Cladribine to treat disease exacerbation after fingolimod discontinuation in progressive multiple sclerosis

Abstract

Rebound disease following cessation of disease modifying treatment (DMT) has been reported in people with both relapsing and progressive multiple sclerosis (pwRMS, pwPMS) questioning strict separation between these two phenotypes. While licensed DMT is available for pwRMS to counter rebound disease, no such option exists for pwPMS. We report on a pwPMS who developed rebound disease, with 45 Gadolinium-enhancing lesions on T₁ weighted MRI brain, within 6 months after fingolimod 0.5 mg/day was stopped. Treatment with a short course of subcutaneous cladribine 60 mg led to effective suppression of inflammatory activity and partial recovery with no short-term safety issues or adverse events.

http://ift.tt/2rtklkb

Pediatric nasal surgery prior to puberty is not only safe, but may prevent facial deformity in certain patients.

http://alexandrossfa.blogspot.com/2017/05/pediatric-nasal-surgery-prior-to.html

Pediatric nasal surgery: timing and technique.

από Gary, Celeste C. στο Current Opinion in Otolaryngology & Head and Neck Surgery - Published Ahead-of-Print

Μετάφραση άρθρου

Purpose of review: Timing of pediatric nasal surgery has always been a controversial topic. Concern over disrupting growing parts of the face and causing permanent facial deformity has led to a primarily conservative approach. Many surgeons feel that it is prudent to wait until the patient has completed nasal growth after puberty to pursue nasal surgery. Recent findings: Recently, this attitude has been challenged with evidence that not only is nasal surgery in the pediatric age group not a detriment to facial growth, but failure to correct significant nasal deformity may actually cause dysmorphic facial growth secondary to obligate mouth breathing. Because of this, recent studies have focused on determining safe surgical techniques for pediatric nasal surgery, including inferior turbinate reduction, septoplasty and rhinoplasty. Research focus on this topic has also been expanded to include quality-of-life measures after nasal surgery. Summary: Pediatric nasal surgery prior to puberty is not only safe, but may prevent facial deformity in certain patients. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Klebsiella pneumoniae : a major worldwide source and shuttle for antibiotic resistance

Abstract

Klebsiella pneumoniae is an important multidrug-resistant (MDR) pathogen affecting humans and a major source for hospital infections associated with high morbidity and mortality due to limited treatment options. We summarize the wide resistome of this pathogen, which encompasses plentiful chromosomal and plasmid-encoded antibiotic resistance genes (ARGs). Under antibiotic selective pressure, K. pneumoniae continuously accumulates ARGs, by de novo mutations, and via acquisition of plasmids and transferable genetic elements, leading to extremely drug resistant (XDR) strains harboring a 'super resistome'. In the last two decades, numerous high-risk (HiR) MDR and XDR K. pneumoniae sequence types have emerged showing superior ability to cause multicontinent outbreaks, and continuous global dissemination. The data highlight the complex evolution of MDR and XDR K. pneumoniae, involving transfer and spread of ARGs, and epidemic plasmids in highly disseminating successful clones. With the worldwide catastrophe of antibiotic resistance and the urgent need to identify the main pathogens that pose a threat on the future of infectious diseases, further studies are warranted to determine the epidemic traits and plasmid acquisition in K. pneumoniae. There is a need for future genomic and translational studies to decipher specific targets in HiR clones to design targeted prevention and treatment.

http://ift.tt/2pN2F69

Perspectives for clinical use of engineered human host defense antimicrobial peptides

Abstract

Infectious diseases caused by bacteria, viruses or fungi are among the leading causes of death worldwide. The emergence of drug-resistance mechanisms, especially among bacteria, threatens the efficacy of all current antimicrobial agents, some of them already ineffective. As a result, there is an urgent need for new antimicrobial drugs. Host defense antimicrobial peptides (HDPs) are natural occurring and well-conserved peptides of innate immunity, broadly active against Gram-negative and Gram-positive bacteria, viruses and fungi. They also are able to exert immunomodulatory and adjuvant functions by acting as chemotactic for immune cells, and inducing cytokines and chemokines secretion. Moreover, they show low propensity to elicit microbial adaptation, probably because of their non-specific mechanism of action, and are able to neutralize exotoxins and endotoxins. HDPs have the potential to be a great source of novel antimicrobial agents. The goal of this review is to provide an overview of the advances made in the development of human defensins as well as the cathelicidin LL-37 and their derivatives as antimicrobial agents against bacteria, viruses and fungi for clinical use.

http://ift.tt/2qyUYxw

Chemical ecology of antibiotic production by actinomycetes

Abstract

Actinomycetes are a diverse family of filamentous bacteria that produce a plethora of natural products relevant for agriculture, biotechnology and medicine, including the majority of the antibiotics we use in the clinic. Rather than as free-living bacteria, many actinomycetes have evolved to live in symbiosis with among others plants, fungi, insects and sponges. As a common theme, these organisms profit from the natural products and enzymes produced by the actinomycetes, for example, for protection against pathogenic microbes, for growth promotion or for the degradation of complex natural polymers such as lignocellulose. At the same time, the actinomycetes benefit from the resources of the hosts they interact with. Evidence is accumulating that these interactions control the expression of biosynthetic gene clusters and have played a major role in the evolution of the high chemical diversity of actinomycete-produced secondary metabolites. Many of the biosynthetic gene clusters for antibiotics are poorly expressed under laboratory conditions, but they are likely expressed in response to host-specific demands. Here, we review the environmental triggers and cues that control natural product formation by actinomycetes and provide pointers as to how these insights may be harnessed for drug discovery.

http://ift.tt/2pNha9Q

Editorial: Bacterial pathogens, antibiotics and antibiotic resistance

http://ift.tt/2qyIPIF

From Nano to Micro: using nanotechnology to combat microorganisms and their multidrug resistance

Abstract

The spread of antibiotic resistance and increasing prevalence of biofilm-associated infections is driving demand for new means to treat bacterial infection. Nanotechnology provides an innovative platform for addressing this challenge, with potential to manage even infections involving multidrug-resistant (MDR) bacteria. The current review summarizes recent progress over the last 2 years in the field of antibacterial nanodrugs, and describes their unique properties, mode of action and activity against MDR bacteria and biofilms. Biocompatibility and commercialization are also discussed. As opposed to the more common division of nanoparticles (NPs) into organic- and inorganic-based materials, this review classifies NPs into two functional categories. The first includes NPs exhibiting intrinsic antibacterial properties and the second is devoted to NPs serving as a cargo for delivering antibacterial agents. Antibacterial nanomaterials used to decorate medical devices and implants are reviewed here as well.

http://ift.tt/2pNxw2r

Antibiotic resistance in Staphylococcus aureus . Current status and future prospects

Abstract

The major targets for antibiotics in staphylococci are (i) the cell envelope, (ii) the ribosome and (iii) nucleic acids. Several novel targets emerged from recent targeted drug discovery programmes including the ClpP protease and FtsZ from the cell division machinery. Resistance can either develop by horizontal transfer of resistance determinants encoded by mobile genetic elements viz plasmids, transposons and the staphylococcal cassette chromosome or by mutations in chromosomal genes. Horizontally acquired resistance can occur by one of the following mechanisms: (i) enzymatic drug modification and inactivation, (ii) enzymatic modification of the drug binding site, (iii) drug efflux, (iv) bypass mechanisms involving acquisition of a novel drug-resistant target, (v) displacement of the drug to protect the target. Acquisition of resistance by mutation can result from (i) alteration of the drug target that prevents the inhibitor from binding, (ii) derepression of chromosomally encoded multidrug resistance efflux pumps and (iii) multiple stepwise mutations that alter the structure and composition of the cell wall and/or membrane to reduce drug access to its target. This review focuses on development of resistance to currently used antibiotics and examines future prospects for new antibiotics and informed use of drug combinations.

http://ift.tt/2qyK7n3

Mining prokaryotes for antimicrobial compounds: from diversity to function

Abstract

The bacterial kingdom provides a major source of antimicrobials that can either be directly applied or used as scaffolds to further improve their functionality in the host. The rapidly increasing amount of bacterial genomic, metabolomic and transcriptomic data offers unique opportunities to apply a variety of approaches to mine for existing and novel antimicrobials. Here, we discuss several powerful mining approaches to identify novel molecules with antimicrobial activity across structurally diverse natural products, including ribosomally synthesized and posttranslationally modified peptides, nonribosomal peptides and polyketides. We not only discuss the direct mining of genomes based on identification of biosynthetic gene clusters, but also describe more advanced and integrative approaches in ecology-based mining, functionality-based mining and mode-of-action-based mining. These efforts are likely to accelerate the discovery and development of novel antimicrobial drugs.

http://ift.tt/2pNh3eq

Molecular mechanisms of biofilm-based antibiotic resistance and tolerance in pathogenic bacteria

Abstract

Biofilms are surface-attached groups of microbial cells encased in an extracellular matrix that are significantly less susceptible to antimicrobial agents than non-adherent, planktonic cells. Biofilm-based infections are, as a result, extremely difficult to cure. A wide range of molecular mechanisms contribute to the high degree of recalcitrance that is characteristic of biofilm communities. These mechanisms include, among others, interaction of antimicrobials with biofilm matrix components, reduced growth rates and the various actions of specific genetic determinants of antibiotic resistance and tolerance. Alone, each of these mechanisms only partially accounts for the increased antimicrobial recalcitrance observed in biofilms. Acting in concert, however, these defences help to ensure the survival of biofilm cells in the face of even the most aggressive antimicrobial treatment regimens. This review summarises both historical and recent scientific data in support of the known biofilm resistance and tolerance mechanisms. Additionally, suggestions for future work in the field are provided.

http://ift.tt/2qyJ2vm

Antimicrobial resistance in Mycobacterium tuberculosis : mechanistic and evolutionary perspectives

Abstract

Antibiotic-resistant Mycobacterium tuberculosis strains are threatening progress in containing the global tuberculosis epidemic. Mycobacterium tuberculosis is intrinsically resistant to many antibiotics, limiting the number of compounds available for treatment. This intrinsic resistance is due to a number of mechanisms including a thick, waxy, hydrophobic cell envelope and the presence of drug degrading and modifying enzymes. Resistance to the drugs which are active against M. tuberculosis is, in the absence of horizontally transferred resistance determinants, conferred by chromosomal mutations. These chromosomal mutations may confer drug resistance via modification or overexpression of the drug target, as well as by prevention of prodrug activation. Drug resistance mutations may have pleiotropic effects leading to a reduction in the bacterium's fitness, quantifiable e.g. by a reduction in the in vitro growth rate. Secondary so-called compensatory mutations, not involved in conferring resistance, can ameliorate the fitness cost by interacting epistatically with the resistance mutation. Although the genetic diversity of M. tuberculosis is low compared to other pathogenic bacteria, the strain genetic background has been demonstrated to influence multiple aspects in the evolution of drug resistance. The rate of resistance evolution and the fitness costs of drug resistance mutations may vary as a function of the genetic background.

http://ift.tt/2pNt6Zf

Toxin–antitoxin systems and their role in disseminating and maintaining antimicrobial resistance

Abstract

Toxin–antitoxin systems (TAs) are ubiquitous among bacteria and play a crucial role in the dissemination and evolution of antibiotic resistance, such as maintaining multi-resistant plasmids and inducing persistence formation. Generally, activities of the toxins are neutralised by their conjugate antitoxins. In contrast, antitoxins are more liable to degrade under specific conditions such as stress, and free active toxins interfere with essential cellular processes including replication, translation and cell-wall synthesis. TAs have also been shown to be responsible for plasmid maintenance, stress management, bacterial persistence and biofilm formation. We discuss here the recent findings of these multifaceted TAs (type I–VI) and in particular examine the role of TAs in augmenting the dissemination and maintenance of multi-drug resistance in bacteria.

http://ift.tt/2qyAnZV

Environmental and genetic modulation of the phenotypic expression of antibiotic resistance

Abstract

Antibiotic resistance can be acquired by mutation or horizontal transfer of a resistance gene, and generally an acquired mechanism results in a predictable increase in phenotypic resistance. However, recent findings suggest that the environment and/or the genetic context can modify the phenotypic expression of specific resistance genes/mutations. An important implication from these findings is that a given genotype does not always result in the expected phenotype. This dissociation of genotype and phenotype has important consequences for clinical bacteriology and for our ability to predict resistance phenotypes from genetics and DNA sequences. A related problem concerns the degree to which the genes/mutations currently identified in vitro can fully explain the in vivo resistance phenotype, or whether there is a significant additional amount of presently unknown mutations/genes (genetic 'dark matter') that could contribute to resistance in clinical isolates. Finally, a very important question is whether/how we can identify the genetic features that contribute to making a successful pathogen, and predict why some resistant clones are very successful and spread globally? In this review, we describe different environmental and genetic factors that influence phenotypic expression of antibiotic resistance genes/mutations and how this information is needed to understand why particular resistant clones spread worldwide and to what extent we can use DNA sequences to predict evolutionary success.

http://ift.tt/2pNsQtg

Formation, physiology, ecology, evolution and clinical importance of bacterial persisters

Abstract

Persisters are transiently tolerant variants that allow populations to avoid eradication by antibiotic treatment. Their antibiotic tolerance is non-genetic, not inheritable and results from a phenotypic switch from the normal, sensitive cell type to the tolerant, persister state. Here we give a comprehensive overview on bacterial persistence. We first define persistence, summarize the various aspects of persister physiology and show their heterogeneous nature. We then focus on the role of key cellular processes and mechanisms controlling the formation of a subpopulation of tolerant cells. Being a prime example of a risk-spreading strategy, we next discuss the eco-evolutionary aspects of persistence, e.g. how persistence evolves in the face of treatment with antibiotics. Finally, we illustrate the clinical importance of persisters, as persistence is worsening the worldwide antibiotic crisis by prolonging antibiotic treatment, causing therapy failure or catalyzing the development of genetically encoded antibiotic resistance. A better understanding of this phenotype is critical in our fight against pathogenic bacteria and to obtain a better outlook on future therapies.

http://ift.tt/2qyC4Xu

The Comprehensive Complication Index (CCI®): Added Value and Clinical Perspectives 3 Years “Down the Line”

Objective: To explore the added value of the comprehensive complication index (CCI®) to standard assessment of postoperative morbidity, and to clarify potential controversies for its application. Background: The CCI® was introduced about 3 years ago as a novel metric of postoperative morbidity, integrating in a single formula all complications by severity, ranging from 0 (uneventful course) to 100 (death). It remains unclear, how often the CCI® adds to standard reporting of complications and how to apply it in complex postoperative courses. Methods: CCI® data were prospectively collected over a 1-year period at our institution. The proportion of patients with more than 1 complication and the severity of those complications were assessed to determine the additional value of the CCI® compared to the Clavien–Dindo classification. Complex and controversial cases were presented to 90 surgeons worldwide to achieve consensus in weighing each postoperative event. Descriptive statistics were used to evaluate agreement among surgeons and to suggest solutions for consistent use of the CCI®. Results: Complications were identified in 24% (290/1212) of the general surgical population. Of those, 44% (127/290) developed more than 1 complication by the time of discharge, and thereby CCI® added information to the standard grading system of complications. Information gained by the CCI® increased with the complexity of surgery and observation time. Conclusions: The CCI® adds information on postoperative morbidity in almost half of the patients developing complications, with particular value following extensive surgery and longer postoperative observation up to 3 months. Each single complication, independently of their inter-connection, should be included in the CCI® calculation to best mirror the patients' postoperative morbidity.

http://ift.tt/2r0WEyv

Intraoperative Adverse Events in Abdominal Surgery: What Happens in the Operating Room Does Not Stay in the Operating Room

Objective: We sought to assess the impact of intraoperative adverse events (iAEs) on 30-day postoperative mortality, 30-day postoperative morbidity, and postoperative length of stay (LOS) among patients undergoing abdominal surgery. We hypothesized that iAEs would be associated with significant increases in each outcome. Summary of Background Data: The relationship between iAEs and postoperative clinical outcomes remains largely unknown. Methods: The 2007 to 2012 institutional ACS-NSQIP and administrative databases for abdominal surgeries were matched then screened for iAEs using the Agency for Healthcare Research and Quality's 15th Patient Safety Indicator, "Accidental Puncture/Laceration". Each chart flagged during the initial screen was then manually reviewed to confirm whether an iAE occurred. Univariate then multivariable logistic regression models were constructed to assess the independent impact of iAEs on 30-day mortality, 30-day morbidity, and prolonged (≥7 days) postoperative LOS, controlling for preoperative/intraoperative variables (eg, age, comorbidities, ASA, wound classification), procedure type (eg, laparoscopic vs open, intestinal, foregut, hepatopancreaticobiliary vs abdominal wall procedure), and complexity (eg, adhesions; relative value units). Propensity score analyses were conducted with each iAE patient matched with 5 non-iAE patients. Sensitivity analyses were performed. Results: A total of 9288 cases were included; 183 had iAEs. Most iAEs consisted of bowel (44%) or vessel (29%) injuries and were addressed intraoperatively (92%). In multivariable analyses, iAEs were independently associated with increased 30-day mortality [OR = 3.19, 95% confidence interval (CI) 1.52–6.71, P = 0.002], 30-day morbidity (OR = 2.68, 95% CI 1.89–3.81, P

http://ift.tt/2r0LBp5

Long noncoding RNAs: emerging regulators of tumor angiogenesis

Future Oncology Ahead of Print.


http://ift.tt/2quN3mL

The March of Science — The True Story

"The human understanding when it has once adopted an opinion...draws all things else to support and agree with it." Francis Bacon, the "Father of Empiricism," came to this conclusion in the 17th century, and some 350 years later, three Stanford psychologists confirmed its validity. They recruited…

http://ift.tt/2qTFJlA

The Mapping of Predicted Triplex DNA:RNA in the Drosophila Genome Reveals a Prominent Location in Development- and Morphogenesis-Related Genes

Double-stranded DNA is able to form triple-helical structures by accommodating a third nucleotide strand. A nucleic acid triplex occurs according to Hoogsteen rules that predict the stability and affinity of the third strand bound to the Watson-Crick duplex. The "triplex-forming oligonucleotide" (TFO) can be a short sequence of RNA that binds to the major groove of the targeted duplex only when this duplex presents a sequence of purine or pyrimidine bases in one of the DNA strands. Many nuclear proteins are known to bind triplex DNA or DNA:RNA, but their biological functions are unexplored. We identified sequences that are capable of engaging as the "triplex-forming oligonucleotide" in both the pre-lncRNA and pre-mRNA collections of Drosophila melanogaster. These motifs were matched against the Drosophila genome in order to identify putative sequences of triplex formation in intergenic regions, promoters and introns/exons. Most of the identified TFOs appear to be located in the intronic region of the analyzed genes. Computational prediction of the most targeted genes by TFOs originating from pre-lncRNAs and pre-mRNAs revealed that they are restrictively associated with development- and morphogenesis-related gene networks. The refined analysis by Gene Ontology enrichment demonstrates that some individual TFOs present genome-wide scale matches that are located in numerous genes and regulatory sequences. The triplex DNA:RNA computational mapping at the genome-wide scale suggests broad interference in the regulatory process of the gene networks orchestrated by TFO RNAs acting in association simultaneously at multiple sites.

http://ift.tt/2qyopzC

A Generalized Linear Model for Decomposing Cis-regulatory, Parent-of-Origin, and Maternal Effects on Allele-Specific Gene Expression

Joint quantification of genetic and epigenetic effects on gene expression is important for understanding the establishment of complex gene regulation systems in living organisms. In particular, genomic imprinting and maternal effects play important roles in the developmental process of mammals and flowering plants. However, the influence of these effects on gene expression are difficult to quantify because they act simultaneously with cis-regulatory mutations. Here we propose a simple method to decompose cis-regulatory (i.e., allelic genotype, AG), genomic imprinting (i.e., parent-of-origin, PO), and maternal (i.e., maternal genotype, MG) effects on allele-specific gene expression using RNA-seq data obtained from reciprocal crosses. We evaluated the efficiency of method using a simulated dataset and applied the method to whole-body Drosophila and mouse trophoblast stem cell (TSC) and liver RNA-seq data. Consistent with previous studies, we found little evidence of PO and MG effects in adult Drosophila samples. In contrast, we identified dozens and hundreds of mouse genes with significant PO and MG effects, respectively. Interestingly, a similar number of genes with significant PO effect were detect in mouse TSCs and livers, whereas more genes with significant MG effect were observed in livers. Further application of this method will clarify how these three effects influence gene expression levels in different tissues and developmental stages, and provide novel insight into the evolution of gene expression regulation.

http://ift.tt/2pNfGfH

Essential Function of the Serine Hydroxymethyl Transferase (SHMT) Gene During Rapid Syncytial Cell Cycles in Drosophila

Many metabolic enzymes are evolutionary highly conserved and serve a central function for catabolism and anabolism of cells. The serine hydroxymethyl transferase (SHMT) catalysing the conversion of serine and glycine and vice versa feeds into the tetrahydrofolate mediated C1 metabolism. We identified a Drosophila mutation in SHMT (CG3011) in a screen for blastoderm mutants. Embryos from SHMT mutant germline clones specifically arrest the cell cycle in interphase 13 at the time of the mid blastula transition (MBT) and prior to cellularisation. The phenotype is due to a loss of enzymatic activity as it cannot be rescued by an allele with a point mutation in the catalytic center but by an allele based on the SHMT coding sequence from E. coli. Onset of zygotic gene expression and degradation of maternal RNAs in SHMT mutant embryos are largely similar to wild type embryos. The specific timing of the defects in SHMT mutants indicates that at least one of the SHMT-dependent metabolites becomes limiting in interphase 13, if it is not produced by the embryo. Our data suggest that mutant eggs contain maternally provided and SHMT-dependent metabolites in amounts which suffice for early development until interphase 13.

http://ift.tt/2qy47Xa

FDA Warns Americans About Risk of Inaccurate Results from Certain Lead Tests

May 17, 2017 -- The U.S. Food and Drug Administration and Centers for Disease Control and Prevention are warning Americans that certain lead tests manufactured by Magellan Diagnostics may provide inaccurate results for some children and adults in...

http://ift.tt/2rsRITE

The inimitable mouth: task-dependent kinematic differences are independent of terminal precision

Abstract

Previous studies in our lab have described kinematic difference between grasp-to-eat and grasp-to-place movements, whereby participants produce smaller maximum grip apertures (MGAs) when grasping to bring the item to the mouth than when grasping to bring the item to a container near the mouth. This task difference is limited to right-handed movements, regardless of handedness; it has, therefore, been interpreted as evidence of left-hemisphere lateralization of the grasp-to-eat and other hand-to-mouth grasping movements. However, the difference in end-goal aperture may have accounted for both the kinematic signature (smaller MGAs) and their lateralized expression. Specifically, if the right hand is more sensitive to the precision requirements of secondary movements, it may have produced more precise MGAs for actions whose ultimate goal is the small-aperture mouth rather than a comparatively large aperture container. The current study addresses this question by replacing the previously-used bib with a small drinking glass whose aperture more closely resembles that of the mouth. 25 adult participants reached-to-grasp small cereal items to either (a) eat them, or (b) place them into a small-aperture glass hanging beneath their chin. Results once more showed a lateralised kinematic signature in the form of smaller MGAs for the eat action, demonstrating that the signature is not a result of lateralized sensitivity to a movement's secondary precision requirements. We discuss these results in terms of their impact on predominant theories regarding visual guidance of grasping movements.

http://ift.tt/2rrD1jC

Interference between a fast-paced spatial puzzle task and verbal memory demands

Abstract

Research continues to provide evidence that people are poor multi-taskers. Cognitive resource theory is a common explanation for the inability to efficiently perform multiple tasks at the same time. This theory proposes that one's limited supply of cognitive resources can be utilized faster than it is replenished, which results in a performance decline, particularly when these limited resources must be allocated among multiple tasks. Researchers have proposed both domain-specific, for example, spatial versus verbal processing resources, and domain general cognitive resources. In the present research, we investigated whether a spatial puzzle task performed simultaneously with a verbal recall task would impair performance in either task or both tasks, compared to performance on the tasks individually. As hypothesized, a reduction in word recall was found when dual-tasking, though performance on the puzzle task did not significantly differ between the single- and dual-task conditions. This is consistent, in part, with both a general resource theory and a Multiple Resource Theory, but further work is required to better understand the cognitive processing system. The employment of the recall task in the dual-task paradigm with a variety of secondary tasks will help to continue mapping out the specificity (or lack thereof) of cognitive resources utilized in various mental and physical tasks.

http://ift.tt/2rrRMCL

Changing the size of a mirror-reflected hand moderates the experience of embodiment but not proprioceptive drift: a repeated measures study on healthy human participants

Abstract

Mirror visual feedback is used for reducing pain and visually distorting the size of the reflection may improve efficacy. The findings of studies investigating size distortion are inconsistent. The influence of the size of the reflected hand on embodiment of the mirror reflection is not known. The aim of this study was to compare the effect of magnifying and minifying mirror reflections of the hand on embodiment measured using an eight-item questionnaire and on proprioceptive drift. During the experiment, participants (n = 45) placed their right hand behind a mirror and their left hand in front of a mirror. Participants watched a normal-sized, a magnified and a minified reflection of the left hand while performing synchronised finger movements for 3 min (adaptive phase). Measurements of embodiment were taken before (pre) and after (post) synchronous movements of the fingers of both hands (embodiment adaptive phase). Results revealed larger proprioceptive drift post-adaptive phase (p = 0.001). Participants agreed more strongly with questionnaire items associated with location, ownership and agency of the reflection of the hand post-adaptive phase (p < 0.001) and when looking at the normal-sized reflection (p < 0.001). In conclusion, irrespective of size, watching a reflection of the hand while performing synchronised movements enhances the embodiment of the reflection of the hand. Magnifying and minifying the reflection of the hand has little effect on proprioceptive drift, but it weakens the subjective embodiment experience. Such factors need to be taken into account in future studies using this technique, particularly when assessing mirror visual feedback for pain management.

http://ift.tt/2rrSRL8

The power law of movement: an example of a behavioral illusion

Abstract

The curved movements produced by living organisms follow a power law where the velocity of movement is a power function of the degree of curvature through which the movement is made. The exponent of the power function is close to either 1/3 or 2/3 depending on how velocity and curvature are measured. This power law is thought to reflect biological and/or kinematic constraints on how organisms produce movements. The present paper shows that the power law is actually a statistical artifact that results from mistaking a correlational for a causal relationship between variables. The power law implies that curvature influences the velocity of movement. In fact, the power law is a mathematical consequence of the way that these variables are calculated. The appearance that curvature affects the velocity of movement is shown to be an example of a "behavioral illusion" that results from ignoring the purpose of behavior.

http://ift.tt/2qtzBj7

Apolipoprotein E: the resilience gene

Abstract

The apolipoprotein E (apoE) gene has been implicated in various conditions, most notably Alzheimer's disease and coronary artery disease. A predisposing role of the apoE4 isoform and a protective role of apoE2 isoform in those diseases have been documented. Here we investigated the role of apoE in resilience to trauma. Three hundred and forty-three US veterans were genotyped for apoE and were assessed for their lifetime trauma exposure (trauma score, T) and severity of posttraumatic stress disorder symptoms (PCL). The ratio PCL/T indicates sensitivity to trauma; hence, its inverse indicates resilience, R, to trauma. We found a significantly higher resilience in participants with apoE genotype containing the E2 allele (E2/2, E2/3) as compared to participants with the E4 allele (E4/4, E4/3). In addition, when the categorical apoE genotype was reexpressed as the number of cysteine residues per apoE mole (CysR/mole), a highly significant positive association was found between resilience and CysR/mole, such that resilience was systematically higher as the number of CysR/mole increased, from zero CysR/mole in E4/4 to four CysR/mole in E2/2. These findings demonstrate the protective role of the CysR/mole apoE in resilience to trauma: the more CysR/mole, the higher the resilience. Thus, they are in accord with other findings pointing to a generally protective role of increasing number of CysR/mole (from E4/4 to E2/2) in other diseases. However, unlike other conditions (e.g., Alzheimer's disease and coronary artery disease), resilience to trauma is not a disease but an adaptive response to trauma. Therefore, the effects of apoE seem to be more pervasive along the CysR/mole continuum, most probably reflecting underlying effects on brain synchronicity and its variability that we have documented previously (Leuthold et al., Exp Brain Res 226:525–536, 2013).

http://ift.tt/2qtvkfi

Oculomotor prismatic training is effective in ameliorating spatial neglect: a pilot study

Abstract

Visuomotor prismatic training has been demonstrated to be among the most effective rehabilitative techniques of spatial neglect, a neurological syndrome manifested by a number of right brain-damaged patients characterized by unawareness of the egocentric left half of the world. In the present study, we demonstrate that a novel oculomotor prismatic training procedure only consisting in a sequence of gaze shifts to visual targets, can reduce spatial neglect symptoms. Following oculomotor prismatic training, patients show a significant decrease in neglect severity in straight ahead and paper and pencil tasks. We propose that during oculomotor prismatic training, the inconsistency between the prisms-biased visual/oculomotor input and the unbiased head-on-trunk proprioceptive information relative to the straight-ahead position determines the observed aftereffects and the amelioration of spatial neglect symptoms.

http://ift.tt/2rrMSG9

Postural and cortical responses following visual occlusion in standing and sitting tasks

Abstract

Perturbation-evoked responses (PERs) to a physical perturbation of postural stability have been detected using electroencephalography (EEG). Components of these responses are hypothesized to demonstrate the detection (P1) and evaluation (N1) of postural instability. Despite the important contribution of the visual system to postural control, PERs to a visual perturbation of posture have yet to be reported. Ten healthy young adults were exposed to unpredictable visual occlusion mediated through liquid crystal glasses under two conditions of postural demand: quiet standing and quiet sitting. The participants' PERs and postural responses were recorded and differences between conditions assessed using Wilcoxon signed-rank tests. In response to unpredictable visual occlusion, both P1 and N1 components of the PER were observed in both postural conditions. The amplitude of the P1 response remained consistent between postural conditions ( \(Z=-0.5606\) , \(p=0.5751\) ), whereas N1 amplitude and postural responses were significantly smaller in the sitting condition ( \(Z=-2.2934\) , \(p=0.0218\) ). This is the first study to demonstrate cortical responses to visual perturbation of posture. The responses to postural perturbation by sudden visual occlusion are similar in nature to that seen in relation to a physical perturbation. In addition, the amplitude of the N1 response is not only consistent with the relative magnitude of the perturbation, but also the underlying postural set, with a larger N1 seen in standing relative to sitting. The study informs the relative importance of vision to postural stability, postural set and provides a protocol to objectively assess sensory-based postural disorders.

http://ift.tt/2qtriE1

Changing hands: persistent alterations to body image following brief exposure to multisensory distortions

Abstract

The dynamic flexibility of body representation has been highlighted through numerous lines of research that range from clinical studies reporting disorders of body ownership, to experimentally induced somatic illusions that have provided evidence for the embodiment of manipulated representations and even fake limbs. While most studies have reported that enlargement of body parts alters somatic perception, and that these can be more readily embodied, shrunken body parts have not been found to consistently alter somatic experiences, perhaps due to reduced feelings of ownership over smaller body parts. Over two experiments, we aimed to investigate the mechanisms responsible for altered somatic representations following exposure to both enlarged and shrunken body parts. Participants were given the impression that their hand and index finger were either longer or shorter than veridical length and asked to judge veridical finger length using online and offline size estimation tasks, as well as to report the degree of ownership towards the distorted finger and hand representations. Ownership was claimed over all distorted representations of the hand and finger and no differences were seen across ownership ratings, while the online and offline measurements of perceived size demonstrated differing response patterns. These findings suggest that ownership towards manipulated body representations is more bidirectional than previously thought and also suggest differences in perceived body representation with respect to the method of measurement suggesting that online and offline tasks may tap into different aspects of body representation.

http://ift.tt/2qtMFEZ

Does affective touch influence the virtual reality full body illusion?

Abstract

The sense of how we experience our physical body as our own represents a fundamental component of human self-awareness. Body ownership can be studied with bodily illusions which are generated by inducing a visuo-tactile conflict where individuals experience illusionary ownership over a fake body or body part, such as a rubber hand. Previous studies showed that different types of touch modulate the strength of experienced ownership over a rubber hand. Specifically, participants experienced more ownership after the rubber hand illusion was induced through affective touch vs non-affective touch. It is, however, unclear whether this effect would also occur for an entire fake body. The aim of this study was, therefore, to investigate whether affective touch modulates the strength of ownership in a virtual reality full body illusion. To elicit this illusion, we used slow (3 cm/s; affective touch) and fast (30 cm/s; non-affective touch) stroking velocities on the participants' abdomen. Both stroking velocities were performed either synchronous or asynchronous (control condition), while participants viewed a virtual body from a first-person-perspective. In our first study, we found that participants experienced more subjective ownership over a virtual body in the affective touch condition, compared to the non-affective touch condition. In our second study, we found higher levels of subjective ownership for synchronous stimulation, compared to asynchronous, for both touch conditions, but failed to replicate the findings from study 1 that show a difference between affective and non-affective touch. We, therefore, cannot conclude unequivocally that affective touch enhances the full-body illusion. Future research is required to study the effects of affective touch on body ownership.

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Bimanual coordination patterns are stabilized under monitoring-pressure

Abstract

The influence of monitoring-pressure on the performance of anti-phase and in-phase bimanual coordination was examined. The two bimanual patterns were produced under no-monitoring and monitoring-pressure conditions at self-paced frequencies. Anti-phase coordination was always less stable than in-phase coordination, with or without monitoring. When performed under monitoring-pressure, the coordination patterns were performed with less variability in relative phase for both patterns across a range of self-paced movement frequencies compared to performance without monitoring. Thus, while monitoring-pressure did induce a behavioral change, it consisted of performance stabilization rather than degradation, a finding inconsistent with explicit-monitoring theory. However, the findings are consistent with the theory of coordination dynamics and studies that have revealed increased stability for the system's intrinsic dynamics as a result of attentional focus and intentional control.

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Rotational error in path integration: encoding and execution errors in angle reproduction

Abstract

Path integration is fundamental to human navigation. When a navigator leaves home on a complex outbound path, they are able to keep track of their approximate position and orientation and return to their starting location on a direct homebound path. However, there are several sources of error during path integration. Previous research has focused almost exclusively on encoding error—the error in registering the outbound path in memory. Here, we also consider execution error—the error in the response, such as turning and walking a homebound trajectory. In two experiments conducted in ambulatory virtual environments, we examined the contribution of execution error to the rotational component of path integration using angle reproduction tasks. In the reproduction tasks, participants rotated once and then rotated again to face the original direction, either reproducing the initial turn or turning through the supplementary angle. One outstanding difficulty in disentangling encoding and execution error during a typical angle reproduction task is that as the encoding angle increases, so does the required response angle. In Experiment 1, we dissociated these two variables by asking participants to report each encoding angle using two different responses: by turning to walk on a path parallel to the initial facing direction in the same (reproduction) or opposite (supplementary angle) direction. In Experiment 2, participants reported the encoding angle by turning both rightward and leftward onto a path parallel to the initial facing direction, over a larger range of angles. The results suggest that execution error, not encoding error, is the predominant source of error in angular path integration. These findings also imply that the path integrator uses an intrinsic (action-scaled) rather than an extrinsic (objective) metric.

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Single-incision totally extraperitoneal inguinal hernia repair is feasible and safe in patients on antithrombotic therapy: A single-center experience of 92 procedures

Abstract

Introduction

The aim of this study was to evaluate the feasibility and safety of SILS for totally extraperitoneal inguinal hernia repair for patients on antithrombotic therapy.

Methods

A total of 365 patients who underwent SILS for totally extraperitoneal inguinal hernia repair between January 2011 and November 2015 were analyzed retrospectively. Antithrombotic drugs were stopped preoperatively, and bridging intravenous heparin therapy was given according to the operative risk of each patient. Data on the patients' characteristics and perioperative outcomes were collected from their medical records.

Results

Ninety-two patients (25%, 92/365) were treated with antithrombotic drugs preoperatively. The mean operative times for unilateral and bilateral hernia repairs were 96 min and 94 min (P = 0.5), respectively, in the antithrombotic therapy group and 140 min and 130 min (P = 0.2), respectively, in the control group. Bleeding volume was minimal in all patients. There was no significant difference in the conversion rate. The mean postoperative hospital stay was 2.5 days in the antithrombotic therapy group and 2.1 days in the control group (P = 0.1). Postoperative complications were seen in 16% (15/92) of patients in the antithrombotic therapy group and in 11% (29/273) of patients in the control group (P = 0.2). Pulmonary embolism was seen in one patient (0.4%, 1/273) in the control group.

Conclusions

SILS for totally extraperitoneal inguinal hernia repair with bridging heparin therapy can be performed safely for patients on antithrombotic therapy.

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Exome Sequencing of African-American Prostate Cancer Reveals Loss-of-Function ERF Mutations [Research Briefs]

African-American men have the highest incidence and mortality from prostate cancer. Whether a biological basis exists for this disparity remains unclear. Exome sequencing (n=102) and targeted validation (n = 90) of localized primary hormone-naïve prostate cancer in African-American men identified several gene mutations not previously observed in this context, including recurrent loss-of-function mutations in ERF, an ETS transcriptional repressor, in 5% of cases. Analysis of existing prostate cancer cohorts revealed ERF deletions in 3% of primary prostate cancers and mutations or deletions in ERF in 3-5% of lethal castration-resistant prostate cancers. Knockdown of ERF confers increased anchorage-independent growth and generates a gene expression signature associated with oncogenic ETS activation and androgen signaling. Together, these results suggest that ERF is a prostate cancer tumor suppressor gene. More generally, our findings support the application of systematic cancer genomic characterization in settings of broader ancestral diversity to enhance discovery and, eventually, therapeutic applications.

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Effect of resistance exercise under conditions of reduced blood insulin on AMPK{alpha} Ser485/491 inhibitory phosphorylation and AMPK pathway activation

Insulin stimulates skeletal muscle glucose uptake via activation of the protein kinase B/Akt (Akt) pathway. Recent studies suggest that insulin down-regulates AMP-activated protein kinase (AMPK) activity via Ser485/491 phosphorylation of the AMPK α-subunit. Thus, lower blood insulin concentrations may induce AMPK signal activation. Acute exercise is one method to stimulate AMPK activation; however, no study has examined the relationship between blood insulin levels and acute resistance exercise-induced AMPK pathway activation. Based on previous findings, we hypothesized that the acute resistance exercise-induced AMPK pathway activation would be augmented by disruptions in insulin secretion through a decrease in AMPKα Ser485/491 inhibitory phosphorylation. To test the hypothesis, 10-week-old male Sprague-Dawley rats were administered the toxin streptozotocin (STZ; 55 mg/kg) to destroy the insulin secreting β-cells. Three-day post-injection, the right gastrocnemius muscle from STZ and control rats was subjected to resistance exercise by percutaneous electrical stimulation. Animals were sacrificed 0, 1, or 3 h later; activation of the Akt/AMPK and downstream pathways in the muscle tissue were analyzed by western blotting and real-time PCR. Notably, STZ rats showed a significant decrease in basal Akt and AMPKα Ser485/491 phosphorylation. However, substantial exercise caused increases in both AMPKα Thr172 and acetyl-CoA carboxylase (ACC) Ser79 phosphorylation. Although no significant impact on resistance exercise-induced Akt pathway activation or glucose uptake was found, resistance exercise–induced PGC-1α gene expression was augmented by STZ treatment. Collectively, these data suggest that circulating insulin levels may regulate acute resistance exercise-induced AMPK pathway activation and AMPK-dependent gene expression relating to basal AMPKα Ser485/491 phosphorylation.

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Impact of acetaminophen consumption and resistance exercise on extracellular matrix gene expression in human skeletal muscle

Acetaminophen (APAP) given during chronic exercise reduces skeletal muscle collagen and cross-linking in rats. We propose that the effect of APAP on muscle ECM may, in part, be mediated by dysregulation of the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs). The purpose of this study was to evaluate the impact of APAP consumption during acute resistance exercise (RE) on several regulators of the ECM in human skeletal muscle. In a double-blinded, placebo-controlled, randomized cross-over design, recreationally active men (n=8, 25±2yr) performed two trials of knee extension. Placebo (PLA) or APAP (1000mg/6h) was given for 24 hours prior to and immediately following RE. Vastus lateralis biopsies were taken at baseline, 1-hr, and 3-hr post-RE. RT-qPCR was used to determine differences in mRNA expression. MMP-2, COL1A1, and COL3A1 mRNA expression were not altered by exercise or APAP (p>0.05). When compared to PLA, TIMP-1 expression was lower at 1-hr post-RE during APAP conditions but greater than PLA at 3-hr post-RE (p<0.05). MMP-9 expression and protein levels were elevated at 3-hr post-RE independent of treatment (p<0.05). LOX expression was greater at 3-hr post-RE during APAP consumption (p<0.05) when compared to PLA. MMP-2 and TIMP-1 protein were not altered by RE or APAP (p>0.05). Phosphorylation of ERK1/2 and p38-MAPK increased (p<0.05) with RE but were not influenced by APAP. Our findings do not support our hypothesis and suggest that short-term APAP consumption prior to RE has a small impact on the measured ECM molecules in human skeletal muscle following acute RE.

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Flexible ammonia handling strategies using both cutaneous and branchial epithelia in the highly ammonia tolerant Pacific hagfish.

Hagfish consume carrion, potentially exposing them to hypoxia, hypercarbia, and high environmental ammonia (HEA). We investigated branchial and cutaneous ammonia handling strategies by which Pacific hagfish (Eptatretus stoutii) tolerate and recover from high ammonia loading. Hagfish were exposed to HEA (20 mmol L^-1) for 48 h to elevate plasma total ammonia (T_Amm) levels before placement into divided chambers for a 4 h recovery period in ammonia-free seawater where ammonia excretion (J_Amm) was measured independently in the anterior and posterior compartments. Localized HEA exposures were also conducted by subjecting hagfish to HEA in either the anterior or posterior compartments. During recovery, HEA-exposed animals increased J_Amm in both compartments, with the posterior compartment comprising ~20% of the total J_Amm compared to ~11% in non-HEA exposed fish. Plasma T_Amm increased substantially when whole hagfish, and the posterior regions, were exposed to HEA. Alternatively, plasma T_Amm did not elevate following anteriorly-localized HEA exposure. J_Amm was concentration-dependent (0.05-5 mmol L^-1) across excised skin patches at up to 8-fold greater rates than in skin sections that were excised from HEA-exposed hagfish. Skin excised from more posterior regions displayed greater J_Amm than those from more anterior regions. Immunohistochemistry with hagfish-specific anti-rhesus glycoprotein type c (α-hRhcg; ammonia transporter) antibodies was characterized by staining on the basal aspect of hagfish epidermis while Western blotting demonstrated greater expression of Rhcg in more posterior skin sections. We conclude that cutaneous Rhcg proteins are involved in cutaneous ammonia excretion by Pacific hagfish, and that this mechanism could be particularly important during feeding.

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Pyruvate kinase inhibits proliferation during postnatal cerebellar neurogenesis and suppresses medulloblastoma formation

Aerobic glycolysis supports proliferation through unresolved mechanisms. We have previously shown that aerobic glycolysis is required for the regulated proliferation of cerebellar granule neuron progenitors (CGNPs), and for the growth of CGNP-derived medulloblastoma. Blocking the initiation of glycolysis via deletion of Hexokinase-2 (Hk2) disrupts CGNP proliferation and restricts medulloblastoma growth. Here, we assessed whether disrupting Pyruvate kinase-M (Pkm), an enzyme that acts in the terminal steps of glycolysis, would alter CGNP metabolism, proliferation and tumorigenesis. We observed a dichotomous pattern of PKM expression, in which post-mitotic neurons throughout the brain expressed the constitutively active PKM1 isoform, while neural progenitors and medulloblastomas exclusively expressed the less active PKM2. Isoform-specific Pkm2 deletion in CGNPs blocked all Pkm expression. Pkm2-deleted CGNPs showed reduced lactate production and increased SHH-driven proliferation. 13C-flux analysis showed that Pkm2 deletion reduced the flow of glucose carbons into lactate and glutamate without markedly increasing glucose-to-ribose flux. Pkm2 deletion accelerated tumor formation in medulloblastoma-prone ND2:SmoA1 mice, indicating the disrupting PKM releases CGNPs from a tumor-suppressive effect. These findings show that distal and proximal disruptions of glycolysis have opposite effects on proliferation, and that efforts to block the oncogenic effect of aerobic glycolysis must target reactions upstream of PKM.

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NEMO, a transcriptional target of estrogen and progesterone, is linked to tumor suppressor PML in breast cancer

The beneficial versus detrimental roles of estrogen plus progesterone (E+P) in breast cancer remains controversial. Here we report a beneficial mechanism of E+P treatment in breast cancer cells driven by transcriptional upregulation of the NFκB modulator NEMO, which in turn promotes expression of the tumor suppressor protein PML. E+P treatment of patient-derived epithelial cells derived from ductal carcinoma in situ (DCIS) increased secretion of the pro-inflammatory cytokine IL-6. Mechanistic investigations indicated that IL-6 upregulation occurred as a result of transcriptional upregulation of NEMO, the gene for which harbored estrogen receptor (ER) binding sites within its promoter. Accordingly, E+P treatment of breast cancer cells increased ER binding to the NEMO promoter, thereby increasing NEMO expression, NFκB activation and IL-6 secretion. In two mouse xenograft models of DCIS, we found that RNAi-mediated silencing of NEMO increased tumor invasion and progression. This seemingly paradoxical result was linked to NEMO-mediated regulation of NFκB and IL-6 secretion, increased phosphorylation of STAT3 on Ser727 and increased expression of PML, a STAT3 transcriptional target. In identifying NEMO as a pivotal transcriptional target of E+P signaling in breast cancer cells, our work offers a mechanistic explanation for the paradoxical anti-tumorigenic roles of E+P in breast cancer by showing how it upregulates the tumor suppressor protein PML.

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Increased T cell infiltration elicited by Erk5 deletion in a Pten-deficient mouse model of prostate carcinogenesis.

Prostate cancer (PCa) does not appear to respond to immune checkpoint therapies where T cell infiltration may be a key limiting factor. Here we report evidence that ablating the growth regulatory kinase Erk5 can increase T cell infiltration in an established Pten-deficient mouse model of human PCa. Mice that were doubly mutant in prostate tissue for Pten and Erk5 (prostate DKO) exhibited a markedly increased median survival with reduced tumor size and proliferation compared to control Pten-mutant mice, the latter of which exhibited increased Erk5 mRNA expression. A comparative transcriptomic analysis revealed upregulation in prostate DKO mice of the chemokines Ccl5 and Cxcl10, two potent chemoattractants for T lymphocytes. Consistent with this effect, we observed a relative increase in a predominantly CD4+ T cell infiltrate in the prostate epithelial and stroma of tumors from DKO mice. Collectively, our results offer a preclinical proof of concept for ERK5 as a target to enhance T cell infiltrates in prostate cancer, with possible implications for leveraging immune therapy in this disease.

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Expression and Histopathological Significance of Disabled-2 in Aldosterone-Producing Adenoma

Horm Metab Res
DOI: 10.1055/s-0043-100935

The current pathological diagnosis of aldosterone-producing adenoma (APA) is challenging because no histological markers of aldosterone production are available in routine practice. A previous study demonstrated that Disabled-2 (DAB2) is a specific marker of the zona glomerulosa (ZG) in rodents. The aim of the present study was to investigate the significance of immunohistochemical staining to detect DAB2 in the adrenal tissue of patients with APA. We investigated the expression of DAB2 in 36 adrenal glands with APA, 23 adrenal glands with cortisol-producing adenoma (CPA), and 33 adrenal glands with non-functioning adenoma (NFA). Immunohistochemical staining was performed using anti-DAB2 antibodies on paraffin-embedded sections. We analysed the expression of DAB2 semi-quantitatively by scoring staining intensity, and assessed the correlation of this information with the clinical findings. DAB2 mRNA expression in adenoma tissues was evaluated by RT-PCR. DAB2 was highly expressed in the ZG in normal human adrenal glands. DAB2 expression was heterogeneous in APA, with spotted, strong staining noted in most samples (25 of 36 APA). CPA and NFA also exhibited extensive low or moderate DAB2 expression. DAB2 mRNA was significantly increased and positively correlated with CYP11B2 in APA (p<0.05). In APA, the DAB2 score adjusted for tumour volume was positively correlated with plasma aldosterone (p<0.05). Patients with low or moderate DAB2 staining more frequently exhibited high blood pressure and were diagnosed at a younger age compared with patients with high DAB2 staining. The present study clearly demonstrates that DAB2 is a specific marker of the ZG in normal human adrenal glands but that DAB2 immunostaining is not sufficiently powerful for histopathological diagnosis of APA. DAB2 might be involved in excessive aldosterone biosynthesis and correlate with specific clinical characteristics of APA patients.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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Human Epicardial Fat Expresses Glucagon-Like Peptide 1 and 2 Receptors Genes

Horm Metab Res
DOI: 10.1055/s-0043-109563

Epicardial adipose tissue (EAT) is an easily measurable visceral fat of the heart with unique anatomy, functionality, and transcriptome. EAT can serve as a therapeutic target for pharmaceutical agents targeting the fat. Glucagon-like peptide-1 (GLP-1) and GLP-2 analogues are newer drugs showing beneficial cardiovascular and metabolic effects. Whether EAT expresses GLP- 1 and 2 receptors (GLP-1R and GLP-2R) is unknown. RNA-seq analysis and quantitative real-time polymerase chain reaction (qRT-PCR) were performed to evaluate the presence of GLP-1R and GLP-2R in EAT and subcutaneous fat (SAT) obtained from 8 subjects with coronary artery disease and type 2 diabetes mellitus undergoing elective cardiac surgery. Immunofluorescence was also performed on EAT and SAT samples using Mab3f52 against GLP-1R. Our RNA-sequencing (RNA-seq) analysis showed that EAT expresses both GLP-1R and GLP-2R genes. qRT-PCR analysis confirmed that GLP-1R expression was low but detected by 2 different sets of intron-spanning primers. GLP-2R expression was detected in all patients and was found to be 5-fold higher than GLP-1R. The combination of accurately spliced reads from RNA-seq and successful amplification using intron-spanning primers indicates that both GLP-1R and GLP-2R are expressed in EAT. Immunofluorescence clearly showed that GLP-1R is present and more abundant in EAT than SAT. This is the first time that human EAT is found to express both GLP-1R and GLP-2R genes. Pharmacologically targeting EAT may induce beneficial cardiovascular and metabolic effects.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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“Turning the outside in”: bariatric gastroplication

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Cortical function and corticomotoneuronal adaptation in monomelic amyotrophy

http://ift.tt/2qu3nnJ

Pilot Prospective Study of Post-Surgery Sleep and EEG Predictors of Post-Operative Delirium

Delirium, a fluctuating disturbance of attention and awareness that develops over a short time period, occurs post-operatively in 37% of patients and is associated with poor outcomes, cognitive decline, longer hospital stays, and increased costs, morbidity and mortality (Dyer et al., 1995; Flink et al., 2012; Shim and Leung, 2012). Yet, interventions are extremely limited. It is impossible to identify the impending onset of delirium early enough to allow development or implementation of preventative therapies.

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Association of posterior semicircular canal hypofunction on video-head-impulse testing with other vestibulo-cochlear deficits

http://ift.tt/2rso152

Sex differences underlying orofacial varicella zoster associated pain in rats

Most people are initially infected with varicella zoster virus (VZV) at a young age and this infection results in chickenpox. VZV then becomes latent and reactivates later in life resulting in herpes zoster (H...

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The Development of FLT3 Inhibitors in Acute Myeloid Leukemia

FLT3 mutations, generally associated with a poor prognosis, are found in approximately one-third of patients with acute myeloid leukemia (AML) and represent an attractive therapeutic target. FLT3 inhibitors undergoing clinical evaluation include first-generation relatively non-specific small molecules and second-generation compounds with higher potency and selectivity against mutant FLT3. Recently presented results from a prospective randomized clinical trial will likely lead to a change in the standard of care for younger patients with FLT3-mutated AML: addition of the multi-targeted FLT3 inhibitor midostaurin to standard induction and consolidation chemotherapy. Thus, personalized therapies for this subset of AML will soon be possible.

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Targeting Aberrant Signaling in Myeloid Malignancies

Clonal myeloid disorders are characterized by genetic alterations that activate cytokine signaling pathways and stimulate cell proliferation. These activated signaling pathways have been extensively studied as potential therapeutic targets, and tyrosine kinase inhibitors have indeed had extraordinary success in treating BCR/ABL-positive chronic myeloiud leukemia. However, although inhibitors of other activated kinases have been developed that perform well in preclinical studies, the therapeutic efficacy of these drugs in patients has been unimpressive. This article discusses potential reasons for these discordant results and outlines recent scientific advances that are informing future efforts to target activated kinases in clonal myeloid disorders.

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The Development and Use of Janus Kinase 2 Inhibitors for the Treatment of Myeloproliferative Neoplasms

Following the discovery of the JAK2V617F mutation, Janus kinase (JAK) 2 inhibitors were developed as rationally designed therapy in myeloproliferative neoplasms (MPNs). Although JAK2 inhibitors have clinical efficacy in MPN, they are not clonally selective for the JAK2V617F-mutant cells. Because activated JAK-signal transducer and activator of transcription (STAT) signaling is a common feature of MPN, JAK2 inhibitors are efficacious regardless of the specific MPN phenotypic driver mutation. The Food and Drug Administration approved the JAK1/JAK2 inhibitor, ruxolitinib, for the treatment of myelofibrosis and polycythemia vera. Additional JAK2 inhibitors are currently in advanced phased clinical trials.

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Identification and Targeting of Kinase Alterations in Histiocytic Neoplasms

Histiocytic disorders represent clonal disorders of cells believed to be derived from the monocyte, macrophage, and/or dendritic cell lineage presenting with a range of manifestations. Although their nature as clonal versus inflammatory nonclonal conditions have long been debated, recent studies identified numerous somatic mutations that activate mitogen-activated protein kinase signaling in clinically and histologically diverse forms of histiocytosis. Clinical trials and case series have revealed that targeting aberrant kinase signaling using BRAF and/or MEK inhibitors may be effective. These findings suggest that a personalized approach in which patient-specific alterations are identified and targeted may be a critically important therapeutic approach.

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A multicenter randomized trial comparing the use of touch versus no-touch guidewire technique for deep biliary cannulation: the TNT study

There are 2 techniques described for selective bile duct guidewire cannulation, the touch (T) technique (engaging the papilla with a sphincterotome and then advancing the guidewire) and the no-touch (NT) technique (engaging the papilla only with the guidewire). The aim of this prospective, multicenter randomized study was to compare the outcomes of the 2 guidewire cannulation techniques.

http://ift.tt/2qt6iNf

Bronchopulmonary Dysplasia and Perinatal Characteristics Predict 1-Year Respiratory Outcomes in Newborns Born at Extremely Low Gestational Age: A Prospective Cohort Study

To assess the utility of clinical predictors of persistent respiratory morbidity in extremely low gestational age newborns (ELGANs).

http://ift.tt/2rsaxq2

Caring for Infants and Children Following Alternative Dietary Patterns

The number of people that refrain from eating meat has apparently increased. This is due to a variety of factors other than economic constraints or religious concerns, which have long been reasons for such dietetic conduct. Several reasons for adopting diets excluding meat include improved health, concerns regarding animal welfare, the use of antibiotics and hormones in livestock, and the excessive exploitation of environmental resource. Consequently, the number of children whose parents decide to follow alternative diets, such as vegetarian, vegan, macrobiotic, or fruitarian, is also growing.

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Cancer Biotherapy: More Than Immunotherapy

Cancer Biotherapy & Radiopharmaceuticals May 2017, Vol. 32, No. 4: 111-114.


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Circadian Gene CLOCK Affects Drug-Resistant Gene Expression and Cell Proliferation in Ovarian Cancer SKOV3/DDP Cell Lines Through Autophagy

Cancer Biotherapy & Radiopharmaceuticals May 2017, Vol. 32, No. 4: 139-146.


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Clinical Significance and Tumor-Suppressive Function of miR-516b in Nonsmall Cell Lung Cancer

Cancer Biotherapy & Radiopharmaceuticals May 2017, Vol. 32, No. 4: 115-123.


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APJ Is Associated with Treatment Response in Gastric Cancer Patients Receiving Concurrent Chemoradiotherapy and Endostar Therapy

Cancer Biotherapy & Radiopharmaceuticals May 2017, Vol. 32, No. 4: 133-138.


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First-in-Human PET/CT Imaging of Metastatic Neuroendocrine Neoplasms with Cyclotron-Produced 44Sc-DOTATOC: A Proof-of-Concept Study

Cancer Biotherapy & Radiopharmaceuticals May 2017, Vol. 32, No. 4: 124-132.


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Gynecological brachytherapy for postoperative endometrial cancer: dosimetric analysis (Ir-192 vs Co-60)

Abstract

Introduction

Endovaginal brachytherapy treatment dosimetry differences were studied using Ir-192 or Co-60 sources for postoperative endometrial cancer.

Materials and methods

A prospective descriptive study was conducted. Thirty-six dosimetry plans of different patients were studied (15 by Ir-192 and 21 by Co-60). Variables studied included D2cc Rectum, D2cc Bladder, D2cc Sigmoid, dose percentage at point 0 (applicator surface on the top of the cylinder) and dose percentage at point 1 (5 mm deep on the top of the cylinder). A comparative analysis was performed of the values obtained from each variable between Ir-192 and Co-60 treatments. We compared average of each variables between Iridium and Cobalt by T Student for independent samples (SPSS 22).

Results

There were no significant differences on using Ir-192 or Co-60 by variables, except for dose percentage at point 1 in which we detected significant differences (Table 1).

The results

Variables

Sources

Iridium 192

Cobalt 60

D2cc Rectum

(mean dose)

[rank]

6.01 Gy [3.99–7.90]

5.28 Gy [3.87–6,34]

D2cc Bladder

(mean dose)

[rank]

5.82 Gy [4.20–8.38]

5.05 Gy [2.23–6.95]

D2cc Sigmoid

(mean dose)

[rank]

4.43 Gy [1.66–6.67]

2.33 Gy [0.60–4.28]

Dose percentage at point 0^a

(mean)

[rank]

210.74% [120.90–234.90]

204.75% [177.10–223]

Dose percentage at point 1^b

(mean)

[rank]

93.49% [87.30–100.60]

100.11% [96.70–102]

^aPoint 0: point to the applicator surface

^bPoint 1: point to 5 mm applicator surface

Discussion

Brachytherapy treatment dosimetry plans are similar using Ir-192 or Co-60, except dose percentage at point 1. In the scientific literature, some differences exist and there are some advantages in using cobalt.

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Hangeshashinto (TJ-14) prevents radiation-induced mucositis by suppressing cyclooxygenase-2 expression and chemotaxis of inflammatory cells

Abstract

Purpose

Radiation-induced oral mucositis is the most common side effect of radiotherapy in head and neck cancer; however, effective modalities for its prevention have not been established. In this study, we evaluated the effectiveness of Hangeshashinto (TJ-14), a Japanese herbal medicine, for preventing radiation-induced mucositis and elucidated its effect on inflammatory responses, including inflammatory cell chemotaxis and cyclooxygenase-2 (COX2) expression, in an animal model.

Methods

Syrian hamsters, 8–9 weeks old, were enrolled in this study. Animals were irradiated with a single 40 Gy dose to the buccal mucosa. Hamsters freely received a treatment diet mixed with 2% TJ-14 or a normal diet daily. The therapeutic effect was determined based on the visual mucositis score, body weight, and histological examination of infiltrated neutrophils and COX2 expression.

Results

TJ-14 significantly reduced the severity of mucositis. The percentage with severe mucositis (score ≥3) was 100% in the untreated group and 16.7% in the TJ-14 group (P < 0.05). There was no difference in body weight change between the groups; however, weight gain in the untreated group tended to be suppressed compared to that in the TJ-14 group during the peak period of mucositis. In addition, TJ-14 inhibited the infiltration of neutrophils and COX2 expression in irradiated mucosa (P < 0.05).

Conclusions

TJ-14 reduced the severity of mucositis in an animal model by suppressing the inflammatory response. Because TJ-14 is inexpensive and its safety is established, it is a promising candidate for the standard treatment of radiation-induced mucositis in cancer patients.

http://ift.tt/2qsVLBH

Optimized immunohistochemistry using the D5F3 antibody provides a reliable test for identification of ALK-positive lung adenocarcinomas

Abstract

We used optimized immunohistochemistry (IHC) with the D5F3 antibody for detection of tumours in a prospective study of 307 pulmonary adenocarcinomas. Cases positive by IHC (1+, 2+, 3+) were further investigated by fluorescent in situ hybridization (FISH). Of 307 cases, 22 (7.2%) were moderately intensely positive (2+/3+); 18 of these (82%) were also positive by FISH. Of the four IHC-positive/FISH-negative cases, one was unsuitable for FISH and three had abnormalities of the ALK gene. All cases with weak reactivity with D5F3 (1+) were FISH-negative. The FISH positive/IHC-positive cases with moderately intense reactivity had the typical clinicopathologic features of ALK-positive patients (younger age, p < 0.01; higher frequency in metastatic sites, p < 0.01; cribriform/mucinous/signet histology, p < 0.01; stage IV disease, p < 0.01). In conclusion, our findings indicate that optimized IHC using the D5F3 antibody provides a reliable and inexpensive test for identification of ALK-positive adenocarcinomas. Inclusion of this information in the pathology report at the time of the histological diagnosis might significantly shorten time to treatment.

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Accept or Decline? An Analytics-Based Decision Tool for Kidney Offer Evaluation.

Background: When a deceased-donor kidney is offered to a waitlisted candidate, the decision to accept or decline the organ relies primarily upon a practitioner's experience and intuition. Such decisions must achieve a delicate balance between estimating the immediate benefit of transplantation and the potential for future higher-quality offers. However, the current experience-based paradigm lacks scientific rigor and is subject to the inaccuracies that plague anecdotal decision-making. Methods: A data-driven analytics-based model was developed to predict whether a patient will receive an offer for a deceased-donor kidney at KDPI thresholds of 0.2, 0.4, and 0.6, and at time frames of 3, 6, and 12 months. The model accounted for OPO, blood group, wait time, DR antigens, and prior offer history to provide accurate and personalized predictions. Performance was evaluated on datasets spanning various lengths of time to understand the adaptability of the method. Results: Using UNOS match-run data from 03/2007 to 06/2013, out-of-sample AUC was approximately 0.87 for all KDPI thresholds and time frames considered for the 10 most populous OPOs. As more data becomes available, AUC values increase and subsequently level off. Conclusions: The development of a data-driven analytics-based model may assist transplant practitioners and candidates during the complex decision of whether to accept or forgo a current kidney offer in anticipation of a future high-quality offer. The latter holds promise to facilitate timely transplantation and optimize the efficiency of allocation. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Hepatic hemodynamics and portal flow modulation: The A2ALL experience.

Objective: A principal aim of the Adult-to-Adult Living Donor Liver Transplantation Cohort Study was to study hepatic blood flow and effect of portal flow modulation on graft outcomes in the setting of increasing use of smaller and left lobe grafts. Methods: Recipients of 274 living donor liver transplant were enrolled in A2ALL-2, including 233 (85.0%) right lobes, 40 (14.6%) left lobes, and 1 (0.5%) left lateral section. Hepatic hemodynamics were recorded after reperfusion. A total of 57 portal flow modulations were performed on 52 subjects. Results: Modulation lowered portal pressure in 68% of subjects with inconsistent effects on hepatic arterial and portal flow. A higher rate of graft dysfunction was observed in modulated vs. unmodulated subjects (31% vs. 18%; p=0.03); however, graft survival in modulated subjects was not different from unmodulated subjects at 3 years. Conclusions: These results suggest the need for a study using a prespecified portal flow modulation protocol with defined indications to better define the effects of these interventions. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2qSyavp

Heart Transplantation From DCD Donors: From the Bedside to the Bench.

No abstract available

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Membrane of Candida albicans as a target of berberine

We investigated the mechanisms of anti-Candida action of isoquinoline alkaloid berberine, active constituent of medically important plants of Barberry species.

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Spotlight: Angel Armor's unparalleled ballistic solutions protect those who protect the public

Company: Angel Armor Headquarters: Colorado Signature Product: Ballistic Armor Website: http://ift.tt/1MXu5Hy Q&A Questions: 1. Where did your company name originate from" The name came from the essence of what an angel stands for and the emotion that an angel's presence provides. An angel's first words to those they protect are, "Do not be afraid." An angel brings ...

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Identification of Novel Agents for the Treatment of Brain Metastases of Breast Cancer

Background: Brain cancer from metastasized breast cancer has a high mortality rate in women. The treatment of lesions is hampered in large part by the blood-brain barrier (BBB), which prevents adequate distribution of anti-cancer compounds to brain metastases. Method: In this study we used a novel screening method to identify candidate molecules that are well-suited to utilizing the BBB choline transporter for distribution into the brain parenchyma. Results: From our screen we identified two compounds, Ch-1 and Ch-2 that were able to reduce the brain tumor burden in a murine mouse model of brain metastasis of breast cancer. These compounds also significantly increased the survival of mice by more than 10 days. Mechanistic studies indicated that Ch-1 is able to prevent the activation of the pro-survival mitogen-activated kinases (MAPKs) by osteoactivin (OA; Glycoprotein nonmetastatic melanoma protein B GPNMB). Conclusion: The results from this study show that nutrient transporter virtual screening is a viable novel alternative to traditional drug screening programs to identify anti-cancer compounds for the treatment of brain cancers.

http://ift.tt/2rs6XwF

Histone Deacetylase Inhibitors for the Treatment of Colorectal Cancer: Recent Progress and Future Prospects

Background: Colorectal cancer is a devastating disease with a dismal prognosis which is heavily hampered by delayed diagnosis. Surgical resection, radiation therapy and chemotherapy are the curative options. Due to few therapeutic treatments available i.e., mono and combination therapy and development of resistance towards drug response, novel and efficacious therapy are urgently needed. Objective: In this study, we have studied the potential of histone deacetylase inhibitors in colorectal cancer. Results: Histone deacetylase inhibitors (HDACIs) are an emerging class of therapeutic agents having potential anticancer activity with minimal toxicity for different types of malignancies in preclinical studies. HDACIs have proven less effective in monotherapy thus the combination of HDACIs with other anticancer agents are being assessed for the treatment of colorectal cancer. Conclusion: The molecular mechanism emphasizing the anticancer effect of HDACIs in colorectal cancer was illustrated and a recapitulation was carried out on the recent advances in the rationale behind combination therapies currently underway in clinical evaluations.

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Cathepsin D as a Promising Target for the Discovery of Novel Anticancer Agents

Background: Cathepsin D (CATD), one of the aspartyl endoproteinase involved in different physiological processes and signaling pathways, is accountable for metabolic breakdown of intracellular proteins, the activation of growth factors, hormones, and precursors of enzyme, the processing of antigens, enzyme inhibitors and activators and the regulation of apoptosis. Implication as a Target: Studies have confirmed the role and significance of CATD in an assortment of pathological conditions like Atherosclerosis, Alzheimer, Cancer, Cardiovascular, Huntington and Parkinson diseases. Amalgamated and veiled as inactive proCATD, it undergoes diverse cleavages to attain a desired conformation in an acidic milieu to act as a functionally active protein. In search of new candidate target (s) for cancer, CATD has attracted a wide group of investigators across the globe and is being recognized as a well-defined marker in cancer especially for breast and hormone-dependent cancer. Methods: In this review, PubMed, Sci-finder and other search engines were used to gather information on Cathepsin D. The necessary and relevant information was thoroughly studied to make the article appropriate to highlight all the aspects related to Cathepsin D and its role in cancer. Findings & Conclusion: The present review illustrates structural, functional and regulatory aspects of CATD in cancer, its significant role in angiogenesis, metastasis, invasion, apoptosis, cell proliferation, and therapeutic potential besides the benefits of targeting CATD by the natural products in cancer chemoprevention.

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Meet Our Editorial Board Member

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CD20-based Immunotherapy of B-cell Derived Hematologic Malignancies

Background: CD20 is a surface antigen, which is expressed at certain stages of B-cell differentiation. Targeting the CD20-positive B-cells with therapeutic monoclonal antibodies (MAbs) has been an effectual strategy in the treatment of hematologic malignancies such as non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Initial success with Rituximab (RTX) has encouraged the creation and development of more effective CD20 based therapeutics. However, treatment with conventional MAbs has not been adequate to overcome the problems such as refractory/ relapsed disease. In this regard, new generations of MAbs with enhanced affinity or improved anti-tumor properties have been developed. Objective: CD20 directed therapeutics have heterogeneous features and mechanisms of action. Hence, having sufficient knowledge on the immunological and molecular aspects of CD20 based cancer therapy is necessary for predicting the clinical outcomes and taking the necessary measures. Method: An extensive search was performed in PubMed and similar databases for peer-reviewed articles concerning the biology, function and characteristics of CD20 molecule as well as the mechanisms of action and evolutionary process of CD20 targeting agents. Results: This review provides information about the current situation of CD20 targeting immunotherapeutics including MAbs, bispecific antibodies (which exert multiple functions or involve Tcells in tumor elimination) and CAR T-cells (engineered T-cells armed with chimeric antigen receptors). Moreover, limitations, challenges and available solutions regarding the application of CD20 targeting treatments are addressed. Conclusion: Utilization of CD20-targeted therapeutics, due to their diverse properties, requires special considerations.

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NSAIDs Induced Regulation of Alternatively Spliced Transcript Isoforms: Possible Role in Cancer and Alzheimer Disease

Background: Alternative splicing is one of the post transcriptional modifications through which multiple mRNA isoforms are produced from any gene, also known as splice variants. These are expressed in tissue and developmental stage specific manner that are important during the development. Most human genes undergo alternative splicing, thus contributing to the diversity of proteins. However, many abnormal splicing processes may result in human diseases. Non-steroidal antiinflammatory drugs (NSAIDs) are medications that act as analgesics, anti-pyretics and antiinflammatory by affecting Cox genes and their products. Usually NSAIDs cause gastrotoxicity however, isozyme-specific NSAIDs exhibit a comparatively reduced gastrotoxic effect. Such NSAIDs have a broader range of application particularly as chemo-preventive drugs. It is known that changes at the active site of an enzyme may illicit a diverse range of responses. Such changes might explain the underlying reason as to why patients appear to respond differently to different NSAIDs. Methods: An extensive literature search has been carried out using Pubmed and web of science databases considering the papers in last 10 years mainly on alternative splicing and NSAIDs. Conclusion: We have reviewed in detail the insight into the action of NSAIDs targeting specific isoforms of different genes. In future, the complete understanding of NSAIDs associated genes and their expression studies may be helpful in generating drugs with increased specificity.

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Recent Advances in Application of Poly-Epsilon-Caprolactone and its Derivative Copolymers for Controlled Release of Anti-Tumor Drugs

Background: Due to their excellent biocompatibility and biodegradability, poly-epsiloncaprolactone and its derivative copolymers have been extensively studied as drug carriers in pharmaceutical and medical fields, especially for controlled release of anti-tumor drugs. Poly-epsiloncaprolactone based drug delivery systems lead to major advantages including uniform drug distribution, long term of degradation and drug release process, non-toxic in nature and cyto-compatible with body tissues. Approved by US Food and Drug Administration, poly-epsilon-caprolactone provides a promising platform for design and fabrication of anti-tumor drug delivery systems with controllable drug release behaviors. Methods: This mini-review focused on the recent progress in application of poly-epsiloncaprolactone based materials for controlled release of cancer therapy drugs. A careful search was performed on web of science, mainly focused on the related papers published from 2013 to 2016. Conclusion: Recent advances in applying poly-epsilon-caprolactone for controlled delivery and targeting release of chemical anti-tumor drugs were summarized in this mini-review. Benefited from the efforts of scientists all over the world, various chemotherapeutic drug delivery systems based on different formulations of poly-epsilon-caprolactone related materials have been evaluated. It has been widely recognized that the introduction of of poly-epsilon-caprolactone components into drug delivery systems would increase drug loading capacity, decrease leakage, prolong releasing period and result in controllable releasing rate. Especially with the development of environment-responsive delivery systems (pH-, thermo-, magnetic field- and light-responsive drug carriers), enhanced tumor cell targeting potential, as well as decreased systemic toxicity would be realized.

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Calcium-calpain Dependent Pathways Regulate Vesiculation in Malignant Breast Cells

Background: Multidrug resistance in cancer (MDR) occurs when tumours become crossresistant to a range of different anticancer agents. One mechanism by which MDR can be acquired is through cell to cell communication pathways. Membrane-derived microparticles (MPs) are emerging as important signaling molecules in this process. MPs are released from most eukaryotic cells and transfer functional proteins and nucleic acids to recipient cells conferring deleterious traits within the cancer cell population including MDR, metastasis, and angiogenesis. MP formation is known to be dependent on calpain, an intracellular cysteine protease which acts to cleave the cytoskeleton underlying the plasma membrane, resulting in cellular surface blebbing Objective: To establish the role of calpain in vesiculation in malignant and non-malignant cells by 1) comparing membrane vesiculation at rest and following the release of intracellular calcium, and 2) comparing vesiculation in the presence and absence of calpain inhibitor II (ALLM). Method: This study examines the differences in vesiculation between malignant and non-malignant cells using high-resolution Atomic Force Microscopy (AFM). HBEC, MBE-F, MCF-7, and MCF- 7/Dx cells were analysed at rest and following treatment with calcium ionophore A23187 for 18 hours. Vesiculation of calcium activated and resting malignant and non-malignant cells was also assessed after 18 hour treatment of calpain inhibitor II (ALLM). Results: We demonstrate that malignant MCF-7 and MCF-7/Dx cells have an intrinsically higher degree of vesiculation at rest when compared to non-malignant human brain endothelial cells (HBEC) and human mammary epithelial cells (MBE-F). Cellular activation with the calcium ionophore A23187 resulted in an increase in vesiculation in all cell types. We show that calpain-mediated MP biogenesis is the dominant pathway at rest in malignant cells as vesiculation was shown to be inhibited with calpain inhibitor II (ALLM). Conclusion: These results suggest that differences in the biogenic pathways exist in malignant and non-malignant cells and have important implications in defining novel strategies to selectively target malignant cells for the circumvention of deleterious traits acquired through intercellular exchange of extracellular vesicles.

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Dissection and Culture of Mouse Embryonic Kidney

This protocol describes a method for isolating and culturing metanephric rudiments from mouse embryos.

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Effect of Intravesical Liposome-Based Nerve Growth Factor Antisense Therapy on Bladder Overactivity and Nociception in a Rat Model of Cystitis Induced by Hydrogen Peroxide

Human Gene Therapy , Vol. 0, No. 0.


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TUmor-volume to breast-volume RAtio for improving COSmetic results in breast cancer patients (TURACOS); a randomized controlled trial

Abstract

Background

Cosmetic result following breast conserving surgery (BCS) for cancer influences quality of life and psychosocial functioning in breast cancer patients. A preoperative prediction of expected cosmetic result following BCS is not (yet) standard clinical practice and therefore the choice for either mastectomy or BCS is still subjective. Recently, we showed that tumour volume to breast volume ratio as well as tumour location in the breast are independent predictors of superior cosmetic result following BCS. Implementation of a prediction model including both factors, has not been studied in a prospective manner. This study aims to improve cosmetic outcome by implementation of a prediction model in the treatment decision making for breast cancer patients opting for BCS.

Methods/design

Multicentre, single-blinded, randomized controlled trial comparing standard preoperative work-up to a preoperative work-up with addition of the prediction model. Tumour volume to breast volume ratio and tumour location in the breast will be used to predict cosmetic outcome in invasive breast cancer patients opting for BCS. Three dimensional (3D)-ultrasonography will be used to measure the tumour volume to breast volume ratio needed for the prediction model. Sample size was estimated based on a 14% improvement in incidence of superior cosmetic result one year after BCS (71% in the control group versus 85% in the intervention group). Primarily cosmetic outcome will be evaluated by a 6-member independent panel. Secondary endpoints include; (1) patient reported outcome measured by BREAST-Q, EORTC-QLQ-C30/BR23 and EQ-5D-5 L (2) cosmetic outcome as assessed through the BCCT.core software, (3) radiation-induced reaction (4) surgical treatment performed, (5) pathological result and (6) cost-effectiveness. Follow-up data will be collected for 3 years after surgery or finishing radiotherapy.

Discussion

This randomized controlled trial examines the value of a preoperative prediction model for the treatment-decision making. It aims for a superior cosmetic result in breast cancer patients opting for BCS. We expect improvement of patients' quality of life and psychosocial functioning in a cost-effective way.

Trial registration

Prospectively registered, February 17th 2015, at 'Nederlands Trialregister - NTR4997'.

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High lymphatic vessel density and presence of lymphovascular invasion both predict poor prognosis in breast cancer

Abstract

Background

Lymphatic vessel density and lymphovascular invasion are commonly assessed to identify the clinicopathological outcomes in breast cancer. However, the prognostic values of them on patients' survival are still uncertain.

Methods

Databases of PubMed, Embase, and Web of Science were searched from inception up to 30 June 2016. The hazard ratio with its 95% confidence interval was used to determine the prognostic effects of lymphatic vessel density and lymphovascular invasion on disease-free survival and overall survival in breast cancer.

Results

Nineteen studies, involving 4215 participants, were included in this study. With the combination of the results of lymphatic vessel density, the pooled hazard ratios and 95% confidence intervals were 2.02 (1.69–2.40) for disease-free survival and 2.88 (2.07–4.01) for overall survival, respectively. For lymphovascular invasion study, the pooled hazard ratios and 95% confidence intervals were 1.81 (1.57–2.08) for disease-free survival and 1.64 (1.43–1.87) for overall survival, respectively. In addition, 29.56% (827/2798) of participants presented with lymphovascular invasion in total.

Conclusions

Our study demonstrates that lymphatic vessel density and lymphovascular invasion can predict poor prognosis in breast cancer. Standardized assessments of lymphatic vessel density and lymphovascular invasion are needed.

http://ift.tt/2rrIYgn

Second-line pazopanib in patients with relapsed and refractory small-cell lung cancer: a multicentre phase II study of the Hellenic Oncology Research Group

Second-line pazopanib in patients with relapsed and refractory small-cell lung cancer: a multicentre phase II study of the Hellenic Oncology Research Group

British Journal of Cancer advance online publication, May 16 2017. doi:10.1038/bjc.2017.137

Authors: F Koinis, S Agelaki, V Karavassilis, N Kentepozidis, E Samantas, S Peroukidis, P Katsaounis, E Hartabilas, I I Varthalitis, I Messaritakis, G Fountzilas, V Georgoulias & A Kotsakis

http://ift.tt/2qpYWds

BAG-1 as a biomarker in early breast cancer prognosis: a systematic review with meta-analyses

BAG-1 as a biomarker in early breast cancer prognosis: a systematic review with meta-analyses

British Journal of Cancer advance online publication, May 16 2017. doi:10.1038/bjc.2017.130

Authors: E S Papadakis, T Reeves, N H Robson, T Maishman, G Packham & R I Cutress

http://ift.tt/2qpLuqj

Transplantation of Zebrafish Pediatric Brain Tumors into Immune-competent Hosts for Long-term Study of Tumor Cell Behavior and Drug Response

The transplantation of cancer cells is an important tool for the identification of cancer mechanisms and therapeutic responses. Current techniques depend on immune-incompetent animals. Here, we describe a method to transplant zebrafish tumor cells into immune-competent embryos for the long-term analysis of tumor cell behavior and in vivo drug responses.

http://ift.tt/2qtngLQ

Prospective External Validation of Three Preoperative Risk Scores for Prediction of New Onset Atrial Fibrillation After Cardiac Surgery.

BACKGROUND: Postoperative atrial fibrillation (POAF) is associated with early and late morbidity and mortality of cardiac surgical patients. Prophylactic treatment of atrial fibrillation (AF) has been recommended to improve outcome in cardiac surgical patients at high risk of developing POAF. Reliable models for prediction of POAF are needed to achieve that goal. This study attempted to externally validate 3 risk models proposed for preoperative prediction of POAF in cardiac surgical patients: the POAF score, the CHA2DS2-VASc score, and the Atrial Fibrillation Risk Index. METHODS: This was a prospective cohort study of 1416 adult patients who underwent nonemergent coronary artery bypass graft and/or valve surgery in a single cardiac surgical center between February 2014 and September 2015. A risk score for each of the 3 prediction models was calculated in each patient. All patients were followed for up to 2 weeks, or until hospital discharge, to observe the primary outcome of new onset AF requiring treatment. Discrimination was assessed using receiver operating characteristic curves. Calibration was assessed using the Pearson [chi]2 goodness-of-fit test and calibration plots. Utility of the score to implement AF prophylaxis based on the risk of POAF, in comparison to strategies of treating all patients, or not treating any patients, was assessed via a net benefit analysis. RESULTS: Of the 1416 patients included in this study, 478 had the primary outcome (33.8%). The areas under the receiver operating characteristic curve for prediction of POAF in the population subsets for which the scores were validated were as follows: 0.651 (95% confidence interval [CI], 0.621-0.681) for the POAF score, 0.593 (95% CI, 0.557-0.629) for the CHA2DS2-VASc score (P

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Preoperative Warming Versus no Preoperative Warming for Maintenance of Normothermia in Women Receiving Intrathecal Morphine for Cesarean Delivery: A Single Blinded, Randomized Controlled Trial.

BACKGROUND: Rates of hypothermia for women undergoing spinal anesthesia for cesarean delivery are high and prevention is desirable. This trial compared the effectiveness of preoperative warming versus usual care among women receiving intrathecal morphine, which is thought to exacerbate perioperative heat loss. METHODS: A prospective, single-blinded, randomized controlled trial compared 20 minutes of forced air warming (plus intravenous fluid warming) versus no active preoperative warming (plus intravenous fluid warming) in 50 healthy American Society of Anesthesiologists graded II women receiving intrathecal morphine as part of spinal anesthesia for elective cesarean delivery. The primary outcome of maternal temperature change was assessed via aural canal and bladder temperature measurements at regular intervals. Secondary outcomes included maternal thermal comfort, shivering, mean arterial pressure, agreement between aural temperature, and neonatal outcomes (axillary temperature at birth, Apgar scores, breastfeeding, and skin-to-skin contact). The intention-to-treat population was analyzed with descriptive statistics, general linear model analysis, linear mixed-model analysis, [chi]2 test of independence, Mann-Whitney, and Bland-Altman analysis. Full ethical approval was obtained, and the study was registered on the Australia and New Zealand Clinical Trials Registry (Trial No: 367160, registered at http://ift.tt/17L6Qgm). RESULTS: Intention-to-treat analysis (n = 50) revealed no significant difference in aural temperature change from baseline to the end of the procedure between groups: F (1, 47) = 1.2, P = .28. There were no other statistically significant differences between groups in any of the secondary outcomes. CONCLUSIONS: A short period of preoperative warming is not effective in preventing intraoperative temperature decline for women receiving intrathecal morphine. A combination of preoperative and intraoperative warming modalities may be required for this population. (C) 2017 International Anesthesia Research Society

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Patient Blood Management in Major Orthopedic Surgery: Less Erythropoietin and More Iron?.

Erythropoietin (EPO) is proposed preoperatively to reduce blood transfusion in anemic patients (hemoglobin

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Relationship Between a Sepsis Intervention Bundle and In-Hospital Mortality Among Hospitalized Patients: A Retrospective Analysis of Real-World Data.

BACKGROUND: Sepsis is a systemic response to infection that can lead to tissue damage, organ failure, and death. Efforts have been made to develop evidence-based intervention bundles to identify and manage sepsis early in the course of the disease to decrease sepsis-related morbidity and mortality. We evaluated the relationship between a minimally invasive sepsis intervention bundle and in-hospital mortality using robust methods for observational data. METHODS: We performed a retrospective cohort study at the University of California, San Francisco, Medical Center among adult patients discharged between January 1, 2012, and December 31, 2014, and who received a diagnosis of severe sepsis/septic shock (SS/SS). Sepsis intervention bundle elements included measurement of blood lactate; drawing of blood cultures before starting antibiotics; initiation of broad spectrum antibiotics within 3 hours of sepsis presentation in the emergency department or 1 hour of presentation on an inpatient unit; administration of intravenous fluid bolus if the patient was hypotensive or had a lactate level >4 mmol/L; and starting intravenous vasopressors if the patient remained hypotensive after fluid bolus administration. Poisson regression for a binary outcome variable was used to estimate an adjusted incidence-rate ratio (IRR) comparing mortality in groups defined by bundle compliance measured as a binary predictor, and to estimate an adjusted number needed to treat (NNT). RESULTS: Complete bundle compliance was associated with a 31% lower risk of mortality (adjusted IRR, 0.69, 95% confidence interval [CI], 0.53-0.91), adjusting for SS/SS presentation in the emergency department, SS/SS present on admission (POA), age, admission severity of illness and risk of mortality, Medicaid/Medicare payor status, immunocompromised host status, and congestive heart failure POA. The adjusted NNT to save one life was 15 (CI, 8-69). Other factors independently associated with mortality included SS/SS POA (adjusted IRR, 0.55; CI, 0.32-0.92) and increased age (adjusted IRR, 1.13 per 10-year increase in age; CI, 1.03-1.24). CONCLUSIONS: The University of California, San Francisco, sepsis bundle was associated with a decreased risk of in-hospital mortality across hospital units after robust control for confounders and risk adjustment. The adjusted NNT provides a reasonable and achievable goal to observe measureable improvements in outcomes for patients diagnosed with SS/SS. (C) 2017 International Anesthesia Research Society

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