in adenocarcinoma and squamous cell carcinoma of the oesophagus in England from 1971 to 2037

http://ift.tt/2pu1iXG

Comment on ‘Clinical significance of BRAF non-V600E mutations on the therapeutic effects of anti-EGFR monoclonal antibody treatment in patients with pretreated metastatic colorectal cancer: the Biomarker Research for anti-EGFR monoclonal Antibodies by Comprehensive Cancer genomics (BREAC) study’

http://ift.tt/2DKAqH5

The tyrosine-kinase inhibitor sunitinib targets vascular endothelial (VE)-cadherin: a marker of response to antitumoural treatment in metastatic renal cell carcinoma

http://ift.tt/2prN5dW

In breast cancer subtypes steroid sulfatase (STS) is associated with less aggressive tumour characteristics

http://ift.tt/2DJ04w3

Fasting blood glucose, glycaemic control and prostate cancer risk in the Finnish Randomized Study of Screening for Prostate Cancer

http://ift.tt/2puihck

Reply to `Comment on `Clinical significance of BRAF non-V600E mutations on the therapeutic effects of anti-EGFR monoclonal antibody treatment in patients with pretreated metastatic colorectal cancer: the Biomarker Research for anti-EGFR monoclonal Antibodies by Comprehensive Cancer genomics (BREAC) study''

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Middle-aged tooth loss linked to increased coronary heart disease risk

Losing two or more teeth during middle age is associated with increased cardiovascular disease risk. Having fewer natural teeth by middle age is linked to higher cardiovascular disease risk.

http://ift.tt/2Gfkhif

Use of Anti-phospho-girdin Antibodies to Visualize Intestinal Tuft Cells in Free-Floating Mouse Jejunum Cryosections

Kuga et al. discovered that phosphorylation-status specific antibodies against the actin binding protein girdin phosphorylated at tyrosine 1798 (pY1798) can be used to label tuft cells (TCs). This protocol allows robust visualization of TCs using immunofluorescent staining of free-floating jejunum cryosections with pY1798 antibodies.

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National DNA Day!

It is fitting that this year's Academy Research Conference, "Genetics & Hearing Loss" falls exactly one week prior to National DNA Day, April 25.

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http://ift.tt/2G2dzsF

Tracking Drosophila Larval Behavior in Response to Optogenetic Stimulation of Olfactory Neurons

This protocol analyzes navigational behavior of Drosophila larva in response to simultaneous optogenetic stimulation of its olfactory neurons. Light of 630 nm wavelength is used to activate individual olfactory neurons expressing a red-shifted channel rhodopsin. Larval movement is simultaneously tracked, digitally recorded, and analyzed using custom-written software.

http://ift.tt/2FXa46J

Cancers, Vol. 10, Pages 88: Use of the Ion PGM and the GeneReader NGS Systems in Daily Routine Practice for Advanced Lung Adenocarcinoma Patients: A Practical Point of View Reporting a Comparative Study and Assessment of 90 Patients

Cancers, Vol. 10, Pages 88: Use of the Ion PGM and the GeneReader NGS Systems in Daily Routine Practice for Advanced Lung Adenocarcinoma Patients: A Practical Point of View Reporting a Comparative Study and Assessment of 90 Patients

Cancers doi: 10.3390/cancers10040088

Authors: Simon Heeke Véronique Hofman Elodie Long-Mira Virginie Lespinet Salomé Lalvée Olivier Bordone Camille Ribeyre Virginie Tanga Jonathan Benzaquen Sylvie Leroy Charlotte Cohen Jérôme Mouroux Charles Marquette Marius Ilié Paul Hofman

Background: With the integration of various targeted therapies into the clinical management of patients with advanced lung adenocarcinoma, next-generation sequencing (NGS) has become the technology of choice and has led to an increase in simultaneously interrogated genes. However, the broader adoption of NGS for routine clinical practice is still hampered by sophisticated workflows, complex bioinformatics analysis and medical interpretation. Therefore, the performance of the novel QIAGEN GeneReader NGS system was compared to an in-house ISO-15189 certified Ion PGM NGS platform. Methods: Clinical samples from 90 patients (60 Retrospectively and 30 Prospectively) with lung adenocarcinoma were sequenced with both systems. Mutations were analyzed and EGFR, KRAS, BRAF, NRAS, ALK, PIK3CA and ERBB2 genes were compared and sampling time and suitability for clinical testing were assessed. Results: Both sequencing systems showed perfect concordance for the overlapping genes. Correlation of allele frequency was r2 = 0.93 for the retrospective patients and r2 = 0.81 for the prospective patients. Hands-on time and total run time were shorter using the PGM system, while the GeneReader platform provided good traceability and up-to-date interpretation of the results. Conclusion: We demonstrated the suitability of the GeneReader NGS system in routine practice in a clinical pathology laboratory setting.

http://ift.tt/2IGNukp

EMS on the Hill: The importance of political advocacy

By Allison G. S. Knox, EMT-B, faculty member at American Military University Emergency medical services are a critically important part of public safety, but its voice is not as loud as that of other healthcare entities, such as insurance providers, pharmaceutical companies and hospital networks. There needs to be considerably more support for EMS – both from those working in the profession as ...

http://ift.tt/2IJGt2A

Model Surgical Training: Skills Acquisition in Fetoscopic Laser Photocoagulation of Monochorionic Diamniotic Twin Placenta Using Realistic Simulators

Practicing the specific skills required for fetoscopic laser coagulation of monochorionic placental anastomoses on realistic models can aid less experienced surgeons in overcoming the steep learning curve associated with this procedure that is now regarded as the standard of care for twin-twin transfusion syndrome.

http://ift.tt/2GaHGkN

Atmospheric Pressure Fabrication of Large-Sized Single-Layer Rectangular SnSe Flakes

A protocol is presented demonstrating a two-step fabrication technique to grow large-sized single-layer rectangular shaped SnSe flakes on low-cost SiO2/Si dielectrics wafers in an atmospheric pressure quartz tube furnace system.

http://ift.tt/2G1s6VD

Guanylate cyclase-C as a therapeutic target in gastrointestinal disorders

Functional gastrointestinal disorders (FGIDs) and IBDs are two of the most prevalent disorders of the GI tract and consume a significant proportion of healthcare resources. Recent studies have shown that membrane-bound guanylate cyclase-C (GC-C) receptors lining the GI tract may serve as novel therapeutic targets in the treatment of FGIDs and IBDs. GC-C receptor activation by its endogenous paracrine hormones uroguanylin and guanylin, and the resulting intracellular production of its downstream effector cyclic GMP, occurs in a pH-dependent manner and modulates key physiological functions. These include fluid and electrolyte homeostasis, maintenance of the intestinal barrier, anti-inflammatory activity and regulation of epithelial regeneration. Studies of the GC-C paracrine signalling axis have revealed the therapeutic potential of these receptors in treating GI disorders, including chronic idiopathic constipation and irritable bowel syndrome–constipation. This review focuses on the evolving understanding of GC-C function in health and disease, and strategies for translating these principles into new treatments for FGIDs and IBDs.

http://ift.tt/2pthwj5

Endoscopic submucosal dissection or endoscopic mucosal resection for large colorectal laterally spreading lesions? Scientific and economic data are still lacking

We read with great interest the paper of Bahin et al comparing piecemeal endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) for large colorectal laterally spreading lesions (LSLs) from a medico-economic point of view.1 Since the expanded use of ESDs in Japan that began in the early 2000s, a debate still persists in Western countries about the absolute need for en bloc resection of large colorectal lesions with a low risk of submucosal cancer.2 3 ESDs are associated with a high en bloc resection rate, low risk of recurrence and perfect pathological analysis.4 Defenders of piecemeal EMR point out the higher risk of ESD, the long duration of procedures, the discrepancies between Eastern and Western series, and the low proportion of lesions with superficial submucosal cancer.5 They also point out the good results of wide-field (WF)-EMR for complete eradication...

http://ift.tt/2GcadX7

Ultrasound Elicits Behavioral Responses through Mechanical Effects on Neurons and Ion Channels in a Simple Nervous System

Focused ultrasound has been shown to stimulate excitable cells, but the biophysical mechanisms behind this phenomenon remain poorly understood. To provide additional insight, we devised a behavioral-genetic assay applied to the well-characterized nervous system of Caenorhabditis elegans nematodes. We found that pulsed ultrasound elicits robust reversal behavior in wild-type animals in a pressure-, duration-, and pulse protocol-dependent manner. Responses were preserved in mutants unable to sense thermal fluctuations and absent in mutants lacking neurons required for mechanosensation. Additionally, we found that the worm's response to ultrasound pulses rests on the expression of MEC-4, a DEG/ENaC/ASIC ion channel required for touch sensation. Consistent with prior studies of MEC-4-dependent currents in vivo, the worm's response was optimal for pulses repeated 300–1000 times per second. Based on these findings, we conclude that mechanical, rather than thermal, stimulation accounts for behavioral responses. Further, we propose that acoustic radiation force governs the response to ultrasound in a manner that depends on the touch receptor neurons and MEC-4-dependent ion channels. Our findings illuminate a complete pathway of ultrasound action, from the forces generated by propagating ultrasound to an activation of a specific ion channel. The findings further highlight the importance of optimizing ultrasound pulsing protocols when stimulating neurons via ion channels with mechanosensitive properties.

SIGNIFICANCE STATEMENT How ultrasound influences neurons and other excitable cells has remained a mystery for decades. Although it is widely understood that ultrasound can heat tissues and induce mechanical strain, whether or not neuronal activation depends on heat, mechanical force, or both physical factors is not known. We harnessed Caenorhabditis elegans nematodes and their extraordinary sensitivity to thermal and mechanical stimuli to address this question. Whereas thermosensory mutants respond to ultrasound similar to wild-type animals, mechanosensory mutants were insensitive to ultrasound stimulation. Additionally, stimulus parameters that accentuate mechanical effects were more effective than those producing more heat. These findings highlight a mechanical nature of the effect of ultrasound on neurons and suggest specific ways to optimize stimulation protocols in specific tissues.

http://ift.tt/2GPkXsl

Simple and Rapid Method to Obtain High-quality Tumor DNA from Clinical-pathological Specimens Using Touch Imprint Cytology

Obtaining high-quality genomic DNA from tumor tissues is an essential first step for analyzing genetic alterations using next generation sequencing. In this article, we present a simple and rapid method to enrich tumor cells and obtain intact DNA from touch imprint cytology specimens.

http://ift.tt/2FSUs8s

The Effect of Locomotion on Early Visual Contrast Processing in Humans

Most of our knowledge about vision comes from experiments in which stimuli are presented to immobile human subjects or animals. In the case of human subjects, movement during psychophysical, electrophysiological, or neuroimaging experiments is considered to be a source of noise to be eliminated. Animals used in visual neuroscience experiments are typically restrained and, in many cases, anesthetized. In reality, however, vision is often used to guide the motion of awake, ambulating organisms. Recent work in mice has shown that locomotion elevates visual neuronal response amplitudes (Niell and Stryker, 2010; Erisken et al., 2014; Fu et al., 2014; Lee et al., 2014; Mineault et al., 2016) and reduces long-range gain control (Ayaz et al., 2013). Here, we used both psychophysics and steady-state electrophysiology to investigate whether similar effects of locomotion on early visual processing can be measured in humans. Our psychophysical results show that brisk walking has little effect on subjects' ability to detect briefly presented contrast changes and that co-oriented flankers are, if anything, more effective masks when subjects are walking. Our electrophysiological data were consistent with the psychophysics indicating no increase in stimulus-driven neuronal responses while walking and no reduction in surround suppression. In summary, we have found evidence that early contrast processing is altered by locomotion in humans but in a manner that differs from that reported in mice. The effects of locomotion on very low-level visual processing may differ on a species-by-species basis and may reflect important differences in the levels of arousal associated with locomotion.

SIGNIFICANCE STATEMENT Mice are the current model of choice for studying low-level visual processing. Recent studies have shown that mouse visual cortex is modulated by behavioral state: primary visual cortex neurons in locomoting mice tend to be more sensitive and less influenced by long-range gain control. Here, we tested these effects in humans by measuring psychophysical detection thresholds and electroencephalography (EEG) responses while subjects walked on a treadmill. We found no evidence of increased contrast sensitivity or reduced surround suppression in walking humans. Our data show that fundamental measurements of early visual processing differ between humans and mice and this has important implications for recent work on the links among arousal, behavior, and vision in these two species.

http://ift.tt/2GRttqM

The Nucleus Reuniens Controls Long-Range Hippocampo-Prefrontal Gamma Synchronization during Slow Oscillations

Gamma oscillations are involved in long-range coupling of distant regions that support various cognitive operations. Here we show in adult male rats that synchronized bursts of gamma oscillations bind the hippocampus (HPC) and prefrontal cortex (mPFC) during slow oscillations and slow-wave sleep, a brain state that is central for consolidation of memory traces. These gamma bursts entrained the firing of the local HPC and mPFC neuronal populations. Neurons of the nucleus reuniens (NR), which is a structural and functional hub between HPC and mPFC, demonstrated a specific increase in their firing before gamma burst onset, suggesting their involvement in HPC–mPFC binding. Chemical inactivation of NR disrupted the temporal pattern of gamma bursts and their synchronization, as well as mPFC neuronal firing. We propose that the NR drives long-range hippocampo–prefrontal coupling via gamma bursts providing temporal windows for information exchange between the HPC and mPFC during slow-wave sleep.

SIGNIFICANCE STATEMENT Long-range coupling between hippocampus (HPC) and prefrontal cortex (mPFC) is believed to support numerous cognitive functions, including memory consolidation occurring during sleep. Gamma-band synchronization is a fundamental process in many neuronal operations and is instrumental in long-range coupling. Recent evidence highlights the role of nucleus reuniens (NR) in consolidation; however, how it influences hippocampo–prefrontal coupling is unknown. In this study, we show that HPC and mPFC are synchronized by gamma bursts during slow oscillations in anesthesia and natural sleep. By manipulating and recording the NR–HPC–mPFC network, we provide evidence that the NR actively promotes this long-range gamma coupling. This coupling provides the hippocampo–prefrontal circuit with a novel mechanism to exchange information during slow-wave sleep.

http://ift.tt/2GPgIgH

Dendritic A-Current in Rhythmically Active PreBötzinger Complex Neurons in Organotypic Cultures from Newborn Mice

The brainstem preBötzinger complex (preBötC) generates the inspiratory rhythm for breathing. The onset of neural activity that precipitates the inspiratory phase of the respiratory cycle may depend on the activity of type-1 preBötC neurons, which exhibit a transient outward K⁺ current, I_A. Inspiratory rhythm generation can be studied ex vivo because the preBötC remains rhythmically active in vitro, both in acute brainstem slices and organotypic cultures. Advantageous optical conditions in organotypic slice cultures from newborn mice of either sex allowed us to investigate how I_A impacts Ca²⁺ transients occurring in the dendrites of rhythmically active type-1 preBötC neurons. The amplitude of dendritic Ca²⁺ transients evoked via voltage increases originating from the soma significantly increased after an I_A antagonist, 4-aminopyridine (4-AP), was applied to the perfusion bath or to local dendritic regions. Similarly, glutamate-evoked postsynaptic depolarizations recorded at the soma increased in amplitude when 4-AP was coapplied with glutamate at distal dendritic locations. We conclude that I_A is expressed on type-1 preBötC neuron dendrites. We propose that I_A filters synaptic input, shunting sparse excitation, while enabling temporally summated events to pass more readily as a result of I_A inactivation. Dendritic I_A in rhythmically active preBötC neurons could thus ensure that inspiratory motor activity does not occur until excitatory synaptic drive is synchronized and well coordinated among cellular constituents of the preBötC during inspiratory rhythmogenesis. The biophysical properties of dendritic I_A might thus promote robustness and regularity of breathing rhythms.

SIGNIFICANCE STATEMENT Brainstem neurons in the preBötC generate the oscillatory activity that underlies breathing. PreBötC neurons express voltage-dependent currents that can influence inspiratory activity, among which is a transient potassium current (I_A) previously identified in a rhythmogenic excitatory subset of type-1 preBötC neurons. We sought to determine whether I_A is expressed in the dendrites of preBötC. We found that dendrites of type-1 preBötC neurons indeed express I_A, which may aid in shunting sparse non-summating synaptic inputs, while enabling strong summating excitatory inputs to readily pass and thus influence somatic membrane potential trajectory. The subcellular distribution of I_A in rhythmically active neurons of the preBötC may thus be critical for producing well coordinated ensemble activity during inspiratory burst formation.

http://ift.tt/2DJUuJy

Hippocampal Ripple Oscillations and Inhibition-First Network Models: Frequency Dynamics and Response to GABA Modulators

Hippocampal ripples are involved in memory consolidation, but the mechanisms underlying their generation remain unclear. Models relying on interneuron networks in the CA1 region disagree on the predominant source of excitation to interneurons: either "direct," via the Schaffer collaterals that provide feedforward input from CA3 to CA1, or "indirect," via the local pyramidal cells in CA1, which are embedded in a recurrent excitatory-inhibitory network. Here, we used physiologically constrained computational models of basket-cell networks to investigate how they respond to different conditions of transient, noisy excitation. We found that direct excitation of interneurons could evoke ripples (140–220 Hz) that exhibited intraripple frequency accommodation and were frequency-insensitive to GABA modulators, as previously shown in in vitro experiments. In addition, the indirect excitation of the basket-cell network enabled the expression of intraripple frequency accommodation in the fast-gamma range (90–140 Hz), as in vivo. In our model, intraripple frequency accommodation results from a hysteresis phenomenon in which the frequency responds differentially to the rising and descending phases of the transient excitation. Such a phenomenon predicts a maximum oscillation frequency occurring several milliseconds before the peak of excitation. We confirmed this prediction for ripples in brain slices from male mice. These results suggest that ripple and fast-gamma episodes are produced by the same interneuron network that is recruited via different excitatory input pathways, which could be supported by the previously reported intralaminar connectivity bias between basket cells and functionally distinct subpopulations of pyramidal cells in CA1. Together, our findings unify competing inhibition-first models of rhythm generation in the hippocampus.

SIGNIFICANCE STATEMENT The hippocampus is a part of the brain of humans and other mammals that is critical for the acquisition and consolidation of memories. During deep sleep and resting periods, the hippocampus generates high-frequency (~200 Hz) oscillations called ripples, which are important for memory consolidation. The mechanisms underlying ripple generation are not well understood. A prominent hypothesis holds that the ripples are generated by local recurrent networks of inhibitory neurons. Using computational models and experiments in brain slices from rodents, we show that the dynamics of interneuron networks clarify several previously unexplained characteristics of ripple oscillations, which advances our understanding of hippocampus-dependent memory consolidation.

http://ift.tt/2GODRQ7

Heterogeneous Origins of Human Sleep Spindles in Different Cortical Layers

Sleep spindles are a cardinal feature in human NREM sleep and may be important for memory consolidation. We studied the intracortical organization of spindles in men and women by recording spontaneous sleep spindles from different cortical layers using linear microelectrode arrays. Two patterns of spindle generation were identified using visual inspection, and confirmed with factor analysis. Spindles (10–16 Hz) were largest and most common in upper and middle channels, with limited involvement of deep channels. Many spindles were observed in only upper or only middle channels, but approximately half occurred in both. In spindles involving both middle and upper channels, the spindle envelope onset in middle channels led upper by ~25–50 ms on average. The phase relationship between spindle waves in upper and middle channels varied dynamically within spindle epochs, and across individuals. Current source density analysis demonstrated that upper and middle channel spindles were both generated by an excitatory supragranular current sink while an additional deep source was present for middle channel spindles only. Only middle channel spindles were accompanied by deep low (25–50 Hz) and high (70–170 Hz) gamma activity. These results suggest that upper channel spindles are generated by supragranular pyramids, and middle channel by infragranular. Possibly, middle channel spindles are generated by core thalamocortical afferents, and upper channel by matrix. The concurrence of these patterns could reflect engagement of cortical circuits in the integration of more focal (core) and distributed (matrix) aspects of memory. These results demonstrate that at least two distinct intracortical systems generate human sleep spindles.

SIGNIFICANCE STATEMENT Bursts of ~14 Hz oscillations, lasting ~1 s, have been recognized for over 80 years as cardinal features of mammalian sleep. Recent findings suggest that they play a key role in organizing cortical activity during memory consolidation. We used linear microelectrode arrays to study their intracortical organization in humans. We found that spindles could be divided into two types. One mainly engages upper layers of the cortex, which are considered to be specialized for associative activity. The other engages both upper and middle layers, including those devoted to sensory input. The interaction of these two spindle types may help organize the interaction of sensory and associative aspects of memory consolidation.

http://ift.tt/2DIBHOY

ER program aims to catch patients bouncing from one to another

Dr. Scott Weiner's PreManage ED project aims to coordinate better care for "high risk and complex patients" who regularly visit several ERs

http://ift.tt/2G1u5sK

Impact of oral potentially malignant disorders on quality of life: a systematic review

Future Oncology, Ahead of Print.


http://ift.tt/2GbfTRj

Does the Width of the Bony Cochlear Nerve Canal Predict the Outcomes of Cochlear Implantation?

A narrow bony cochlear nerve canal (BCNC) is associated with sensorineural hearing loss necessitating cochlear implantation (CI). This study evaluated the implications of BCNC width for post-CI outcomes. A total of 56 children who had received CIs were included. The patients were divided into three groups according to the width of the BCNC (Group 1: diameter 2.0 mm, ). The post-CI speech performances were compared among the three groups according to BCNC width. The correlation between BCNC width and post-CI speech performance was evaluated. Logistic regression analysis was also performed to investigate factors that can impact post-CI speech performance. Cochlear nerve deficiency (CND) occurred more frequently in Group 1. Groups 1 and 2 had significantly worse post-CI outcomes. Patients with intact cochlear nerves had significantly better post-CI outcomes than those with CND. When the cochlear nerve was intact, patients with a narrower BCNC showed less favorable results. Therefore, patients with either a narrow BCNC or CND seemed to have poorer outcomes. A narrow BCNC is associated with higher CND rates and poor outcomes. Measurement of BCNC diameter may help predict CI outcomes.

http://ift.tt/2FQscTO

Diet and health—finding a path to Veritas

http://ift.tt/2u8N7fw

Cancers, Vol. 10, Pages 87: Study of the Influence of NanOx Parameters

Cancers, Vol. 10, Pages 87: Study of the Influence of NanOx Parameters

Cancers doi: 10.3390/cancers10040087

Authors: Caterina Monini Micaela Cunha Etienne Testa Michaёl Beuve

NanOx is a new biophysical model that aims at predicting the biological effect of ions in the context of hadron therapy. It integrates the fully-stochastic nature of ionizing radiation both at micrometric and nanometric scales and also takes into account the production and diffusion of reactive chemical species. In order to further characterize the new framework, we discuss the meaning and relevance of most of the NanOx parameters by evaluating their influence on the linear-quadratic coefficient α and on the dose deposited to achieve 10% or 1% of cell survival, D 10 % or D 1 % , as a function of LET. We perform a theoretical study in which variations in the input parameters are propagated into the model predictions for HSG, V79 and CHO-K1 cells irradiated by monoenergetic protons and carbon ions. We conclude that, in the current version of NanOx, the modeling of a specific cell line relies on five parameters, which have to be adjusted to several experimental measurements: the average cellular nuclear radius, the linear-quadratic coefficients describing photon irradiations and the α values associated with two carbon ions of intermediate and high-LET values. This may have interesting implications toward a clinical application of the new biophysical model.

http://ift.tt/2FZSRtc

Effectiveness of urine fibronectin as a non-invasive diagnostic biomarker in bladder cancer patients: a systematic review and meta-analysis

Abstract

Background

Previous researches pointed out that the measurement of urine fibronectin (Fn) could be a potential diagnostic test for bladder cancer (BCa). We conducted this meta-analysis to fully assess the diagnostic value of urine Fn for BCa detection.

Methods

A systematic literature search in PubMed, ISI Web of Science, EMBASE, Cochrane library, and CBM was carried out to identify eligible studies evaluating the urine Fn in diagnosing BCa. Pooled sensitivity, specificity, and diagnostic odds ratio (DOR) with their 95% confidence intervals (CIs) were calculated, and summary receiver operating characteristic (SROC) curves were established. We applied the STATA 13.0, Meta-Disc 1.4, and RevMan 5.3 software to the meta-analysis.

Results

Eight separate studies with 744 bladder cancer patients were enrolled in this meta-analysis. The pooled sensitivity, specificity, and DOR were 0.80 (95%CI = 0.77–0.83), 0.79 (95%CI = 0.73–0.84), and 15.18 (95%CI = 10.07–22.87), respectively, and the area under the curve (AUC) of SROC was 0.83 (95%CI = 0.79–0.86). The diagnostic power of a combined method (urine Fn combined with urine cytology) was also evaluated, and its sensitivity and AUC were significantly higher (0.86 (95%CI = 0.82–0.90) and 0.89 (95%CI = 0.86–0.92), respectively). Meta-regression along with subgroup analysis based on various covariates revealed the potential sources of the heterogeneity and the detailed diagnostic value of each subgroup. Sensitivity analysis supported that the result was robust. No threshold effect and publication bias were found in this meta-analysis.

Conclusions

Urine Fn may become a promising non-invasive biomarker for bladder cancer with a relatively satisfactory diagnostic power. And the combination of urine Fn with cytology could be an alternative option for detecting BCa in clinical practice. The potential value of urine Fn still needs to be validated in large, multi-center, and prospective studies.

http://ift.tt/2GPUkDE

Expression and Regulation Profile of Mature MicroRNA in the Pig: Relevance to Xenotransplantation

The pig is an important source of meat production and provides a valuable model for certain human diseases. MicroRNA (miRNA), which is noncoding RNA and regulates gene expression at the posttranscriptional level, plays a critical role in various biological processes. Studies on identification and function of mature miRNAs in multiple pig tissues are increasing, yet the literature is limited. Therefore, we reviewed current research to determine the miRNAs expressed in specific pig tissues that are involved in carcass values (including muscle and adipocytes), reproduction (including pituitary, testis, and ovary), and development of some solid organs (e.g., brain, lung, kidney, and liver). We also discuss the possible regulating mechanisms of miRNA. Finally, as pig organs are suitable candidates for xenotransplantation, biomarkers of their miRNA in xenotransplantation were evaluated.

http://ift.tt/2pqgy7Z

Towards 90-90-90 Target: Factors Influencing Availability, Access, and Utilization of HIV Services—A Qualitative Study in 19 Ugandan Districts

Background. UNAIDS has set a new target 90-90-90 by 2020. To achieve this target, current programs need to address challenges that limit access, availability, and utilization of HIV testing and treatment services. Therefore, the aim of this study was to identify the barriers that influence access, availability, and utilization of HIV services in rural Uganda within the setting of a large donor funded program. Methods. We conducted key informant interviews with stakeholders at the district level, staff of existing HIV/AIDS projects, and health facilities in 19 districts. Data were also collected from focus group discussions comprised of clients presenting for HIV care and treatment. Data were transcribed and analyzed using content analysis. Results. Barriers identified were as follows: (1) drug shortages including antiretroviral drugs at health facilities. Some patients were afraid to start ART because of worrying about shortages; (2) distance and (3) staffing shortages; (4) stigma persistence; (5) lack of social and economic support initiatives that enhance retention in treatment. Conclusions. In conclusion, our study has identified several factors that influence access, availability, and utilization of HIV services. Programs need to address drug and staff shortages, HIV stigma, and long distances to health facilities to broaden access and utilization in order to realize the UNAIDS target.

http://ift.tt/2pyfb6z

A practical guide for planning pelvic bone percutaneous interventions (biopsy, tumour ablation and cementoplasty)

Abstract

Percutaneous approaches for pelvic bone procedures (bone biopsies, tumour ablation and cementoplasty) are multiple and less well systematised than for the spine or extremities. Among the different imaging techniques that can be used for guidance, computed tomography (CT) scan is the modality of choice because of the complex pelvic anatomy. In specific cases, such as cementoplasty where real-time evaluation is a determinant, a combination of CT and fluoroscopy is highly recommended. The objective of this article is to propose a systematic approach for image-guided pelvic bone procedures, as well as to provide some technical tips. We illustrate the article with multiple examples, and diagrams of the approaches and important structures to avoid to perform these procedures safely.

Teaching Points

• Pelvic bone procedures are safe to perform if anatomical landmarks are recognised.

• The safest approach varies depending on the pelvic level.

• CT is the modality of choice for guiding pelvic percutaneous procedures.

• Fluoroscopy is recommended when real-time monitoring is mandatory.

• MRI can also be used for guiding pelvic percutaneous procedures.

http://ift.tt/2DGBUSR

Tumor-infiltrating mast cells predict prognosis and gemcitabine-based adjuvant chemotherapeutic benefit in biliary tract cancer patients

Abstract

Background

Recent studies have reported TIMs play an important role in tumors progression or regression, but the effect of TIMs in biliary tract cancer remains unclear. The aim of this study is to investigate the prognostic value of tumor infiltrating mast cells (TIMs) and its influence on gemcitabine-based adjuvant chemotherapy (ACT) benefits in biliary tract cancer patients after surgery.

Methods

TIMs were evaluated by immunohistochemical staining of tryptase in 250 patients with resected gallbladder carcinoma (GBC) or extrahepatic bile duct carcinoma (EBDC) from Zhongshan Hospital. The relationships between TIMs and clinicopathological factors and postoperative prognosis were analyzed respectively.

Results

High TIMs infiltration was significantly correlated with prolonged overall survival (OS). Furthermore, multivariate analysis indicated TNM stage and TIMs as independent prognostic factors for OS. Patients with high TIMs infiltration appeared to significantly benefit from Gemcitabine-based ACT in the discovery and validation cohorts. Spearman analysis identified that TIMs infiltration were positively correlated with anti-tumor CD8+ T cells.

Conclusion

TIMs infiltration is an independent favorable prognostic factor in GBC and EBDC patients, which could better stratify patients with different prognosis and predict benefit from gemcitabine-based ACT.

http://ift.tt/2G1FZTp

Effective osimertinib treatment in a patient with discordant T790 M mutation detection between liquid biopsy and tissue biopsy

Abstract

Background

We report the successful treatment of the patient with osimertinib 80 mg/day following disease progression and a discordance in the detection of a mechanism of resistance epithelial growth factor receptor (EGFR) T790 M between liquid biopsy and tissue biopsy methods.

Case presentation

A 57-year-old Hispanic male patient initially diagnosed with an EGFR 19 deletion positive lung adenocarcinoma and clinically responded to initial erlotinib treatment. The patient subsequently progressed on erlotinib 150 mg/day and repeat biopsies both tissue and liquid were sent for next-generation sequencing (NGS). A T790 M EGFR mutation was detected in the blood sample using a liquid biopsy technique, but the tissue biopsy failed to show a T790 M mutation in a newly biopsied tissue sample. He was then successfully treated with osimertinib 80 mg/day, has clinically and radiologically responded, and remains on osimertinib treatment after 10 months.

Conclusions

Second-line osimertinib treatment, when administered at 80 mg/day, is both well tolerated and efficacious in a patient with previously erlotinib treated lung adenocarcinoma and a T790 M mutation detected by liquid biopsy.

http://ift.tt/2IC1Tyl

Can too little be as bad as too much?

By Madhava Sai Sivapuram

"Any substance which is taken too much or too little is poisonous to our body whether it is a drug or a diet". These were the exact words told by my pharmacology professor when I was studying pharmacology. I thought yes, if there is excessive use of drugs, it is going to cause adverse drug reactions, whereas too little may not help us recover. With regards to the human diet, too much can cause obesity which is a risk for many diseases, whereas too little will make you undernourished. I never thought that a person's diet could be a cause of a life-threatening situation.

I faced such a situation during my BMJ Case Reports elective period[1] It was a completely new environment for me where hospital experiences a very good outpatient and inpatient flow. It was the 3rd or 4th day of my electives where I was still trying to understand the workflow of the hospital. I came across a middle-aged lady waiting outside the ward for my professor, as he was the attending physician of her father, who was admitted due to sudden fall on the ground, following a decrease in blood pressure. He had been taking medication for diabetes and hypertension for the past 10 years.

My professor had asked me to take the patient history and find out the reason for the fall in the blood pressure, but I could not do that as the patient was discharged on the same day.

It was a 3-week elective and I enjoyed working alongside my professor, who always gave me a new prospect to think about. Two days before my departure from the hospital, I got a chance to meet the patient and the family again; they had come in for a follow-up. This time the patient load in the OPD was not as high. My professor spends a lot of time with patients discussing their history and always tells me the cause of the problem is always in the patient's history. If we could figure this out, we would solve the puzzle, which is the beauty of medicine.

The lady told us that her father was having a problem with his blood pressure and during her recent visit to the family doctor, she was told that he should reduce his salt intake. She misunderstood the instruction to be that he should eat no salt at all, and she started cooking dishes exclusively for him without salt in them and was taking extra care that he was not eating any food that contained salt.

From this, we learned that her misunderstanding had cost them a lot of money and precious time. We explained to them what had gone wrong with the patient and suggested they increase his salt intake to a certain threshold.

This BMJ Case Reports elective experience has led me to remember my pharmacology professor's words practically in a real-life scenario. It also made me understand how important it is to fully inform the patient and their attendants, and also the necessity of checking their understanding.  Any misunderstanding with our health education comes at a huge price for the patients and their attendants.

I acknowledge Professor Rakesh Biswas under whom I did this elective.

References:

1. http://promotions.bmj.com/jnl/bmj-case-reports-student-electives-2/

Competing Interests

None Declared

 

 

 

 

http://ift.tt/2DK9OGa

Gynostemma pentaphyllum Attenuates the Progression of Nonalcoholic Fatty Liver Disease in Mice: A Biomedical Investigation Integrated with In Silico Assay

Nonalcoholic fatty liver disease (NAFLD) is the most common type of liver disease in developed countries. Oxidative stress plays a critical role in the progression of NAFLD. Modern pharmacological study and clinical trials have demonstrated the remarkable antioxidant activity of Gynostemma pentaphyllum (GP) in chronic liver disease. One aim of this study was to explore the potential protective effects and mechanisms of action of GP extract on NAFLD. The in vivo results showed that GP extract could alleviate fatty degeneration and haptic fibrosis in NAFLD mice. For exploring the hepatoprotective mechanisms of GP, we used network pharmacology to predict the potential active components of GP and their intracellular targets in NAFLD. Based on the network pharmacology results, we further utilized biomedical assays to validate this in silico prediction. The results showed that Gypenoside XL could upregulate the protein level of PPARα in NAFLD; the transcription level of several PPARα downstream target genes such as acyl-CoA oxidase (ACO) and carnitine palmitoyltransferase-1 (CPT-1) also increased after Gypenoside XL treatment. The overexpression of ACO and CPT-1 may involve the hepatoprotective effects of GP and Gypenoside XL on NAFLD by regulating mitochondrial fatty acid β-oxidation.

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Migration of a fractured inferior vena cava filter strut to the right ventricle of the heart

Inferior vena cava (IVC) filters are increasingly used in patients with recurrent venous thromboembolism in whom anticoagulation is contraindicated or intolerable. Migration of fragments is a known complication of IVC filter use. We present a case of a 32-year-old man, who presented with right-sided chest pain believed to be caused by a migrated IVC fragment to the right ventricle. The filter was removed by an endovascular cook forceps with the assistance of intracardiac echocardiography. This case serves as an addition to the existing reports of successful removal of intracardiac fragments via minimally invasive endovascular approach, amid a larger number of intracardiac fragments that have been removed by an open-heart approach.

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Sequential retinal necrosis secondary to varicella zoster in unrecognised long-standing HIV infection: patient safety report

A retired woman with left ophthalmic shingles of over 2 years' duration attended with bilateral vision loss and systemic upset. Acute retinal necrosis with detachment was detected on right fundus examination. Cataract in left eye precluded funduscopy. Ocular ultrasonography revealed fibrotic retinal detachment in the left eye. MRI brain and orbits also showed signals of retinal detachment. No abnormal MRI signal within the optic nerve or brain was found. Varicella zoster virus was detected in ocular aqueous and blood samples. High-dose intravenous acyclovir was administered. HIV test was positive with a very low CD4 count. Antiretroviral medications were prescribed. There was no recovery of vision. She was certified as blind, and social services were involved in seeking to provide alterations to her home in view of her severe disability. This case highlights the importance of suspecting HIV in patients with severe or chronic ophthalmic shingles. Images and implications for clinical practice are presented.

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Serpentine thrombus in the heart: a rare case of trapped thrombus in patent foramen ovale

A 77-year-old Caucasian woman with recent abdominal surgery was diagnosed with multiple paradoxical systemic emboli in the mesenteric and renal circulation. Diagnosis was made by direct visualisation of a serpentine thrombus traversing both atria through patent foramen ovale (PFO) by transesophageal echocardiogram (TEE). Concomitantly, the patient was found to have deep venous thrombosis and pulmonary embolism. A decision was made to pursue cardiothoracic surgery preceded by inferior vena cava filter placement. She was started on intravenous anticoagulation. Repeat TEE was negative for thrombus and the patient did not present any new clinical signs of embolisation by this time. Consequently, the treatment plan was modified and the patient received oral systemic anticoagulation followed by PFO closure with the use of St. Jude Amplatzer Cribriform septal occluder device. During the outpatient follow-up the patient was asymptomatic and there was no significant flow through the device on transthoracic echocardiogram.

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Metastatic primary anorectal melanoma developing in a patient treated for multicentric glioblastoma multiforme: two rare malignancies presenting in synchronicity

Description

A 66-year-old woman presented with complaints of dizziness, headache and forgetfulness, which had been worsening over the last 2 months. General physical examination revealed weakness in the left upper and lower limbs (power 4/5) with spasticity (deep tendon reflexes 3+ on left side). A non-contrast MRI brain revealed a mass lesion involving the right thalamus and another lesion in the right cerebellar peduncle. Both lesions were hyperintense on T2 and hypointense on T1 sequences (figure 1). A stereotactic biopsy from the thalamic lesion revealed glioblastoma multiforme (WHO Grade IV) on histopathological evaluation and immunohistochemistry (Ki67 index: 15%–20%). Due to financial constraints, O(6)-methylguanine-DNA methyltransferase(MGMT) promoter methylation status was not determined.

Figure 1

Pretreatment non-contrast MRI images of multicentric glioma. (A) T1-weighted axial image reveals a hypointense space-occupying lesion in the right thalamus involving the right basal ganglia (red arrow). (B) T1-weighted axial image reveals a hypointense space-occupying lesion in the...

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Renal injury in a patient with lumbar scoliosis

Kidney laceration following blunt trauma is responsible for up to 3% of trauma cases. The risk factors associated with renal injury are attributed to the risks of mechanical injury. However, anatomical variations that may accelerate the insult of injury are poorly documented. This case report describes a 25-year-old with degenerative lumbar scoliosis who presented with flank pain and visible haematuria following a low-impact injury. The patient had a grade IV renal injury. The curvature of the spine, shown on CT imaging, revealed a reduced retroperitoneal space around the left kidney. This case explores lumbar scoliosis as a risk factor for kidney laceration. We hypothesise that this increased risk is associated with asymmetry of the spine and reduced anatomical space in the retroperitoneum. Patients with lumbar scoliosis may be considered a high-risk category for renal injury, following low-impact trauma.

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FAST examination diagnosing bladder rupture following blunt pelvic trauma

Description

A 52-year-old man presented as a level 2 trauma notification after a plywood fell on him from 15 feet. On presentation, he was evaluated according to Advanced Trauma Life Support (ATLS) protocol. Secondary survey was significant for suprapubic tenderness and abrasions to bilateral hips. A focused assessment with sonography in trauma (FAST) examination was performed, showing echogenic fluid filling the bladder (video 1).

Video 1

Focused assessment with sonography in trauma examination performed in the trauma bay showing echogenic fluid filling the bladder.

A Foley catheter was placed, and gross haematuria was noted. X-ray in the trauma bay showed fractures of the left superior and inferior pubic rami (figure 1). Subsequently, a CT cystogram was performed which showed large clot within the bladder with small extraperitoneal extravasation (figure 2). The injury was managed with transurethral Foley and gentle...

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Severe autosomal dominant polycystic kidney disease

Description 

A 61-year-old man with a known history of autosomal dominant polycystic kidney disease (ADPKD) and stage IV chronic kidney disease presented with a 6-month history of abdominal pain, nausea, vomiting and fatigue. In addition to the ADPKD, the right kidney had a 4.4 cm inferior pole mass concerning for renal cell carcinoma (RCC). Preoperative imaging (figure 1), a coronal CT of abdomen and pelvis, demonstrates bilateral ADPKD. His total kidney volume was calculated to be 9980.5 mL, which in combination with his age made him a '1E' (most severe) based on the Mayo Clinic risk stratification schema. The following aggregate of issues led the patient to undergo bilateral open nephrectomies: the suspicion for malignancy associated with the right renal mass, a slight increase in malignancy risk associated with polycystic kidney disease in general, and the likely need for postoperative dialysis if left with only a single poorly...

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The human clone ST22 SCCmec IV methicillin-resistant Staphylococcus aureus isolated from swine herds and wild primates in Nepal: Is man the common source?

Abstract

Swine nasal samples [n = 282] were collected from 12 randomly selected farms around Kathmandu, Nepal, from healthy animals. In addition, wild monkey (Macaca mulatta) saliva samples [n = 59] were collected near temples areas in Kathmandu using a non-invasive sampling technique. All samples were processed for MRSA using standardized selective media and conventional biochemical tests. MRSA verification was done and isolates characterized by SCCmec, multilocus sequence typing, whole genome sequencing [WGS] and antibiotic susceptibilities. Six (2.1%) swine MRSA were isolated from five of the different swine herds tested, five were ST22 type IV and one ST88 type V. Four (6.8%) macaques MRSA were isolated, with three ST22 SCCmec type IV and one ST239 type III. WGS sequencing showed that the eight ciprofloxacin resistant ST22 isolates carried gyrA mutation [S84L]. Six isolates carried the erm(C) genes, five isolates carried aacC-aphD genes, and four isolates carried blaZ genes. The swine linezolid resistant ST22 did not carry any known acquired linezolid resistance genes, but had a mutation in ribosomal protein L22 [A29V] and an insertion in L4 [68KG69], both previously associated with linezolid resistance. Multiple virulence factors were also identified. This is the first time MRSA ST22 SCCmec IV has been isolated from livestock or primates.

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Tracking the invasion: dispersal of Hymenoscyphus fraxineus airborne inoculum at different scales

Summary

Ash dieback is caused by an invasive pathogen, Hymenoscyphus fraxineus, which emerged in Europe in the 1990s and jeopardizes the management of ash stands. Although the biological cycle of the pathogen is well understood, its dispersal patterns via airborne spores remain poorly described. We investigated the seasonal and spatial patterns of dispersal in France using both a passive spore-trapping method coupled with a real-time PCR assay and reports of ash dieback based on symptom observations. Spores detection varies from year to year, with a detection ability of 30 to 47%, depending on meteorological conditions, which affect both production of inoculum and efficiency of the trapping. Nevertheless, our results are consistent and we showed that sporulation peak occurred from June to August and that spores were detected up to 50–100 km ahead of the disease front, proving the presence of the pathogen before any observation of symptoms. The spore dispersal gradient was steep, most of inoculum remaining within 50 m of infected ashes. Two dispersal kernels were fitted using Bayesian methods to estimate the mean dispersal distance of H. fraxineus from inoculum sources. The estimated mean distances of dispersal, either local or regional scale, were 1.4 km and 2.6 km, respectively, the best fitting kernel being the inverse power-law. This information may help to design disease management strategies.

http://ift.tt/2Gf0mjH

Novel bacterial diversity is enriched with chloroperoxidase-reacted organic matter under anaerobic conditions.

Abstract

Fungal chloroperoxidases (CPOs) are one class of enzymes that produce natural organochlorides in soils. The microbial degradation of these organochlorides is not well known, though has implications for bioremediation, microbial ecology, and natural chlorine and carbon cycling. In this study, Illumina-based 16S rRNA gene sequencing and real-time quantitative PCR (qPCR) was used to characterize the bacterial community enriched from an amendment of organic matter reacted with CPO under conditions conducive towards chlorination (CPO-OM). In total, 17 bacterial groups were enriched in triplicate microcosms inoculated with creek sediment and amended with CPO-OM. These bacterial groups were not enriched with amendments of non-reacted organic matter extract, with or without oxidative stress induced by H₂O_2, nor with amendments of organic matter reacted with CPO under non-chlorinating conditions. Of these, only two represented genera with known organohalide respiring bacteria (OHRB)—Dehalogenimonas and Dehalobacter. The genus Acetobacterium was also found to be enriched but the other 14 groups of enriched bacteria do not currently have any close phylogenetically related isolates. This study highlights a gap in the current understanding of the microbiology involved in natural organochloride turnover and suggests that CPO-OM could be used for isolating and culturing strains from novel bacteria genera.

http://ift.tt/2u8CFo3

Effect of CBM1 and linker region on enzymatic properties of a novel thermostable dimeric GH10 xylanase (Xyn10A) from filamentous fungus Aspergillus fumigatus Z5

Xylanase with a high thermostability will satisfy the needs of raising the temperature of hydrolysis to improve the rheology of the broth in industry of biomass conversion. In this study, a xylanase gene (xyn10A)...

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Biodegradation of 2-chloro-4-nitrophenol via a hydroxyquinol pathway by a Gram-negative bacterium, Cupriavidus sp. strain CNP-8

Cupriavidus sp. strain CNP-8 isolated from a pesticide-contaminated soil was able to utilize 2-chloro-4-nitrophenol (2C4NP) as a sole source of carbon, nitrogen and energy, together with the release of nitrite an...

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Temporal Trends of Common Female Malignances on Breast, Cervical, and Ovarian Cancer Mortality in Japan, Republic of Korea, and Singapore: Application of the Age-Period-Cohort Model

Background. Reproductive system cancer is an important cause of morbidity and mortality worldwide which threatens women's health and lives. Breast, cervical, and ovarian cancer have the higher incidence and mortality among a series of gynecology malignant tumor. We aimed to compare and assess the temporal trends of common female malignances on breast, cervical, and ovarian cancer mortality in developed regions of Asia including Japan, Republic of Korea, and Singapore and analyze the detached effects of chronological age, time period, and birth cohort by age-period-cohort (APC) analysis. Methods. The mortality data for these three cancers were collected from the WHO Mortality Database in Japan, Republic of Korea, and Singapore from 1954 to 2013, from 1989 to 2013, and from 1964 to 2013, respectively. We fitted an age-period-cohort model and intrinsic estimator method to estimate the independent effect of each age, time period, and birth cohort on cancer mortality and describe the secular changes in three Asian countries. Results. For the overall trends of breast cancer, the ASMRs of breast cancer showed a general increasing trend among three countries during the study periods while the change pattern in Singapore was different from the rest of the two countries for cervical and ovarian cancer. By APC analysis, the three cancer mortality risks generally increased with age and decreased with birth cohort. For period effects of breast and ovarian cancer, increasing effects with time were observed; however, for period effects of cervical cancer, converse change pattern was presented among three countries. Conclusions. Our study shows that the ASMRs of breast, cervical, and ovarian cancer remain high in Singapore compared to Japan and Korea. Generally speaking, the mortality risk of three cancers increased with age, and period and cohort effects may collectively affect the common female malignances mortality for East Asian women.

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Convert Academic CV to 2-Page Document

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Transmission of hepatitis E virus with plasma exchange in kidney-transplant recipients: a retrospective cohort study

Background: After observing a case of plasma exchange-mediated HEV infections in a kidney transplant recipient, we investigated the relationship between plasma exchange and HEV infection after kidney transplantation. Methods: A cohort of 263 patients who underwent kidney transplantation from January 1, 2011 through December 31, 2012 was screened for HEV markers, including anti-HEV IgG and IgM antibodies and HEV RNA, on 3 consecutive blood samples: 1 before, 1 a mean (SD) of 9.5 (9) months and 1 a mean (SD) of 18.2 (6.6) months after transplantation, respectively. Transfusional investigation was performed in patients with detectable HEV RNA. We explored the relationships between plasma exchange, posttransplantation transaminase elevation and HEV markers acquisition. Results: Overall, 24 (9.1%) patients had acquired HEV markers on the first posttransplantation sample, including 2 patients with detectable HEV RNA, and 7 (2.3%) patients had long-term persistent HEV markers on the second posttransplantation sample, including 3 patients with detectable HEV RNA without detectable anti-HEV antibodies. Plasma exchange was an independent risk factor for the acquisition of posttransplantation and long-term persistent HEV markers. Pathogen-reduced plasma-borne transmission of HEV was demonstrated. Plasma exchange and long-term persistent HEV markers were risk factors of posttransplantation transaminase elevation. Conclusion: Plasma exchange, including with pathogen-reduced plasma, is a risk factor for posttransplantation HEV infection and transaminase elevation. Screening for HEV RNA should be carried out in kidney transplant recipients treated with plasma exchange. Corresponding author: Vincent Mallet, MD, PhD, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Hépatologie, 27 rue du Faubourg Saint Jacques, 75014 Paris, France; e-mail, vincent.mallet@aphp.fr Role of the funding source The Agence Nationale de la Recherche (ANR) paid for the serological tests. Vincent Mallet is funded by la fondation ARC pour la Recherche sur le Cancer. The Renal Transplant Unit at Necker Hospital belongs to the Fondation Centaure and the Transplantex group, which supports the French network for transplantation research. Conflicts of interest: none Authors Contributions: Conception and design: V. Mallet Analysis and interpretation of the data: V. Mallet, R. Sberro-Soussan, AM Roque-Afonso, L Hauser Drafting of the article: V. Mallet, AM Roque-Afonso, S Pol Critical revision of the article for important intellectual content: V. Mallet, R Sberro-Soussan, AM Roque-Afonso, S Pol Provision of study materials or patients: V Mallet, R Sberro-Soussan, AM Roque-Afonso, A Vallet-Pichard, B Deau, A Portal, ML Chaix, L Hauser, A Beylouné, A Mercadier, J Izopet, C Legendre, S Pol. Final approval of the article: V Mallet, R Sberro-Soussan, AM Roque-Afonso, A Vallet-Pichard, B Deau, A Portal, ML Chaix, L Hauser, A Beylouné, A Mercadier, J Izopet, C Legendre, S Pol Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Organ Transplantation in the Czech Republic

No abstract available

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Hypothermic Machine Preservation Benefits Deceased Donor Kidneys with Short Cold Ischaemic Times

No abstract available

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E-xchange: Hepatitis E and the risk of plasma products for organ transplant recipients

No abstract available

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Histopathologic analysis of stage pT1b kidney neoplasms for optimal surgical margins of nephron-sparing surgery

Abstract

Objective

To evaluate the pathological features and define the optimal surgical margins (SM) of nephron-sparing surgery (NSS) for kidney neoplasms 4–7 cm (stage pT1b) on preoperative imaging.

Materials and methods

The retrospective study included 748 patients who were diagnosed stage pT1b renal tumors and underwent either radical nephrectomy (RN, n = 475) or NSS (n = 273) from January 2004 to March 2017. The tumor size, pathological subtype, Fuhrman grade, status of peritumoral pseudocapsule (PC) and tumor multifocality were recorded. The relationship between peritumoral PC and positive SM was calculated statistically by Fisher's exact probability test.

Results

The mean tumor diameter was 5.4 cm (range: 4.1–7.0 cm), 65 (8.7%) cases were discovered with multifocal lesions and 686 (91.7%) were surrounded with peritumoral PC in all 748 specimens. 57 (8.3%) of 686 cases were proved with tumor infiltrated beyond PC [infiltration (+)], and the presence of PC infiltration (+) was significantly correlated with positive SM (p = 0.016). The infiltrative depth of tumor cells into renal parenchyma beyond PC was all limited in 3 mm and the proportion of ≤ 1, 1–2 and 2–3 mm was 21.1% (12/57), 59.6% (34/57) and 19.3% (11/57), respectively.

Conclusions

Our report indicates a 3 mm excisional margin is acceptable to ensure negative SM when operating NSS on stage pT1b kidney neoplasms.

http://ift.tt/2HS38IN

From symptom discovery to treatment - women's pathways to breast cancer care: a cross-sectional study

Abstract

Background

Typically, women in South Africa (SA) are diagnosed with breast cancer when they self-present with symptoms to health facilities. The aim of this study was to determine the pathway that women follow to breast cancer care and factors associated with this journey.

Methods

A cross-sectional study was conducted at a tertiary hospital in the Western Cape Province, SA, between May 2015 and May 2016. Newly diagnosed breast cancer patients were interviewed to determine their socio-demographic profile; knowledge of risk factors, signs and symptoms; appraisal of breast changes; clinical profile and; key time events in the journey to care. The Model of Pathways to Treatment Framework underpinned the analysis. The total time (TT) between a woman noticing the first breast change and the date of scheduled treatment was divided into 3 intervals: the patient interval (PI); the diagnostic interval (DI) and the pre-treatment interval (PTI). For the PI, DI and PTI a bivariate comparison of median time intervals by various characteristics was conducted using Wilcoxon rank-sum and Kruskal-Wallis tests. Cox Proportional-Hazards models were used to identify factors independently associated with the PI, DI and PTI.

Results

The median age of the 201 participants was 54 years, and 22% presented with late stage disease. The median TT was 110 days, with median patient, diagnostic and pre-treatment intervals of 23, 28 and 37 days respectively. Factors associated with the PI were: older age (Hazard ratio (HR) 0.59, 95% CI 0.40–0.86), initial symptom denial (HR 0.43, 95% CI 0.19–0.97) and waiting for a lump to increase in size before seeking care (HR 0.51, 95% CI 0.33–0.77). Women with co-morbidities had a significantly longer DI (HR 0.67, 95% CI 0.47–0.96) as did women who mentioned denial of initial breast symptoms (HR 4.61, 95% CI 1.80–11.78). The PTI was associated with late stage disease at presentation (HR 1.78, 95% CI 1.15–2.76).

Conclusion

The Model of Pathways to Treatment provides a useful framework to explore patient's journeys to care and identified opportunities for targeted interventions.

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PulmCrit Wee- Secondary endpoints: Can we separate the wheat from the chaff?

This post will attempt to create a rough framework for analyzing secondary endpoints.  This is primarily intended as a springboard for debate, rather than a final answer to this thorny issue (one which has remained unresolved for decades).

EMCrit Project by Josh Farkas.

http://ift.tt/2ptUjNz

Sedentary behavior during leisure time, physical activity and dietary habits as risk factors of overweight among school children aged 14–15 years: case control study

To determine the risk of sedentary behavior during leisure time, physical activity and dietary habits on overweight among school children aged 14–15 years in Kalutara District, Sri Lanka.

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Editorial Board [Masthead]

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Radiotherapy for Adult Medulloblastoma: Evaluation of Helical Tomotherapy, Volumetric Intensity Modulated Arc Therapy, and Three-Dimensional Conformal Radiotherapy and the Results of Helical Tomotherapy Therapy

Introduction. All adult medulloblastoma (AMB) patients should be treated with craniospinal irradiation (CSI) postoperatively. Because of the long irradiation range, multiple radiation fields must be designed for conventional radiotherapy technology. CSI can be completed in only one session with helical tomotherapy (HT). We evaluated the dose of HT, volumetric intensity modulated arc therapy (VMAT), and three-dimensional conformal radiotherapy (3D-CRT) of AMB and the results of 5 cases of AMB treated with HT. Methods. Complete craniospinal and posterior cranial fossa irradiation with HT, VMAT, and 3D-CRT and dose evaluation were performed. And results of 5 cases of AMB treated with HT were evaluated. Results. A large volume of tissue was exposed to low dose radiation in the organs at risk (OAR), while a small volume was exposed to high dose radiation with HT. The conformity and uniformity of the targets were good with HT and VMAT, and the volume of targets exposed to high dose with VMAT was larger than that of HT. The uniformity of 3D-CRT was also good, but the dose conformity was poor. The main toxicity was hematologic toxicity, without 4th-degree bone marrow suppression. There was 3rd-degree inhibition in the white blood cells, hemoglobin, and platelets. The three female patients suffered menstrual disorders during the course of radiation. Two female patients with heavy menstruation suffered 3rd-degree anemia inhibition, and 2 patients suffered amenorrhea after radiotherapy. Although menstrual cycle was normal, the third patient was not pregnant. Conclusion. CSI with HT is convenient for clinical practice, and the side effects are mild. With good conformity and uniformity, VMAT can also be used for selection in CSI. For poor conformity, 3D-CRT should not be the priority selection for CSI. In female patients, the ovaries should be protected.

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Tacrine(10)-hupyridone, a dual-binding acetylcholinesterase inhibitor, potently attenuates scopolamine-induced impairments of cognition in mice

Abstract

Tacrine(10)-hupyridone (A10E) was designed as a dual-binding acetylcholinesterase (AChE) inhibitor from the modification of tacrine and a fragment of huperzine A. We have found that A10E effectively inhibited AChE in a mixed competitive manner, with an IC₅₀ of 26.4 nM, which is more potent than those of tacrine and huperzine A. Most importantly, we have shown, for the first time that A10E attenuated scopolamine-induced cognitive impairments without affecting motor function in mice. A10E effectively attenuated impairments of learning and memory to a similar extent as donepezil, an inhibitor of AChE used for treating Alzheimer's disease (AD). In addition, A10E significantly decreased AChE activity in the brain of mice, suggesting that A10E might cross the brain blood-barrier. Taken together, our results demonstrated that A10E, a designed dual-binding AChE inhibitor, could effectively reverse cognitive impairments, indicating that A10E might provide therapeutic efficacy for AD treatment.

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Gelidiella acerosa inhibits lung cancer proliferation

Lung adenocarcinoma is the most common subtype of Non small cell lung cancer in which the PI3K/Akt cascade is frequently deregulated. The ubiquitous expression of the PI3K and the frequent inactivation of PTEN...

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