Fat attacks!: a case of fat embolisation syndrome postliposuction

Liposuction is a procedure commonly performed in the UK usually with a low incidence of serious sequelae; however with larger patients and increased volumes of lipoaspirate, complications have been reported more frequently. One of the rare but very serious complications postliposuction is fat embolism syndrome (FES), a life-threatening condition difficult to diagnose and limited in treatment.

The authors present the case of a 45-year-old woman who was admitted to the intensive care unit postelective liposuction for bilateral leg lipoedema. She presented with the triad of respiratory failure, cerebral dysfunction and petechial rash requiring a brief period of organ support. This case highlights that with the recent increase in liposuction procedures worldwide, FES is a differential to always consider. Although still a rare condition this article emphasises the importance of thinking outside the box and how to identify and manage such a life-threatening complication.

http://ift.tt/2yo2HF5

Pharmacological versus classical approaches in the design of first in man clinical drug trials

Aims

To investigate the role of pharmacology in the design of first in man (FIM) trials in the Netherlands, and to evaluate the change in design approaches between 2007 and 2015.

Methods

All FIM drug trials approved by all Dutch Institutional Review Boards (IRBs) in 2007 and in 2015 were selected. The original trial protocols, investigator's brochures and investigational medicinal product dossiers were the data sources. The design elements preclinical information, dose calculation, endpoints and dose escalation were assessed on the justification of the chosen approaches.

Results

In 2007, the Dutch IRBs approved 21 FIM trials and in 2015 they approved 34 FIM trials (55 in total). Seven out of 21 (33%) of the FIM trials from 2007, and 14 out of the 34 (41%) FIM trials from 2015 discussed only the NOAEL or NOEL as preclinical information. Furthermore, 5 of the 21 (24%) 2007 FIM trials and 12 of the 34 (35%) 2015 FIM trials used unexplained allometric scaling. PD parameters were measured in 15 of the 21 (71%) 2007 FIM trials and in 31 of the 34 (91%) of the 2015 FIM trials, and allometric scaling was only guided by safety/tolerability in 11 of the 20 (55%) dose escalation trials in 2007 and in 9 of the 33 (27%) dose escalation trials in 2015.

Conclusions

Trial protocols and investigator's brochures commonly lack PK/PD approaches. Investigators, sponsors and IRBs should require an upfront consideration of pharmacology in these aspects for all FIM-trials.

http://ift.tt/2hOrefO

Randomized clinical trial of immersive virtual reality tour of the operating theatre in children before anaesthesia

Background

A virtual reality (VR) tour of the operating theatre before anaesthesia could provide a realistic experience for children. This study was designed to determine whether a preoperative VR tour could reduce preoperative anxiety in children.

Methods

Children scheduled for elective surgery under general anaesthesia were randomized into a control or VR group. The control group received conventional information regarding anaesthesia and surgery. The VR group watched a 4-min video showing Pororo, the famous little penguin, visiting the operating theatre and explaining what is in it. The main outcome was preoperative anxiety, assessed using the modified Yale Preoperative Anxiety Scale (m-YPAS) before entering the operating theatre. Secondary outcomes included induction compliance checklist (ICC) and procedural behaviour rating scale (PBRS) scores during anaesthesia.

Results

A total of 69 children were included in the analysis, 35 in the control group and 34 in the VR group. Demographic data and induction time were similar in the two groups. Children in the VR group had a significantly lower m-YPAS score than those in the control group (median 31·7 (i.q.r. 23·3–37·9) and 51·7 (28·3–63·3) respectively; P < 0·001). During anaesthesia, the VR group had lower ICC and PBRS scores than the control group.

Conclusion

This preoperative VR tour of the operating theatre was effective in alleviating preoperative anxiety and increasing compliance during induction of anaesthesia in children undergoing elective surgery. Registration number: UMIN000025232 (http://ift.tt/1zqOmCP).

http://ift.tt/2xPJeNd

T cell Receptor Alpha Variable 12-2 bias in the immunodominant response to Yellow fever virus

The repertoire of human αβ T cell receptors (TCRs) is generated via somatic recombination of germline gene segments. Despite this enormous variation, certain epitopes can be immunodominant, associated with high frequencies of antigen-specific T cells and/or exhibit bias towards a TCR gene segment. Here, we studied the TCR repertoire of the HLA-A*0201-restricted epitope LLWNGPMAV (hereafter, A2/LLW) from Yellow Fever virus, which generates an immunodominant CD8⁺ T cell response to the highly effective YF-17D vaccine. We discover that these A2/LLW-specific CD8⁺ T cells are highly biased for the TCR α chain TRAV12-2. This bias is already present in A2/LLW-specific naïve T cells before vaccination with YF-17D. Using CD8⁺ T cell clones, we show that TRAV12-2 does not confer a functional advantage on a per cell basis. Molecular modeling indicated that the germline-encoded complementarity determining region (CDR) 1α loop of TRAV12-2 critically contributes to A2/LLW binding, in contrast to the conventional dominant dependence on somatically rearranged CDR3 loops. This germline component of antigen recognition may explain the unusually high precursor frequency, prevalence and immunodominance of T-cell responses specific for A2/LLW epitope.

This article is protected by copyright. All rights reserved

http://ift.tt/2yHzgtM

Erratum to: A multi-stage genome-wide association study of uterine fibroids in African Americans

The article "A multi-stage genome-wide association study of uterine fibroids in African Americans", written by Jacklyn N. Hellwege, was originally published Online First without open access. After publication in volume 136, issue 10, page 1363–1373 the author decided to opt for Open Choice and to make the article an open access publication. Therefore, the copyright of the article has been changed to © The Author(s) 2017 and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License (http://ift.tt/1iwynXF), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

http://ift.tt/2yVqMQJ

Editorial Board

http://ift.tt/2fJRSBU

Table of Contents

http://ift.tt/2xXk3ap

NMDAR encephalitis: passive transfer from man to mouse by a recombinant antibody

Abstract

Objective

Autoimmune encephalitis is most frequently associated with anti-NMDAR autoantibodies. Their pathogenic relevance has been suggested by passive transfer of patients' cerebrospinal fluid (CSF) in mice in vivo. We aimed to analyze the intrathecal plasma cell repertoire, identify autoantibody-producing clones, and characterize their antibody signatures in recombinant form.

Methods

Patients with recent onset typical anti-NMDAR encephalitis were subjected to flow cytometry analysis of the peripheral and intrathecal immune response before, during, and after immunotherapy. Recombinant human monoclonal antibodies (rhuMab) were cloned and expressed from matching immunoglobulin heavy- (IgH) and light-chain (IgL) amplicons of clonally expanded intrathecal plasma cells (cePc) and tested for their pathogenic relevance.

Results

Intrathecal accumulation of B and plasma cells corresponded to the clinical course. The presence of cePc with hypermutated antigen receptors indicated an antigen-driven intrathecal immune response. Consistently, a single recombinant human GluN1-specific monoclonal antibody, rebuilt from intrathecal cePc, was sufficient to reproduce NMDAR epitope specificity in vitro. After intraventricular infusion in mice, it accumulated in the hippocampus, decreased synaptic NMDAR density, and caused severe reversible memory impairment, a key pathogenic feature of the human disease, in vivo.

Interpretation

A CNS-specific humoral immune response is present in anti-NMDAR encephalitis specifically targeting the GluN1 subunit of the NMDAR. Using reverse genetics, we recovered the typical intrathecal antibody signature in recombinant form, and proved its pathogenic relevance by passive transfer of disease symptoms from man to mouse, providing the critical link between intrathecal immune response and the pathogenesis of anti-NMDAR encephalitis as a humorally mediated autoimmune disease.

http://ift.tt/2xdLeiF

Prebiotic potential of pectin and pectic oligosaccharides to promote anti-inflammatory commensal bacteria in the human colon

Abstract

Dietary plant cell wall carbohydrates are important in modulating the composition and metabolism of the complex gut microbiota, which can impact on health. Pectin is a major component of plant cell walls. Based on studies in model systems and available bacterial isolates and genomes, the capacity to utilize pectins for growth is widespread among colonic Bacteroidetes but relatively uncommon among Firmicutes. One Firmicutes species promoted by pectin is Eubacterium eligens. E. eligens DSM3376 utilizes apple pectin and encodes a broad repertoire of pectinolytic enzymes, including a highly abundant pectate lyase of around 200 kDa that is expressed constitutively. We confirmed that certain Faecalibacterium prausnitzii strains possess some ability to utilize apple pectin and report here that F. prausnitzii strains in common with E. eligens, can utilize the galacturonide oligosaccharides DP4 and DP5 derived from sugar beet pectin. F. prausnitzii strains have been shown previously to exert anti-inflammatory effects on host cells, but we show here for the first time that E. eligens strongly promotes the production of the anti-inflammatory cytokine IL-10 in in vitro cell-based assays. These findings suggest the potential to explore further the prebiotic potential of pectin and its derivatives to re-balance the microbiota towards an anti-inflammatory profile.

http://ift.tt/2yXhq6X

Broad-range survey of vector-borne pathogens and tick host identification of Ixodes ricinus from Southern Czech Republic

Abstract

Ixodes ricinus ticks are vectors of numerous human and animal pathogens. They are host generalists able to feed on more than 300 vertebrate species. The prevalence of tick-borne pathogens is influenced by host-vector-pathogen interactions that results in spatial distribution of infection risk. Broad-range PCR and electrospray ionization mass-spectrometry (PCR/ESI-MS) was used to analyze 435 I. ricinus nymphs from four localities in the south of the Czech Republic for the species identification of tick-borne pathogens. Borrelia burgdorferi sensu lato spirochetes were the most common pathogen detected in the ticks; 21% of ticks were positive for a single genospecies and 2% were co-infected with two genospecies. Other tick-borne pathogens detected included Rickettsia helvetica (3.9%), R. monacensis (0.2%), Anaplasma phagocytophilum (2.8%), Babesia venatorum (0.9%), and Ba. microti (0.5%). The vertebrate host of the ticks was determined using PCR followed by reverse line blot hybridization from the tick's blood-meal remnants. The host was identified for 61% of ticks. DNA of two hosts was detected in 16% of samples with successful host identification. The majority of ticks had fed on artiodactyls (50.7%) followed by rodents (28.6%) and birds (7.8%). Other host species were wild boar, deer, squirrels, field mice, and voles.

http://ift.tt/2xRUyYS

Community structure of rare methanogenic archaea: insight from a single functional group

Abstract

The rare biosphere, the low-abundant microbial populations, is suggested to be a conserved way of microbial life. Here we conducted a molecular survey of rare methanogenic archaea in the environment targeting the mcrA gene in order to test if general concepts associated with the structure of the rare bacterial biosphere also apply to single functional groups. Similar to what is known about rare bacterial communities, the overall contribution of rare methanogens to the alpha diversity is much larger than to Bray-Curtis measures. Moreover, a similar core group of methanogens harbored by the abundant and rare communities suggests similar sources and environmental controls of both groups. Among the communities of different levels of rarity, the conditionally rare methanogenic taxa largely account for the overall community dynamics of the rare biosphere and likely enter the dominant community under favorable environmental conditions. In addition, we observed a positive correlation between the alpha diversity and the production of methane when the rare taxa were taken into account. This supports the concept that increasing microbial biodiversity enhances ecological function. The composition and environmental associations of the rare methanogenic biosphere allow us to conclude that rarity is a conserved way also for single functional groups.

http://ift.tt/2yVj49f

Geographical distance and local environmental conditions drive the genetic population structure of a freshwater microalga (Bathycoccaceae; Chlorophyta) in Patagonian lakes

Abstract

The patterns and mechanisms underlying the genetic structure of microbial populations remain unresolved. Herein we investigated the role played by two non-mutually exclusive models (i.e. isolation by distance and isolation by environment) in shaping the genetic structure of lacustrine populations of a microalga (a freshwater Bathycoccaceae) in the Argentinean Patagonia. To our knowledge, this was the first study to investigate the genetic population structure in a South American microorganism. Population-level analyses based on ITS1–5.8S-ITS2 sequences revealed high levels of nucleotide and haplotype diversity within and among populations. Fixation index and a spatially explicit Bayesian analysis confirmed the occurrence of genetically distinct microalga populations in Patagonia. Isolation by distance and isolation by environment accounted for 38.5 and 17.7% of the genetic structure observed, respectively; whereas together these models accounted for 41% of the genetic differentiation. While our results highlighted isolation by distance and isolation by environment as important mechanisms in driving the genetic population structure of the microalga studied, none of these models (either alone or together) could explain the entire genetic differentiation observed. The unexplained variation in the genetic differentiation observed could be the result of founder events combined with rapid local adaptations, as proposed by the monopolization hypothesis.

http://ift.tt/2xPBfzB

Comparison of thaumarchaeotal populations from four deep sea basins

Abstract

The nitrogen cycle in the marine environment is strongly affected by ammonia oxidizing Thaumarchaeota. In some marine settings Thaumarchaeotes can comprise a large % of the prokaryotic population. To better understand the biogeographic patterns of Thaumarchaeotes, we sought to investigate differences in their abundance and phylogenetic diversity between geographically distinct basins. Samples were collected from four marine basins (The Caspian Sea, the Great Australian Bight, and the Central and Eastern Mediterranean). The concentration of bacterial and archaeal 16S rRNA genes and archaeal amoA genes were assessed using qPCR. Minimum entropy decomposition (MED) was used to elucidate the fine-scale diversity of Thaumarchaeotes. We demonstrated that there were significant differences in the abundance and diversity of Thaumarchaeotes between these four basins. The diversity of Thaumarchaeotal oligotypes differed between basins with many oligotypes only present in one of the four basins, which suggests that their distribution showed biogeographic patterning. There were also significant differences in Thaumarchaeotal community structure between these basins. This would suggest that geographically distant, yet geochemically similar basins may house distinct Thaumarchaeaotal populations. These findings suggest that Thaumarchaeota are very diverse and that biogeography in part contributes the determining the diversity and distribution of Thaumarchaeotes.

http://ift.tt/2xRfhfG

Increased Risk for Complications Following Removal of Hardware in Patients with Liver Disease, Pilon or Pelvic Fractures: A Regression Analysis

Publication date: Available online 3 October 2017
Source:Injury
Author(s): Bryan D. Brown, Justin N. Steinert, John W. Stelzer, Richard S. Yoon, Joshua R. Langford, Kenneth J. Koval
PurposeIndications for removing orthopedic hardware on an elective basis varies widely. Although viewed as a relatively benign procedure, there is a lack of data regarding overall complication rates after fracture fixation. The purpose of this study is to determine the overall short-term complication rate for elective removal of orthopedic hardware after fracture fixation and to identify associated risk factors.Materials and MethodsAdult patients indicated for elective hardware removal after fracture fixation between July 2012 and July 2016 were screened for inclusion. Inclusion criteria included patients with hardware related pain and/or impaired cosmesis with complete medical and radiographic records and at least 3-month follow-up. Exclusion criteria were those patients indicated for hardware removal for a diagnosis of malunion, non-union, and/or infection. Data collected included patient age, gender, anatomic location of hardware removed, body mass index, ASA score, and comorbidities. Overall complications, as well as complications requiring revision surgery were recorded. Statistical analysis was performed with SPSS 20.0, and included univariate and multivariate regression analysis.Results391 patients (418 procedures) were included for analysis. Overall complication rates were 8.4%, with a 3.6% revision surgery rate. Univariate regression analysis revealed that patients who had liver disease were at significant risk for complication (p=0.001) and revision surgery (p=0.036). Multivariate regression analysis showed that: 1) patients who had liver disease were at significant risk of overall complication (p=0.001) and revision surgery (p=0.039); 2) Removal of hardware following fixation for a pilon had significantly increased risk for complication (p=0.012), but not revision surgery (p=0.43); and 3) Removal of hardware for pelvic fixation had a significantly increased risk for revision surgery (p=0.017).ConclusionsRemoval of hardware following fracture fixation is not a risk-free procedure. Patients with liver disease are at increased risk for complications, including increased risk for needing revision surgery following hardware removal. Patients having hardware removed following fixation for pilon fractures also are at increased risk for complication, although they may not require a return trip to the operating room. Finally, removal of pelvic hardware is associated with a higher return to the operating room.



http://ift.tt/2yWowJ2

Common TDP1 polymorphisms in relation to survival among small cell lung cancer patients: a multicenter study from the International Lung Cancer Consortium

Purpose: DNA topoisomerase inhibitors are commonly used for treating small cell lung cancer (SCLC). Tyrosyl-DNA phosphodiesterase (TDP1) repairs DNA damage caused by this class of drugs and may therefore influence treatment outcome. In this study, we investigated whether common TDP1 single nucleotide polymorphisms (SNPs) are associated with overall survival among SCLC patients. Experimental Design: Two TDP1 SNPs (rs942190 and rs2401863) were analyzed in 890 patients from 10 studies in the International Lung Cancer Consortium (ILCCO). The Kaplan-Meier method and Cox regression analyses were used to evaluate genotype associations with overall mortality at 36 months post-diagnosis, adjusting for age, sex, race, and tumor stage. Results: Patients homozygous for the minor allele (GG) of rs942190 had poorer survival compared to those carrying AA alleles, with a hazard ratio (HR) of 1.36 (95% confidence interval (CI): 1.08-1.72, p-value=0.01), but no association with survival was observed for patients carrying the AG genotype (HR=1.04, 95% CI:0.84-1.29, p-value=0.72). For rs2401863, patients homozygous for the minor allele (CC) tended to have better survival than patients carrying AA alleles (HR=0.79, 95% CI: 0.61-1.02, p-value=0.07). Results from the Genotype Tissue Expression (GTEx) Project, the Encyclopedia of DNA Elements (ENCODE), and the ePOSSUM web application support the potential function of rs942190. Conclusions: We found the rs942190 GG genotype to be associated with relatively poor survival among SCLC patients. Further investigation is needed to confirm the result and to determine whether this genotype may be a predictive marker for treatment efficacy of DNA topoisomerase inhibitors.

http://ift.tt/2xZGegy

A molecularly annotated model of patient-derived colon cancer stem-like cells to assess genetic and non-genetic mechanisms of resistance to anti-EGFR therapy

Purpose Patient-derived xenografts ("xenopatients") of colorectal cancer metastases have been essential to identify genetic determinants of resistance to the anti-EGF Receptor (EGFR) antibody cetuximab, and to explore new therapeutic strategies. From xenopatients, a genetically annotated collection of stem-like cultures ("xenospheres") was generated and characterized for response to targeted therapies. Experimental Design. Xenospheres underwent exome-sequencing analysis, gene expression profile and in vitro targeted treatments to assess genetic, biological and pharmacological correspondence with xenopatients, and to investigate non-genetic biomarkers of therapeutic resistance. The outcome of EGFR family inhibition was tested in an NRG1-expressing in vivo model. Results. Xenospheres faithfully retained the genetic make-up of their matched xenopatients over in vitro and in vivo passages. Frequent and rare genetic lesions triggering primary resistance to cetuximab through constitutive activation of the RAS signaling pathway were conserved, as well as the vulnerability to their respective targeted treatments. Xenospheres lacking such alterations (RASwt) were highly sensitive to cetuximab, but were protected by ligands activating the EGFR family, mostly NRG1. Upon reconstitution of NRG1 expression, xenospheres displayed increased tumorigenic potential in vivo, generated tumors completely resistant to cetuximab, and sensitive only to comprehensive EGFR family inhibition. Conclusions. Xenospheres are a reliable model to identify both genetic and non-genetic mechanisms of response and resistance to targeted therapies in colorectal cancer. In the absence of RAS pathway mutations, NRG1 and other EGFR ligands can play a major role in conferring primary cetuximab resistance, indicating that comprehensive inhibition of the EGFR family is required to achieve a significant therapeutic response.

http://ift.tt/2fQ0XNk

Modulation of Navitoclax Sensitivity by Dihydroartemisinin-Mediated MCL-1 Repression in BCR-ABL+ B-Lineage Acute Lymphoblastic Leukemia

Purpose: BCR-ABL+ B-ALL leukemic cells are highly dependent on the expression of endogenous anti-apoptotic MCL-1 to promote viability and are resistant to BH3-mimetic agents such as navitoclax (ABT-263) that targets BCL-2, BCL-XL, and BCL-W. However, the survival of most normal blood cells and other cell types are also dependent on Mcl-1. Despite the requirement for MCL-1 in these cell types, initial reports of MCL-1-specific BH3-mimetics have not described any overt toxicities associated with single-agent use, but these agents are still early in clinical development. Therefore, we sought to identify FDA-approved drugs that could sensitize leukemic cells to ABT-263. Experimental Design: A screen identified dihydroartemisinin (DHA), a water-soluble metabolite of the anti-malarial artemisinin. Using mouse and human leukemic cell lines, and primary patient-derived xenografts, the effect of DHA on survival was tested and mechanistic studies were carried out to discover how DHA functions. We further tested in vitro and in vivo whether combining DHA with ABT-263 could enhance the response of leukemic cells to combination therapy. Results: DHA causes the down-modulation of MCL-1 expression by triggering a cellular stress response that represses translation. The repression of MCL-1 renders leukemic cells highly sensitive to synergistic cell death induced by ABT-263 in a mouse model of BCR-ABL+ B-ALL both in vitro and in vivo. Furthermore, DHA synergizes with ABT-263 in human Ph+ ALL cell lines, and primary patient derived xenografts of Ph+ ALL in culture. Conclusions: Our findings suggest that combining DHA with ABT-263 can improve therapeutic response in BCR-ABL+ B-ALL.

http://ift.tt/2xZ39J7

The HRD decision--which PARP inhibitor to use for whom and when

Rucaparib, a polyADPribose polymerase (PARP) inhibitor, was approved recently for use in women with high grade serous ovarian cancer (HGSOC). It is now one of 3 approved PARPi for use in recurrent ovarian cancer, a family of agents that has changed the HGSOC treatment landscape and outcome.

http://ift.tt/2fPfNnp

Whole-Genome Sequence Analysis of Mutations Accumulated in rad27{Delta} Yeast Strains with Defects in the Processing of Okazaki Fragments Indicates Template-Switching Events

Okazaki fragments that are formed during lagging strand DNA synthesis include an initiating primer consisting of both RNA and DNA. The RNA fragment must be removed before the fragments are joined. In Saccharomyces cerevisiae, a key player in this process is the structure-specific flap endonuclease, Rad27p (human homolog FEN1). To obtain a genomic view of the mutational consequence of loss of RAD27, a Saccharomyces cerevisiae rad27 strain was subcultured for 25 generations and sequenced using Illumina paired-end sequencing. Out of the 455 changes observed in ten colonies isolated the two most common types of events were insertions or deletions (INDELs) in simple sequence repeats (SSRs) and INDELs mediated by short direct repeats. Surprisingly, we also detected a previously neglected class of 21 template-switching events. These events were presumably generated by quasi-palindrome to palindrome correction, as well as palindrome elongation. The formation of these events is best explained by folding back of the stalled nascent strand and resumption of DNA synthesis using the same nascent strand as a template. Evidence to quasi palindrome to palindrome correction that could be generated by template switching appears also in yeast genome evolution. Out of the 455 events, 55 events appeared in multiple isolates, further analysis indicate that these loci are mutational hotspots. Since Rad27 acts on the lagging strand when the leading strand should not contain any gaps, we propose a mechanism favoring intramolecular strand switching over an intermolecular mechanism. We note that our results open new ways of understanding template switching that occur during genome instability and evolution.

http://ift.tt/2xRfOLW

Professor Dieter Haas (1945–2017)

http://ift.tt/2yXjbRW

When eukaryotes and prokaryotes look alike: the case of regulatory RNAs

Abstract

The discovery that all living entities express many RNAs beyond mRNAs, tRNAs and rRNAs has been a surprise in the past two decades. In fact, regulatory RNAs (regRNAs) are plentiful, and we report stunning parallels between their mechanisms and functions in prokaryotes and eukaryotes. For instance, prokaryotic CRISPR (clustered regularly interspaced short palindromic repeats) defense systems are functional analogs to eukaryotic RNA interference processes that preserve the cell against foreign nucleic acid elements. Regulatory RNAs shape the genome in many ways: by controlling mobile element transposition in both domains, via regulation of plasmid counts in prokaryotes, or by directing epigenetic modifications of DNA and associated proteins in eukaryotes. RegRNAs control gene expression extensively at transcriptional and post-transcriptional levels, with crucial roles in fine-tuning cell environmental responses, including intercellular interactions. Although the lengths, structures and outcomes of the regRNAs in all life kingdoms are disparate, they act through similar patterns: by guiding effectors to target molecules or by sequestering macromolecules to hamper their functions. In addition, their biogenesis processes have a lot in common. This unifying vision of regRNAs in all living cells from bacteria to humans points to the possibility of fruitful exchanges between fundamental and applied research in both domains.

http://ift.tt/2yXhrrV

Thinking big: the tunability of bacterial cell size

Abstract

The determination of cell size is a fundamental challenge for all living organisms. In a given growth condition, cell size for a particular bacterial species typically falls within a narrow distribution. Nonetheless, size can vary enormously across species, and the size of a single bacterium can even vary substantially across growth conditions. Recent phenomenological studies have revived classic interest in how cells maintain their size and how they adjust their size with changes in growth rate. However, the mechanisms by which cells establish a particular size are relatively enigmatic. Here, we review existing knowledge on how size in rod-shaped bacteria is shaped by nutrient, mechanical, and genetic factors. We also examine obstacles to accurate size measurement and recent technologies that help to overcome these hurdles. Finally, we discuss the relevance of cell size to bacterial physiology.

http://ift.tt/2xdvNXz

Na + -NQR (Na + -translocating NADH:ubiquinone oxidoreductase) as a novel target for antibiotics

Abstract

The recent breakthrough in structural studies on Na⁺-translocating NADH:ubiquinone oxidoreductase (Na⁺-NQR) from the human pathogen Vibrio cholerae creates a perspective for the systematic design of inhibitors for this unique enzyme, which is the major Na⁺ pump in aerobic pathogens. Widespread distribution of Na⁺-NQR among pathogenic species, its key role in energy metabolism, its relation to virulence in different species as well as its absence in eukaryotic cells makes this enzyme especially attractive as a target for prospective antibiotics. In this review, the major biochemical, physiological and, especially, the pharmacological aspects of Na⁺-NQR are discussed to assess its 'target potential' for drug development. A comparison to other primary bacterial Na⁺ pumps supports the contention that NQR is a first rate prospective target for a new generation of antimicrobials. A new, narrowly targeted furanone inhibitor of NQR designed in our group is presented as a molecular platform for the development of anti-NQR remedies.

http://ift.tt/2yWnJrs

Glycerol metabolism and its implication in virulence in Mycoplasma

Abstract

Glycerol and glycerol-containing compounds such as lipids belong to the most abundant organic compounds that may serve as nutrient for many bacteria. For the cell wall-less bacteria of the genus Mycoplasma, glycerol derived from phospholipids of their human or animal hosts is the major source of carbon and energy. The lipids are first degraded by lipases, and the resulting glycerophosphodiesters are transported into the cell and cleaved to release glycerol-3-phosphate. Alternatively, free glycerol can be transported, and then become phosphorylated. The oxidation of glycerol-3-phosphate in Mycoplasma spp. as well as in related firmicutes involves a hydrogen peroxide-generating glycerol-3-phosphate oxidase. This enzyme is a key player in the virulence of Mycoplasma spp. as the produced hydrogen peroxide is one of the major virulence factors of these bacteria. In this review, the different components involved in the utilization of lipids and glycerol in Mycoplasma pneumoniae and related bacteria are discussed.

http://ift.tt/2xeMqlG

Evolution of bacterial virulence

Abstract

Bacterial virulence is highly dynamic and context-dependent. For this reason, it is challenging to predict how molecular changes affect the growth of a pathogen in a host and its spread in host population. Two schools of thought have taken quite different directions to decipher the underlying principles of bacterial virulence. While molecular infection biology is focusing on the basic mechanisms of the pathogen–host interaction, evolution biology takes virulence as one of several parameters affecting pathogen spread in a host population. We review both approaches and discuss how they can complement each other in order to obtain a comprehensive understanding of bacterial virulence, its emergence, maintenance and evolution.

http://ift.tt/2xe2S5O

Overview of surgical death investigations: could a dreaded experience be turned into an opportunity?

http://ift.tt/2xQKC28

Spontaneous rectal perforation post-neoadjuvant chemoradiotherapy and loop stoma

http://ift.tt/2xPeSKL

Light at the end of the virtual tunnel: why hasn't utilization of simulation changed?

http://ift.tt/2yWeoA0

Medicine in small doses

http://ift.tt/2xQKBLC

Perianal cauliflower

http://ift.tt/2xPDNOd

Colorectal multidisciplinary meetings: how do they affect the timeliness of treatment?

Abstract

Background

The aim of this study is to determine whether multidisciplinary team (MDT) meetings alter the length of time to treatment (LOTT) for patients with colorectal cancer.

Methods

We conducted a retrospective audit of all patients with colorectal cancer from the Geelong Hospital (TGH) mandatory colorectal database from 1 January 2006 to 3 February 2011. To be included, patients had to have had elective surgical intervention for primary colorectal adenocarcinoma. A comparison of historical controls was conducted between patients discussed in MDT meetings and those managed prior to the introduction of MDT meetings (3 October 2006) to determine the LOTT in days from definitive diagnosis (colonoscopy) to definitive management (surgery, radiotherapy or chemotherapy).

Results

In total, the median LOTT for the historical control and MDT era patient populations were 19.5 and 20 days, respectively. Within the MDT era, we noticed significantly longer times to treatment for patients with rectal cancer who were seen in an MDT meeting prior to definitive management than patients who did not have an intervening MDT meeting (P < 0.001). With a difference of 7.5 days, the clinical significance of these findings remains contentious. However, it is worthwhile recognizing this trend in patients who are exhibiting symptoms due to near obstruction or significant bleeding. The LOTT for colon cancer patients remained unchanged.

Conclusion

The introduction of MDT meetings to TGH has prolonged the LOTT for patients with rectal cancer. These findings pave the way for further revision of the efficiency of MDT meeting at TGH.

http://ift.tt/2yVTUaK

Non-traumatic biliary duct neuroma masquerading as a Klatskin tumour

http://ift.tt/2xQpWah

Adenocarcinoma of the gastro-oesophageal junction after sleeve gastrectomy: a case report

http://ift.tt/2yVbyvf

Variable presentation of anaplastic large-cell lymphoma in patients with breast implants

Abstract

Background

Anaplastic large-cell lymphoma (ALCL) has recently been reported in women with breast implants. The incidence of breast implant-related ALCL is extremely rare and most surgeons would not expect to see this disease in their career. However, the senior author has had three women present to his practice with ALCL over a 2-year period.

Methods

The three patients and their presentation were reviewed to establish the presenting complaint in each case of subsequently diagnosed ALCL. Literature was reviewed to establish appropriate treatment protocols for any subsequent patients.

Results

The average time between first implant placement and presentation with breast implant-associated ALCL was 13.3 years (range: 10–16 years) and age at presentation was 49 years (range: 45–53 years). Each presentation was somewhat different, being a palpable mass, a painless seroma and a painful seroma. Both patients with seroma underwent ultrasound-guided aspiration of fluid which confirmed ALCL. All patients underwent implant removal and complete capsulectomy. The patient with a mass at presentation initially declined adjuvant treatment but subsequently developed an ALCL-associated seroma and was treated with surgery and post-operative chemotherapy.

Conclusion

Patients with breast implant-associated ALCL can present with different clinical signs and symptoms. Late seroma is a relatively common presentation of breast implant-associated ALCL. While firm guidelines for the management of breast implant-related ALCL are lacking, we suggest that any late seroma in the absence of infection should be managed with aspiration and cytological analysis of the fluid.

http://ift.tt/2xQuPju

Squamous cell carcinoma of the scrotum: the revisit of a rare disease

http://ift.tt/2yWd0xt

Synchronous small intestinal and appendiceal neuroendocrine tumours: a rare case

http://ift.tt/2xP2KJt

Surprise within a meningioma: case report of signet ring cell carcinoma metastasis in a meningioma

http://ift.tt/2yVWFbP

Use of flexor carpi radialis turnover in fasciotomy defects

http://ift.tt/2xRl2dn

Click it: do not risk it: lap seat belt causing extensive abdominal injuries

http://ift.tt/2yWEZNz

Pneumatosis intestinalis: a diagnostic dilemma

http://ift.tt/2xQuRb6

Mechanisms regulating T-cell infiltration and activity in solid tumors

Abstract

T-lymphocytes play a critical role in cancer immunity as evidenced by their presence in resected tumor samples derived from long-surviving patients, and impressive clinical responses to various immunotherapies that reinvigorate them. Indeed, tumors can upregulate a wide array of defense mechanisms, both direct and indirect, to suppress the ability of Tcells to reach the tumor bed and mount curative responses upon infiltration. In addition, patient and tumor genetics, previous antigenic experience, and the microbiome, are all important factors in shaping the T-cell repertoire and sensitivity to immunotherapy. Here, we review the mechanisms that regulate T-cell homing, infiltration, and activity within the solid tumor bed. Finally, we summarize different immunotherapies and combinatorial treatment strategies that enable the immune system to overcome barriers for enhanced tumor control and improved patient outcome.

http://ift.tt/2yXtm98

Pit pattern analysis with high-definition chromoendoscopy and narrow-band imaging for optical diagnosis of dysplasia in patients with ulcerative colitis

Patients with longstanding ulcerative colitis (UC) are at increased risk of developing colorectal neoplasia. Chromoendoscopy (CE) increases detection of lesions, and Kudo pit pattern classification I and II have been suggested to be predictive of benign polyps in UC. Little is known on the use of this classification in non-magnified high-definition (HD) (virtual) CE and narrow-band Imaging (NBI), or on the interobserver agreement. The aim of this pilot study was to assess the diagnostic accuracy and the interobserver agreement of the Kudo pit pattern classification in UC patients undergoing surveillance with methylene blue CE or NBI in a multicenter study.

http://ift.tt/2xf5fAI

Risk of advanced colorectal neoplasm by the proposed combined United States and United Kingdom risk stratification guidelines

/Aims: The United Kingdom (U.K.) guidelines for risk stratification after colon polypectomy differ from the United States (U.S.) guidelines in 2 ways: the U.K. guidelines consider ≥5 adenomas as high risk and do not consider histology (villous or high-grade dysplasia [HGD]) in assessment. Thus, we aimed to investigate the risk of advanced colorectal neoplasm (CRN) by categorized risk groups, considering both ≥5 adenomas and histology.

http://ift.tt/2hLywkn

Long-term Patient and Graft Survival of Kidney Transplant Recipients with Hepatitis C Virus Infection in the United States.

Background: Hepatitis C virus (HCV) infection is common among kidney transplant (KTx) recipients. However, the impact of HCV infection on long-term graft and recipient survival after KTx from the large-scale data remains to be determined. Methods: We used the Organ Procurement and Transplantation Network (OPTN) database to identify all adults undergoing KTx in 2004-2006 in the United States. A propensity score (PS) was created to match each HCV-positive recipient with a HCV-negative control for unbiased comparisons. Survival analysis was conducted to evaluate recipient and death-censored graft survival. Results: Out of 33,357 adult primary KTx recipients, 1470 (4.4%) were HCV-positive. 1,364 HCV-positive and -negative pairs were selected based on PS-matching. Based on the multivariable regression models, HCV is associated with a higher risk of death (hazard ratio [HR]=1.50, 95% confidence interval [95% CI=1.28-1.75) and graft failure (HR=1.26, 95% CI=1.08-1.47). Infection was a more common cause of death in HCV-positive patients than in HCV-negative recipients (HR=1.64, 95% CI=1.12-2.42). The incidence of death due to liver failure was 0.23% per year among HCV-positive recipients, whereas no HCV-negative recipients died from liver failure. Graft failure due to recurrent disease was higher in HCV-positive than in HCV-negative recipients (HR=2.00; 95% CI=1.06-3.78). Conclusion: HCV infection is associated with decreased long-term recipient and graft survival. Future studies are needed to examine whether recently available, safe and effective antiviral therapy improves the long-term clinical outcome in these patients. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2xYILb8

Chronic refractory myofascial pain and denervation supersensitivity as global public health disease

J Chu<br />Jan 13, 2016; 2016:bcr2015211816-bcr2015211816<br />case-report

http://ift.tt/2xQvK3C

Imaging in Fahr's disease: how CT and MRI differ?

Arunkumar Govindarajan<br />Nov 27, 2013; 2013:bcr2013201523-bcr2013201523<br />case-report

http://ift.tt/2xSus5W

Polycystic kidney disease and chronic renal failure in tuberous sclerosis

Mona Dhakal<br />Oct 2, 2013; 2013:bcr2013200711-bcr2013200711<br />case-report

http://ift.tt/2xRkt2S

Rarity revisited: cryptococcal peritonitis

Karim El-Kersh<br />Jul 10, 2013; 2013:bcr2013009099-bcr2013009099<br />case-report

http://ift.tt/2xSsxye

Hydroxocobalamin treatment of acute cyanide poisoning from apricot kernels

Davide Cigolini<br />May 25, 2011; 2011:bcr0320113932-bcr0320113932<br />case-report

http://ift.tt/2xPEl6L

The entrapped twin: a case of fetus-in-fetu

Rashide Yaacob<br />Sep 23, 2017; 2017:bcr-2017-220801-bcr-2017-220801<br />Rare disease

http://ift.tt/2xT0VbY

An airway traffic jam: a plastic traffic cone masquerading as bronchial carcinoma

Nicholas Denny<br />Sep 21, 2017; 2017:bcr-2017-220514-bcr-2017-220514<br />Unusual presentation of more common disease/injury

http://ift.tt/2xR5O8d

An unusual presentation of chronic cyanide toxicity from self-prescribed apricot kernel extract

Alex Konstantatos<br />Sep 11, 2017; 2017:bcr-2017-220814-bcr-2017-220814<br />Reminder of important clinical lesson

http://ift.tt/2xQJTv6

The 150 most important questions in cancer research and clinical oncology series: questions 57–66

Since the beginning of 2017, Chinese Journal of Cancer has published a series of important questions in cancer research and clinical oncology, which sparkle diverse thoughts, interesting communications, and poten...

http://ift.tt/2xWGkoM

Intraocular Injections of a Compounded Triamcinolone, Moxifloxacin, and Vancomycin (TMV) Formulation: FDA Statement - Case of Hemorrhagic Occlusive Retinal Vasculitis

Audience: Opthalmology, Pharmacy [Posted 10/03/2017] ISSUE: FDA received an adverse event report on August 14, 2017, from a physician concerning a patient who was diagnosed postoperatively with bilateral hemorrhagic occlusive retinal vasculitis...

http://ift.tt/2ymlUr4

Discrepancies between biomarkers of primary breast cancer and subsequent brain metastases: an international multicenter study

Abstract

Purpose

Discordances between the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), expression between primary breast tumors and their subsequent brain metastases (BM) were investigated in breast cancer patients.

Methods

We collected retrospective data from 11 institutions in 8 countries in a predefined-standardized format. Receptor status (positive or negative) was determined according to institutional guidelines (immunohistochemically and/or fluorescence in situ hybridization). The study was subject to each institution's ethical research committee.

Results

A total of 167 breast cancer patients with BM were included. 25 patients out of 129 with a complete receptor information from both primary tumor and BM (ER, PR, HER2) available, had a change in receptor status: 7 of 26 (27%) ER/PR-positive/HER2-negative primaries (3 gained HER2; 4 lost expression of ER/PR); 10 of 31 (32%) ER/PR-positive/HER2-positive primaries (4 lost ER/PR only; 3 lost HER2 only; 3 lost both ER/PR and HER2); one of 33 (3%) ER/PR-negative receptor/HER2-positive primaries (gained ER); and 7 of 39 (18%) triple-negative primaries (5 gained ER/PR and 2 gained HER2).

Conclusions

The majority of breast cancer patients with BM in this series had primary HER2-enriched tumors, followed by those with a triple-negative profile. One out of 5 patients had a receptor discrepancy between the primary tumor and subsequent BM. Therefore, we advise receptor status assessment of BM in all breast cancer patients with available histology as it may have significant implications for therapy.

http://ift.tt/2g8wcjv

Alterations in NO/ROS ratio and expression of Trx1 and Prdx2 in isoproterenol-induced cardiac hypertrophy

Abstract

The development of cardiac hypertrophy is a complicated process, which undergoes a transition from compensatory hypertrophy to heart failure, and the identification of new biomarkers and targets for this disease is greatly needed. Here we investigated the development of isoproterenol (ISO)-induced cardiac hypertrophy in an in vitro experimental model. After the induction of hypertrophy with ISO treatment in H9c2 cells, cell surface area, cell viability, cellular reactive oxygen species (ROS), and nitric oxide (NO) levels were tested. Our data showed that the cell viability, mitochondrial membrane potential, and NO/ROS balance varied during the development of cardiac hypertrophy in H9c2 cells. It was also found that the expression of thioredoxin1 (Trx1) and peroxiredoxin2 (Prdx2) was decreased during the cardiac hypertrophy of H9c2 cells. These results suggest a critical role for Trx1 and Prdx2 in the cardiac hypertrophy of H9c2 cells and in the transition from compensated hypertrophy to de-compensated hypertrophy in H9c2 cells, and our findings may have important implications for the management of this disease.

http://ift.tt/2xWdTaB

Effects of 12 C 6+ heavy ion beam irradiation on the p53 signaling pathway in HepG2 liver cancer cells

Abstract

The heavy ion beam is considered to be the ideal source for radiotherapy. The p53 tumor suppressor gene senses DNA damage and transducts intracellular apoptosis signals. Previous reports showed that the heavy ion beam can trigger complex forms of damage to cellular DNA, leading to cell cycle arrest and apoptosis of HepG2 human liver cancer cells; however, the mechanisms remains unclear fully. In order to explore whether the intrinsic or extrinsic pathway participates this process, HepG2 cells were treated with ¹²C⁶⁺ HIB irradiation at doses of 0 (control), 1, 2, 4, and 6 Gy with various methods employed to understand relevant mechanisms, such as detection of apoptosis, cell cycle, and Fas expression by flow cytometry, analysis of apoptotic morphology by electron microscopy and laser scanning confocal microscopy, and screening differentially expressed genes relating to p53 signaling pathway by PCR-array assay following with any genes confirmed by western blot analysis. This study showed that ¹²C⁶⁺ heavy ion beam irradiation at a dose of 6 Gy leads to endogenous DNA double-strand damage, G2/M cell cycle arrest, and apoptosis of human HepG2 cells via synergistic effect of the extrinsic and intrinsic pathways. Differentially expressed genes in the p53 signaling pathway related to DNA damage repair, apoptosis, cycle regulation, metastasis, deterioration and radioresistance were also discovered. Consequently, the expressions of Fas, TP53BP2, TP53AIP1, and CASP9 were confirmed upregulated after ¹²C⁶⁺ HIB irradiation treatment. In conclusion, this study demonstrated the mechanisms of inhibition and apoptosis induced by ¹²C⁶⁺ heavy ion beam irradiation on HepG2 cancer cells is mediated by initiation of the biological function of p53 signaling pathway including extrinsic and intrinsic apoptosis pathway.

http://ift.tt/2fI2qlc

Elabela-APJ axis: a novel therapy target for cardiovascular diseases

http://ift.tt/2xWEWmt

Lipopolysaccharide promotes angiogenesis in mice model of HCC by stimulating hepatic stellate cell activation via TLR4 pathway

Abstract

Angiogenesis plays a key role in the progression of hepatocellular carcinoma (HCC). This study aimed to investigate whether lipopolysaccharide (LPS) could promote HCC angiogenesis and the role of hepatic stellate cell (HSC) in this process. In vivo orthotopic HCC model and the effect of LPS on HSC in vitro were studied. Our results demonstrated that LPS-induced HSC activation during the promotion of HCC growth and angiogenesis in mice. The LPS-TLR4 (Toll-like receptor 4) pathway in HSC is responsible for HCC angiogenesis. LPS-induced secretion of pro-angiogenic factors from HSC could promote endothelial cell migration and tubulogenesis. This study suggests that LPS acts with HSC in tumor stroma and promotes the secretion of pro-angiogenic factors that increase angiogenesis in HCC.

http://ift.tt/2fIW58W

Doxycycline synergizes with doxorubicin to inhibit the proliferation of castration-resistant prostate cancer cells

Abstract

Castration-resistant prostate cancer (CRPC) is fatal and there is currently no effective clinical treatment. The antibiotic doxycycline has shown anti-cancer effect in several kinds of solid tumors including prostate cancer. In this study, a combination of doxycycline and doxorubicin was used to investigate the synergistic effect on CRPC cells. MTT assay was employed to determine the viability of cells in two-dimensional (2D) cultures. Apoptosis was determined by Annexin V/propidium iodide (PI) double staining assay. Cell cycle was analyzed by PI staining, and reverse transcription-PCR (RT-PCR) was used to determine the expressions of apoptosis-related genes at mRNA level. Western blot analysis was used to analyze the expressions of Bcl-2, Bax, and Poly (ADP-ribose) polymerase proteins. Cytotoxicity assay and morphological observation of PC3 cells in three-dimensional (3D) cultures were used to determine the effect of combination treatment. Results showed that doxycycline combined with doxorubicin significantly inhibited PC3 cells in both 2D and 3D cultures, enhanced apoptosis, and increased the accumulation of cells in G2/M phase. RT-PCR showed down-regulation of Bcl-2 and up-regulation of Bax mRNA after combination treatment. Meanwhile, western blot analysis showed that combination treatment resulted in down-regulation of Bcl-2 protein and up-regulation of Bax protein, and that PARP cleavage was obviously exhibited after combination treatment. Confocal imaging analysis indicated that doxorubicin penetrated deeply into the core of spheroids when combined with doxycycline. These data indicated that doxycycline in combination with doxorubicin had a synergistic effect on PC3 cells and may provide a potential novel strategy for the treatment of CRPC.

http://ift.tt/2xX4YG5

Prognostic Significance of Pre- to Postoperative Dynamics of the Prognostic Nutritional Index for Patients with Renal Cell Carcinoma Who Underwent Radical Nephrectomy

Abstract

Background

This study aimed to examine the prognostic role of Prognostic Nutritional Index (PNI) dynamics in the pre- and postoperative periods for patients with renal cell carcinoma (RCC) who undergo radical nephrectomy (RN).

Methods

The study analyzed 324 patients with RCC who underwent RN. The overall population was classified into four groups according to four types of pre- to postoperative PNI dynamics as follows: group 1 (low → low PNI), group 2 (low → high PNI), group 3 (high → low PNI), and group 4 (high → high PNI). The level of PNI was calculated using the following formula: 10 × serum albumin level (g/dL) + 0.005 × absolute lymphocyte counts in blood (/mm³). The primary end point was cancer-specific survival (CSS), and the secondary end point was overall survival (OS).

Results

The patients with higher pre- and postoperative PNI (>45) had better survival outcomes than those with lower pre- and postoperative PNI (≤45). Notably, the patients in group 4 showed the best CSS and OS rates, whereas the patients in group 1 had the worst survival outcomes. Furthermore, PNI dynamics were identified as an independent predictor of CSS and OS outcomes, in addition to pre- and postoperative PNI, tumor size, and pathologic T (pT) stage. The patients with localized RCC (≤pT2) showed significant differences in both CSS and OS estimates, whereas the patients with advanced pT stage (≥pT3) demonstrated a difference only in OS outcomes, according to PNI dynamics.

Conclusions

This study is the first to provide the independent prognostic importance of dynamics of nutritional status for patients with RCC.

http://ift.tt/2wvTSog

Ra-223 SPECT for semi-quantitative analysis in comparison with Tc-99m HMDP SPECT: phantom study and initial clinical experience

Abstract

Background

Image-based measurement of absorbed dose of Ra-223 dichloride may be useful in predicting therapeutic outcome in patients with castration-resistant prostate cancer (CRPC). In general, SPECT has been found to be more accurate than planar imaging in terms of lesion-based analysis. The aims of this study were to assess the feasibility and clinical usefulness of Ra-223 SPECT.

The energy spectrum of Ra-223 and SPECT images of a cylindrical phantom with a hot rod were obtained to determine the collimator candidates and energy window settings suitable for clinical Ra-223 SPECT (basic study A). Another phantom with a tube-shaped chamber and two spheres simulating bowel activity and metastatic lesions in the lumbar spine was scanned with medium-energy general-purpose (MEGP) and high-energy general-purpose (HEGP) collimators (basic study B). Ten patients with CRPC underwent SPECT imaging 2 h after Ra-223 injection successively with MEGP and HEGP collimators in random order for 30 min each. Lesion detectability and semi-quantitative analyses of bone metastasis (i.e. lesion-to-background ratio (LBR)) were performed compared to Tc-99m HMDP SPECT.

Results

Basic study A revealed that an 84-keV photopeak ± 20% using the HEGP collimator offers better SPECT image quality than the other imaging conditions. Basic study B showed that uptake in one of the spheres was overestimated by overlapped activity of the tube-shaped chamber in planar imaging whereas the spheres had similar counts and significantly higher sphere-to-background ratio in SPECT. On both planar and SPECT images, HEGP gave higher image contrast than MEGP (p < 0.01). In the clinical study, Ra-223 SPECT at 84 keV ± 20% depicted more lesions with the HEGP than with the MEGP collimator (51 vs 36, p = 0.013). There was a positive correlation between LBR in Tc-99m SPECT and in Ra-223 SPECT (r = 0.67 with the MEGP and 0.69 with the HEGP collimator, p < 0.01). LBRs were significantly higher with the HEGP than with the MEGP collimator (p < 0.01).

Conclusions

We recommended the use of the HEGP collimator at 84 keV ± 20% for Ra-223 SPECT imaging. Lesion-based semi-quantitative analysis in the human study revealed a good correlation between Ra-223 and Tc-99m HMDP SPECT in the early phase (2–3 h post injection).

http://ift.tt/2xR5G63

Multiple rapidly growing desmoid tumors that were difficult to distinguish from recurrence of rectal cancer

Abstract

Background

Intra-abdominal desmoid tumors are usually slow growing and solitary, but multifocal desmoid tumors develop on rare occasions. Diagnosing desmoid tumors before histological examination of a surgical biopsy is often difficult. In particular, if a patient has a prior history of malignancy, it may be difficult to differentiate between these lesions and disease recurrence or metastasis.

Case presentation

We present a rare case of multiple rapidly growing intra-abdominal desmoid tumors after surgical trauma, without familial adenomatous polyposis. A 51-year-old male underwent abdominal perineal resection with lateral lymph node dissection after neoadjuvant chemotherapy for lower rectal cancer. Follow-up computed tomography (CT), performed 6 months after primary surgery, showed a 20-mm solitary mass in the pelvic mesentery. Another CT scan, performed 3 months later, revealed that the mass had grown to 35 mm in size and that two new masses had formed. Based on imaging studies and his medical history, it was difficult to distinguish the desmoid tumors from recurrence of rectal cancer. Curative resection was chosen for therapeutic diagnosis. The pathological diagnosis was multiple mesenteric desmoid tumors.

Conclusions

Desmoid tumors should not be excluded as a differential diagnosis for intra-abdominal masses after intra-abdominal surgery, even in cases of rapidly growing multiple masses.

http://ift.tt/2xQNJnX

Large Volume, Behaviorally-relevant Illumination for Optogenetics in Non-human Primates

A protocol to build a tissue penetrating illuminator for delivering light over large volumes with minimal diameter is presented.

http://ift.tt/2ynE1gd

The Case of an Ugly Truth

  The great tragedy of Science — the slaying of a beautiful hypothesis by an ugly fact.                                                                             […]

EMCrit by Rory Spiegel.

http://ift.tt/2xefGEt

P 26 Evaluation of clinical, electrophysiological, sonographic and MRI characteristics of the CIDP spectrum disorder

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease with a wide spectrum of clinical presentation and treatment response. Electrophysiological studies constitute the gold standard used to characterise CIDP patients and contribute to treatment decisions. However, mostly at late stages electrophysiological methods show a pronounced axonal damage and are not able to distinguish CIDP subtypes. Therefore, therapeutic decisions have to be based solely on the clinical course.

http://ift.tt/2kj2vkl

P 27 Beyond binary parcellation of the vestibular cortex

A binary approach to resting-state functional connectivity based parcellation (fCBP) provides useful insights into human brain organization, but also entails oversimplifications (Glasser, 2016). This is especially true for multisensory and higher-level associative brain areas, such as the bilateral vestibular cortical network with its multiple multisensory areas (Dieterich and Brandt, 2015). This study aimed to identify subunits of the vestibular cortex whilst accounting for a possible affiliation of voxel to different sensory systems using a multivariate fCBP within a vestibular region of interest (ROI) including known cortical areas of the vestibular network, i.e.

http://ift.tt/2hK4DRu

Roles for RpoS in survival of Escherichia coli during protozoan predation and in reduced moisture conditions highlight its importance in soil environments

Abstract

The soil is a complex ecosystem where interactions between biotic and abiotic factors determine the survival and fate of microbial inhabitants of the system. Having previously shown that Escherichia coli requires the general stress response regulator, RpoS, to survive long term in soil, it was important to determine what specific conditions in this environment necessitate a functional RpoS. This study investigated the susceptibility of soil-persistent E. coli to predation by the single-celled eukaryotes Acanthamoeba polyphaga and Tetrahymena pyriformis, and the role RpoS plays in resisting this predation. Strain-specific differences were observed in the predation of E. coli strains, with soil-persistent strain COB583 being the most resistant to predation by both protozoans. RpoS and curli, proteinaceous fibres used for attachment to biotic and abiotic surfaces, increased the ability of E. coli to resist predation by A. polyphaga and T. pyriformis. Furthermore, soil moisture content impacted the survival of E. coli BW25113 but wild-type COB583 had similar survival irrespective of soil moisture content. Overall, this study confirmed that RpoS contributes to the resistance of E. coli to protozoan predation and that RpoS is crucial for the increased fitness of soil-persistent E. coli against predation and reduced moisture in soil.

http://ift.tt/2ycP9sO

Heat resistance of viable but non-culturable Escherichia coli cells determined by differential scanning calorimetry

Abstract

Several reports have suggested that the viable but non-culturable (VBNC) state is a resistant form of bacterial cells that allows them to remain in a dormant form in the environment. Nevertheless, studies on the resistance of VBNC bacterial cells to ecological factors are limited, mainly because techniques that allow this type of evaluation are lacking. Differential scanning calorimetry (DSC) has been used to study the thermal resistance of culturable bacteria but has never been used to study VBNC cells. In this work, the heat resistance of Escherichia coli cells in the VBNC state was studied using the DSC technique. The VBNC state was induced in E. coli ATCC 25922 by suspending bacterial cells in artificial sea water, followed by storage at 3 ± 2°C for 110 days. Periodically, the behaviour of E. coli cells was monitored by plate counts, direct viable counts and DSC. The entire bacterial population entered the VBNC state after 110 days of storage. The results obtained with DSC suggest that the VBNC state does not confer thermal resistance to E. coli cells in the temperature range analysed here.

http://ift.tt/2xdgU6E

The ploidy of Vibrio cholerae is variable and is influenced by growth phase and nutrient levels

Abstract

The ploidy of Vibrio cholerae was quantified under different growth conditions. The V. cholerae was found to be (mero-) oligoploid or polyploid. The ploidy levels per cell were found to be growth phase regulated. The ploidy is highest during the early stationary phase (56–72 per cell) and lowest in the long-term starved state. In addition to growth phase, an external parameter such as nutrient level influences the ploidy, i.e. ploidy reduces rapidly at the onset of the starvation. The reduction is significant with P-value < 0.05 within 2 h of starvation. Even after prolonged starvation of 10 days, the ploidy number remained above 2 per cell. Failure to obtain a monoploid V. cholerae indicates that during starvation the genome is not distributed equally to daughter cells. The activity of DNase enzyme increased during starvation that decreased the ploidy. The ploidy was restored to the pre-starvation levels with nutrient supplementation.

http://ift.tt/2wOZRFQ

Climate change and vector-borne diseases of public health significance

Abstract

There has been much debate as to whether or not climate change will have, or has had, any significant effect on risk from vector-borne diseases. The debate on the former has focused on the degree to which occurrence and levels of risk of vector-borne diseases are determined by climate-dependent or independent factors, while the debate on the latter has focused on whether changes in disease incidence are due to climate at all, and/or are attributable to recent climate change. Here I review possible effects of climate change on vector-borne diseases, methods used to predict these effects and the evidence to date of changes in vector-borne disease risks that can be attributed to recent climate change. Predictions have both over- and underestimated the effects of climate change. Mostly under-estimations of effects are due to a focus only on direct effects of climate on disease ecology while more distal effects on society's capacity to control and prevent vector-borne disease are ignored. There is increasing evidence for possible impacts of recent climate change on some vector-borne diseases but for the most part, observed data series are too short (or non-existent), and impacts of climate-independent factors too great, to confidently attribute changing risk to climate change.

http://ift.tt/2xQFlUx

Topological analysis of the lipoprotein organophosphate hydrolase from Sphingopyxis wildii reveals a periplasmic localisation

Abstract

Organophosphate hydrolase (OPH) is a membrane-associated lipoprotein. It translocates across the inner membrane via the twin-arginine transport pathway and remains anchored to the periplasmic face of the inner membrane through a diacylglycerol moiety linked to the invariant cysteine residue found at the junction of a SpaseII cleavage site. Due to the existence of a transmembrane helix at the C-terminus of the mature OPH, an inner-membrane topology was predicted suggesting the C-terminus of OPH is cytoplasmic. The predicted topology was validated by generating OPH variants either fused in-frame with β-lactamase or with unique cysteine residues. Sphingopyxis wildii cells expressing OPH variants with Bla fused at the N-terminal, C-terminal or central regions all grew in the presence of ampicillin. Supporting the β-lactamase reporter assay, the OPH variants having unique cysteine residues at different strategic locations were accessible to the otherwise membrane-impermeant PEG-Mal (methoxypolyethylene glycol maleimide) revealing that, with the exception of the lipoprotein anchor, the entire OPH is in the periplasmic space.

http://ift.tt/2g6Vezx

Histone H3 lysine 9 methyltransferase FvDim5 regulates fungal development, pathogenicity and osmotic stress responses in Fusarium verticillioides

Abstract

Histone methylation plays important biological roles in eukaryotic cells. Methylation of lysine 9 at histone H3 (H3K9me) is critical for regulating chromatin structure and gene transcription. Dim5 is a lysine histone methyltransferase (KHMTase) enzyme, which is responsible for the methylation of H3K9 in eukaryotes. In the current study, we identified a single ortholog of Neurospora crassa Dim5 in Fusarium verticillioides. In this study, we report that FvDim5 regulates the trimethylation of H3K9 (H3K9me3). The FvDIM5 deletion mutant (ΔFvDim5) showed significant defects in conidiation, perithecium production and fungal virulence. Unexpectedly, we found that deletion of FvDIM5 resulted in increased tolerance to osmotic stresses and upregulated FvHog1 phosphorylation. These results indicate the importance of FvDim5 for the regulation of fungal development, pathogenicity and osmotic stress responses in F. verticillioides.

http://ift.tt/2vfcsV5

The C. elegans Excretory Canal as a Model for Intracellular Lumen Morphogenesis and In Vivo Polarized Membrane Biogenesis in a Single Cell: labeling by GFP-fusions, RNAi Interaction Screen and Imaging

The C. elegans excretory canal is a unique single-cell model for the visual in vivo analysis of de novo polarized membrane biogenesis. This protocol describes a combination of standard genetic/RNAi and imaging approaches, adaptable for the identification and characterization of molecules directing unicellular tubulogenesis, and apical membrane and lumen biogenesis.

http://ift.tt/2xVPPEU

Oncologist’s knowledge and implementation of guidelines for breakthrough cancer pain in Spain: CONOCE study

Abstract

Purpose

Breakthrough cancer pain (BTcP) has been shown to be a prevalent and poor prognostic factor for oncologic patients, which remain under diagnosed and undertreated. In 2012, the Spanish Society of Medical Oncology (SEOM) published a clinical practice guideline (CPG) for the treatment of cancer pain which specifically addressed the management of BTcP.

Methods

Fundación ECO designed a qualitative study using an Internet-based survey to investigate the attitudes toward, compliance with, and use of SEOM Guideline.

Results

A total of 83 oncologists with a mean experience of 13 years responded. Overall, 82% were aware of different guidelines to manage BTcP. Notably, attitudes toward guidelines were highly positive and there was nearly unanimous agreement that CPG provided the best scientific evidence available (99%), on the minimum information to be gathered for the medical history (100%), on the need for a specific treatment for BTcP (100%), and fentanyl as the first-choice drug (99%). Interestingly, there were discrepancies between what oncologists agreed with and what they do in clinical practice. In fact, 87.6% declare full compliance with SEOM guideline, although adherence to registration of BTcP data in medical records ranged from 30.1 to 91.6% (mean 64.5%); therapeutic management compliance was higher ranging from 75.9 to 91.6%. Main barriers identified were time pressure together with vague statements and limited dissemination of the guidelines.

Conclusion

Despite oncologist's clinical practice is increasingly guided by GPC, it suffers from limited compliance, at least in part due to suboptimal statements. Improved dissemination and education are needed to enhance guideline implementation.

http://ift.tt/2yUR9q7

Timing and Sequence Critical for Immunotherapy Combination

When given at the same time, two immune checkpoint inhibitors were ineffective against breast cancer growth in mice, a new study found. The combination was more effective and safer if the two inhibitors were given in a specific sequence.

http://ift.tt/2wwgxRo

Infant Sleep Positioners: FDA Warning - Risk of Suffocation

Audience: Consumer, Pediatrics [Posted 10/03/2017] ISSUE: FDA is reminding parents and caregivers not to put babies in sleep positioners. These products—sometimes also called "nests" or "anti-roll" products—can cause suffocation (a...

http://ift.tt/2g8JVam

The C. elegans Intestine As a Model for Intercellular Lumen Morphogenesis and In Vivo Polarized Membrane Biogenesis at the Single-cell Level: Labeling by Antibody Staining, RNAi Loss-of-function Analysis and Imaging

The transparent C. elegans intestine can serve as an "in vivo tissue chamber" for studying apicobasal membrane and lumen biogenesis at the single-cell and subcellular level during multicellular tubulogenesis. This protocol describes how to combine standard labeling, loss-of-function genetic/RNAi and microscopic approaches to dissect these processes on a molecular level.

http://ift.tt/2ym0xGm

Expanding the spectrum of germline variants in cancer

Abstract

Our ability to identify germline variants in hereditary cancer cases remains challenged by the incomplete cataloging of relevant genes and lack of consensus on who should be tested. We designed a panel [hereditary oncogenesis predisposition evaluation (HOPE)] that encompasses most of the genes known to be associated with cancer development and tested its yield on more than 1300 samples of cancer patients. Pathogenic or likely pathogenic variants in high and intermediate risk genes were identified in 16, 23.9, 9.7 and 2.7%, respectively, of peripheral blood or normal tissue samples taken from patients with breast, ovarian, colorectal and thyroid cancer. To confirm specificity of these findings, we tested an ethnically matched cohort of 816 individuals and only identified pathogenic or likely pathogenic variants in 1.59% (0.98% in high risk and 0.61% in intermediate risk). Remarkably, pathogenic or likely pathogenic alleles in DNA repair/genomic instability genes (other than BRCA2, ATM and PALB2) accounted for at least 16.8, 11.1, 50 and 45.5% of mutation-positive breast, ovarian, thyroid and colorectal cancer patients, respectively. Family history was noticeably lacking in a substantial fraction of mutation-positive cases (63.7, 81.5, 42.4 and 87.5% in breast, ovarian, colorectal and thyroid, respectively). Our results show high contribution of germline mutations to cancer predisposition that extends beyond "classical" hereditary cancer genes. Family history was lacking in 63.5% mutation-positive cases, shows that hereditary cancer need not appear familial and suggests that relaxed selection of cancer patients for hereditary cancer panels should be considered.

http://ift.tt/2hKSHyK

Augmented O-GlcNAcylation of AMP-activated kinase promotes the proliferation of LoVo cells, a colon cancer cell line

Abstract

Increasing incidence of various cancers has been reported in diabetic patients. O-linked N-acetylglucosamine (O-GlcNAc) modification of proteins at serine/threonine residues (O-GlcNAcylation) is an essential post-translational modification that is upregulated in diabetic patients and has been implicated in tumor growth. However, the mechanisms by which O-GlcNAcylation promotes tumor growth remain unclear. Given that AMP-activated kinase (AMPK) has been thought to play important roles in suppressing tumor growth, we evaluated the involvement of AMPK O-GlcNAcylation on the growth of LoVo cells, a human colon cancer cell line. Results revealed that administration of Thiamet G (TMG), an inhibitor of O-GlcNAc hydrolase, increased both anchorage-dependent and -independent growth of the cells. O-GlcNAc transferase　overexpression also increased the growth. These treatments increased AMPK O-GlcNAcylation in a dose dependent manner, which led to reduced AMPK phosphorylation and mTOR activation. Chemical inhibition or activation of AMPK led to increased or decreased growth, respectively, which was consistent with the data with genetic inhibition of AMPK. In addition, TMG-mediated acceleration of tumor growth was abolished by both chemical and genetic inhibition of AMPK. To examine the effects of AMPK O-GlcNAcylation in vivo, the LoVo cells were subcutaneously transplanted onto the backs of Balb/c-nu/nu mice. TMG injection promoted the growth and enhanced O-GlcNAcylation of the tumors of the mice. Consistent with in vitro data, AMPK O-GlcNAcylation was increased, which reduced AMPK phosphorylation and resulted in activation of the mTOR. Collectively, the higher colon cancer risk of diabetic patients could be due to O-GlcNAcylation-mediated AMPK inactivation and subsequent activation of mTOR.

This article is protected by copyright. All rights reserved.

http://ift.tt/2yW0hdR

Infant Sleep Positioners: FDA Warning - Risk of Suffocation

Audience: Consumer, Pediatrics [Posted 10/03/2017] ISSUE: FDA is reminding parents and caregivers not to put babies in sleep positioners. These products—sometimes also called "nests" or "anti-roll" products—can cause suffocation (a...

http://ift.tt/2g8JVam

The Rabbit Model of Accelerated Atherosclerosis: A Methodological Perspective of the Iliac Artery Balloon Injury

Animal models of atherosclerosis are essential to understand the mechanism and to investigate newer approaches to prevent plaque development or rupture, a leading cause of death in the industrialized world. This protocol uses a combination of balloon injury and cholesterol rich diet to induce atherosclerotic plaques in rabbit iliac artery.

http://ift.tt/2xOoVQ6

Rostro-caudal maturation of glial cells in the accessory olfactory system during development: involvement in outgrowth of GnRH neurites

Abstract

During mammalian embryonic development, GnRH neurones differentiate from the nasal placode and migrate through the nasal septum toward the forebrain. We previously showed that a category of glial cells, the olfactory ensheathing cells (OEC), forms the microenvironment of migrating GnRH neurones. Here, to caraterize the quantitative and qualitative importance of this glial, we investigated the spatio-temporal maturation of glial cells in situ and the role of maturing glia in GnRH neurones development ex vivo. More than 90% of migrating GnRH neurones were found to be associated with glial cells. There was no change in the cellular microenvironment of GnRH neurones in the regions crossed during embryonic development as glial cells formed the main microenvironment of these neurones (53.4%). However, the phenotype of OEC associated with GnRH neurones changed across regions. The OEC progenitors immunoreactive to brain lipid binding protein formed the microenvironment of migrating GnRH neurones from the vomeronasal organ to the telencephalon and were also present in the diencephalon. However, during GnRH neurone migration, maturation of OEC to [GFAP+] state (glial fibrillary acid protein) was only observed in the nasal septum. Inducing depletion of OEC in maturation, using transgenic mice expressing herpes simplex virus thymidine kinase driven by the Gfap promoter, had no impact on neurogenesis or on triggering GnRH neurone migration in nasal explant culture. Nevertheless, depletion of [GFAP+] cells decreased GnRH neurite outgrowth by 57.4%. This study suggests that specific maturation of OEC in the nasal septum plays a role in morphological differentiation of GnRH neurones.

This article is protected by copyright. All rights reserved.

http://ift.tt/2xS4sre

Responding to sounds from unseen locations: Crossmodal attentional orienting in response to sounds presented from the rear

Abstract

To date, most of the research on spatial attention has focused on probing people's responses to stimuli presented in frontal space. That is, few researchers have attempted to assess what happens in the space that is currently unseen (essentially rear space). In a sense, then, "out of sight" is, very much, "out of mind." In this review, we highlight what is presently known about the perception and processing of sensory stimuli (focusing on sounds) whose source isn't currently visible. We briefly summarize known differences in the localizability of sounds presented from different locations in 3-D space, and discuss the consequences for the crossmodal attentional and multisensory perceptual interactions taking place in various regions of space. The latest research now clearly shows that the kinds of crossmodal interactions that take place in rear space are very often different in kind from those that have been documented in frontal space. Developing a better understanding of how people respond to unseen sound sources in naturalistic environments by integrating findings emerging from multiple fields of research will likely lead to the design of better multisensory warning signals in the future. This review highlights the need for neuroscientists interested in spatial attention to spend more time researching what happens (in terms of the covert and overt crossmodal orienting of attention) in rear space.

This article is protected by copyright. All rights reserved.

http://ift.tt/2ymUXDs

The effects of cerebellar transcranial direct current stimulation on static and dynamic postural stability in older individuals: A randomized double-blind sham-controlled study

Abstract

The aging population is growing rapidly. Risk of falling is higher in older people compared to young adults due to several reasons including poor posture and balance. The main aim of this study was to investigate the effect of cerebellar anodal transcranial direct current stimulation (a-tDCS) on static and dynamic postural stability in older individuals. Twenty-nine older adults participated in this study and were randomly allocated to two groups of active a-tDCS (experimental) (n=14) or sham tDCS group (n=15). Experimental group received cerebellar a-tDCS for 20 minutes with intensity of 1.5 mA. Anterior-posterior and medial-lateral postural stability indices (postural sway) in addition to berg balance score were measured before and after the intervention. Postural sways in static and dynamic postural tasks were significantly decreased (P<0.05) after cerebellar a-tDCS, in addition to berg balance score that increased significantly in active cerebellar a-tDCS group (P<0.05). However, there were no significant changes in postural stability indices or berg balance score in sham group (P>0.05). The findings indicated immediate effect of cerebellar a-tDCS on improvement of postural control and balance in older individuals.

This article is protected by copyright. All rights reserved.

http://ift.tt/2xQXFhv

Breast cancer statistics, 2017, racial disparity in mortality by state

Abstract

In this article, the American Cancer Society provides an overview of female breast cancer statistics in the United States, including data on incidence, mortality, survival, and screening. Approximately 252,710 new cases of invasive breast cancer and 40,610 breast cancer deaths are expected to occur among US women in 2017. From 2005 to 2014, overall breast cancer incidence rates increased among Asian/Pacific Islander (1.7% per year), non-Hispanic black (NHB) (0.4% per year), and Hispanic (0.3% per year) women but were stable in non-Hispanic white (NHW) and American Indian/Alaska Native (AI/AN) women. The increasing trends were driven by increases in hormone receptor-positive breast cancer, which increased among all racial/ethnic groups, whereas rates of hormone receptor-negative breast cancers decreased. From 1989 to 2015, breast cancer death rates decreased by 39%, which translates to 322,600 averted breast cancer deaths in the United States. During 2006 to 2015, death rates decreased in all racial/ethnic groups, including AI/ANs. However, NHB women continued to have higher breast cancer death rates than NHW women, with rates 39% higher (mortality rate ratio [MRR], 1.39; 95% confidence interval [CI], 1.35-1.43) in NHB women in 2015, although the disparity has ceased to widen since 2011. By state, excess death rates in black women ranged from 20% in Nevada (MRR, 1.20; 95% CI, 1.01-1.42) to 66% in Louisiana (MRR, 1.66; 95% CI, 1.54, 1.79). Notably, breast cancer death rates were not significantly different in NHB and NHW women in 7 states, perhaps reflecting an elimination of disparities and/or a lack of statistical power. Improving access to care for all populations could eliminate the racial disparity in breast cancer mortality and accelerate the reduction in deaths from this malignancy nationwide. CA Cancer J Clin 2017. © 2017 American Cancer Society.

http://ift.tt/2kk2iO3

Melanotic Schwannomas Are Rarely Seen Pigmented Tumors with Unpredictable Prognosis and Challenging Diagnosis

Melanotic Schwannoma (MS) is rarely seen and potentially malignant neoplasm that is categorized as a variant of Schwannoma. MS most frequently involves intracranial structures followed by posterior nerve roots in the spinal canal. Approximately 50% of the cases with MS have psammomatous calcifications and this type of MS is related to Carney complex with autosomal dominant inheritance. Most cases of MS are benign, though 10% of them are malignant with metastatic potential. MS mimics melanoma and the differential diagnosis should be made excluding other melanin producing neoplasms especially melanoma. Case 1. A 42-year-old hypertensive male presented for checkup. He had a well-defined extraspinal oval lesion measuring 3.5 × 2.5 cm near right adrenal. Case 2. A 22-year-old female presented with neurofibromatosis-2, bilateral acoustic schwannomas and café au lait lesions on sacrococcygeal region. She had an intradural extramedullary lesion measuring 6.1 × 2.0 cm at L1-2 level. MS is a rare neoplasm composed of Schwann cells and melanin pigment. These tumors are usually benign but they may become aggressive. The biologic behavior of MS is difficult to predict; the patients have to be followed up for a longer period due to its malignant potential.

http://ift.tt/2ylsXQD

An extremely severe phenotype due to WDR81 nonsense mutations

http://ift.tt/2xPy4Ig

The prognostic role of MAC30 in advanced gastric cancer patients receiving platinum-based chemotherapy

Future Oncology, Ahead of Print.


http://ift.tt/2xXWgrA

A Novel Method to Induce Cartilage Regeneration with Cubic Microcartilage

Cartilage tissue is characterized by its poor regenerative properties, and the clinical performance of cartilage grafts to replace cartilage defects has been unsatisfactory. Recently, cartilage regeneration with mature chondrocytes and stem cells has been developed and applied in clinical settings. However, there are challenges with the use of mature chondrocytes and stem cells for tissue regeneration, including the high costs associated with the standard stem cell isolation methods and the decreased cell viability due to cell manipulation. Previous studies demonstrated that cartilage can be regenerated from chondrocyte clusters that contain stem cells. Based upon some of the existing techniques, the goal of this study was to develop a novel and practical method to induce cartilage regeneration. A microslicer device was developed to process cartilage tissues into micron-size cartilage (microcartilage) in a minimally invasive manner. We evaluated microcartilage sizes and demonstrated 100-400 µm as optimal for generating a high cell yield with collagenase digestion. In addition, autologous intrafascial implantation of the composites of microcartilage and an absorbable scaffold with a slow-release system of basic fibroblast growth factor (bFGF) was carried out to induce cartilage regeneration. Our results demonstrated that the extent of bFGF diffusion depends on the size of microcartilage, and that cartilage regeneration was induced most effectively with 100 µm of microcartilage via SOX5 upregulation. These findings suggest that cartilage regeneration is possible with microcartilage as a source of cells without ex vivo cell expansion.
Cells Tissues Organs

http://ift.tt/2g7c6Gw

DNA Methylation Landscape Reflects the Spatial Organization of Chromatin in Different Cells

The relationship between DNA methylation and chromatin structure is still largely unknown. By analyzing a large set of published sequencing data, we observed a long-range power law correlation of DNA methylation with cell class-specific scaling exponents in the range of tens of kilobases. We showed that such cell class-specific scaling exponents are caused by different patchiness of DNA methylation in different cells. By modeling the chromatin structure using high-resolution chromosome conformation capture data and mapping the methylation level onto the modeled structure, we demonstrated that the patchiness of DNA methylation is related to chromatin structure.

http://ift.tt/2xYzvUj

Analysis of a Functional Dimer Model of Ubiquinol Cytochrome c Oxidoreductase

Ubiquinol cytochrome c oxidoreductase (bc1 complex) serves as an important electron junction in many respiratory systems. It funnels electrons coming from NADH and ubiquinol to cytochrome c, but it is also capable of producing significant amounts of the free radical superoxide. In situ and in other experimental systems, the enzyme exists as a dimer. But until recently, it was believed to operate as a functional monomer. Here we show that a functional dimer model is capable of explaining both kinetic and superoxide production rate data.

http://ift.tt/2g7CS1B

Analysis of Claims that the Brain Extracellular Impedance Is High and Non-resistive

Numerous measurements in the brain of the impedance between two extracellular electrodes have shown that it is approximately resistive in the range of biological interest, <10 kHz, and has a value close to that expected from the conductivity of physiological saline and the extracellular volume fraction in brain tissue. Recent work from Gomes et al. has claimed that the impedance of the extracellular space is some three orders of magnitude greater than these values and also displays a frequency dependence (above a low-frequency corner frequency).

http://ift.tt/2xYDAaZ

The Incorporation of Ribonucleotides Induces Structural and Conformational Changes in DNA

Ribonucleotide incorporation is the most common error occurring during DNA replication. Cells have hence developed mechanisms to remove ribonucleotides from the genome and restore its integrity. Indeed, the persistence of ribonucleotides into DNA leads to severe consequences, such as genome instability and replication stress. Thus, it becomes important to understand the effects of ribonucleotides incorporation, starting from their impact on DNA structure and conformation. Here we present a systematic study of the effects of ribonucleotide incorporation into DNA molecules.

http://ift.tt/2g8IybJ

Mechanisms Responsible for ω-Pore Currents in Cav Calcium Channel Voltage-Sensing Domains

Mutations of positively charged amino acids in the S4 transmembrane segment of a voltage-gated ion channel form ion-conducting pathways through the voltage-sensing domain, named ω-current. Here, we used structure modeling and MD simulations to predict pathogenic ω-currents in CaV1.1 and CaV1.3 Ca2+ channels bearing several S4 charge mutations. Our modeling predicts that mutations of CaV1.1-R1 (R528H/G, R897S) or CaV1.1-R2 (R900S, R1239H) linked to hypokalemic periodic paralysis type 1 and of CaV1.3-R3 (R990H) identified in aldosterone-producing adenomas conducts ω-currents in resting state, but not during voltage-sensing domain activation.

http://ift.tt/2xYDpMR

Multiple Mechanisms Drive Calcium Signal Dynamics around Laser-Induced Epithelial Wounds

Epithelial wound healing is an evolutionarily conserved process that requires coordination across a field of cells. Studies in many organisms have shown that cytosolic calcium levels rise within a field of cells around the wound and spread to neighboring cells, within seconds of wounding. Although calcium is a known potent second messenger and master regulator of wound-healing programs, it is unknown what initiates the rise of cytosolic calcium across the wound field. Here we use laser ablation, a commonly used technique for the precision removal of cells or subcellular components, as a tool to investigate mechanisms of calcium entry upon wounding.

http://ift.tt/2g8nNga

Comparative Molecular Dynamics Analysis of RNase-S Complex Formation

Limited proteolysis of RNase-A yields a short N-terminal S-peptide segment and the larger S-protein. Binding of S-peptide to S-protein results in the formation of an enzymatically active RNase-S protein. S-peptide undergoes a transition from intrinsic disorder to an ordered helical state upon association with S-protein to form RNase-S and is an excellent model system to study coupled folding and binding. To better understand the dynamics of the RNases-S complex and its isolated partners, comparative molecular dynamics simulations have been performed.

http://ift.tt/2xZ5bsQ

Coupling X-Ray Reflectivity and In Silico Binding to Yield Dynamics of Membrane Recognition by Tim1

The dynamic nature of lipid membranes presents significant challenges with respect to understanding the molecular basis of protein/membrane interactions. Consequently, there is relatively little known about the structural mechanisms by which membrane-binding proteins might distinguish subtle variations in lipid membrane composition and/or structure. We have previously developed a multidisciplinary approach that combines molecular dynamics simulation with interfacial x-ray scattering experiments to produce an atomistic model for phosphatidylserine recognition by the immune receptor Tim4.

http://ift.tt/2g8Njle

Compartmental and Spatial Rule-Based Modeling with Virtual Cell

In rule-based modeling, molecular interactions are systematically specified in the form of reaction rules that serve as generators of reactions. This provides a way to account for all the potential molecular complexes and interactions among multivalent or multistate molecules. Recently, we introduced rule-based modeling into the Virtual Cell (VCell) modeling framework, permitting graphical specification of rules and merger of networks generated automatically (using the BioNetGen modeling engine) with hand-specified reaction networks.

http://ift.tt/2xYQUfH

Disruption of Magnetic Compass Orientation in Migratory Birds by Radiofrequency Electromagnetic Fields

The radical-pair mechanism has been put forward as the basis of the magnetic compass sense of migratory birds. Some of the strongest supporting evidence has come from behavioral experiments in which birds exposed to weak time-dependent magnetic fields lose their ability to orient in the geomagnetic field. However, conflicting results and skepticism about the requirement for abnormally long quantum coherence lifetimes have cast a shroud of uncertainty over these potentially pivotal studies. Using a recently developed computational approach, we explore the effects of various radiofrequency magnetic fields on biologically plausible radicals within the theoretical framework of radical-pair magnetoreception.

http://ift.tt/2g8Nddm

Determination of Cell Membrane Capacitance and Conductance via Optically Induced Electrokinetics

Cell membrane capacitance and conductance are key pieces of intrinsic information correlated with the cellular dielectric parameters and morphology of the plasma membrane; these parameters have been used as electrophysiological biomarkers to characterize cellular phenotype and state, and they have many associated clinical applications. Here, we present our work on the non-invasive determination of cell membrane capacitance and conductance by an optically activated microfluidics chip. The model for determining the cell membrane capacitance and conductance was established by a single layer of the shell-core polarization model.

http://ift.tt/2xYQPbT

Quantitative Deformability Cytometry: Rapid, Calibrated Measurements of Cell Mechanical Properties

Advances in methods that determine cell mechanical phenotype, or mechanotype, have demonstrated the utility of biophysical markers in clinical and research applications ranging from cancer diagnosis to stem cell enrichment. Here, we introduce quantitative deformability cytometry (q-DC), a method for rapid, calibrated, single-cell mechanotyping. We track changes in cell shape as cells deform into microfluidic constrictions, and we calibrate the mechanical stresses using gel beads. We observe that time-dependent strain follows power-law rheology, enabling single-cell measurements of apparent elastic modulus, Ea, and power-law exponent, β.

http://ift.tt/2g8N0qA

Acetylated Microtubules Are Preferentially Bundled Leading to Enhanced Kinesin-1 Motility

The motor proteins kinesin and dynein transport organelles, mRNA, proteins, and signaling molecules along the microtubule cytoskeleton. In addition to serving as tracks for transport, the microtubule cytoskeleton directs intracellular trafficking by regulating the activity of motor proteins through the organization of the filament network, microtubule-associated proteins, and tubulin posttranslational modifications. However, it is not well understood how these factors influence motor motility, and in vitro assays and live cell observations often produce disparate results.

http://ift.tt/2xYQeXH

Cellular Contraction Can Drive Rapid Epithelial Flows

Single, isolated epithelial cells move randomly; however, during wound healing, organism development, cancer metastasis, and many other multicellular phenomena, motile cells group into a collective and migrate persistently in a directed manner. Recent work has examined the physics and biochemistry that coordinates the motions of these groups of cells. Of late, two mechanisms have been touted as being crucial to the physics of these systems: leader cells and jamming. However, the actual importance of these to collective migration remains circumstantial.

http://ift.tt/2g8nnGu

Modulation of Escherichia coli UvrD Single-Stranded DNA Translocation by DNA Base Composition

Escherichia coli UvrD is an SF1A DNA helicase/translocase that functions in chromosomal DNA repair and replication of some plasmids. UvrD can also displace proteins such as RecA from DNA in its capacity as an anti-recombinase. Central to all of these activities is its ATP-driven 3′–5′ single-stranded (ss) DNA translocation activity. Previous ensemble transient kinetic studies have estimated the average translocation rate of a UvrD monomer on ssDNA composed solely of deoxythymidylates. Here we show that the rate of UvrD monomer translocation along ssDNA is influenced by DNA base composition, with UvrD having the fastest rate along polypyrimidines although decreasing nearly twofold on ssDNA containing equal amounts of the four bases.

http://ift.tt/2xYQ8zj

A Degraded Fragment of HIV-1 Gp120 in Rat Hepatocytes Forms Fibrils and Enhances HIV-1 Infection

Identification of the host or viral factors that enhance HIV infection is critical for preventing sexual transmission of HIV. Amyloid fibrils derived from human semen, including semen-derived enhancer of virus infection and semenogelins, enhance HIV-1 infection dramatically in vitro. In this study, we reported that a short-degraded peptide fragment 1 (DPF1) derived from native HIV-1 envelope protein gp120-loaded rat hepatocytes, formed fibrils by self-assembly and thus enhanced HIV-1 infection by promoting the binding of HIV-1 to target cells.

http://ift.tt/2g6rSRY

Is the Extracellular Impedance High and Non-resistive in Cerebral Cortex?

A recent commentary to Biophysical Journal criticized a previous study published in the same journal by Gomes et al. in 2016, and an alternative interpretation of the measurements was proposed. We reply here to these criticisms and provide some additional clarification, in particular, about a possible misinterpretation of the electrical circuit corresponding to these experiments. We suggest that, indeed, the extracellular impedance in cerebral cortex could be high and non-resistive, and we propose further experiments to settle this issue.

http://ift.tt/2xYQsOx

Large Amplitude Oscillatory Shear Rheology of Living Fibroblasts: Path-Dependent Steady States

Mechanical properties of biological cells play a role in cell locomotion, embryonic tissue formation, and tumor migration among many other processes. Cells exhibit a complex nonlinear response to mechanical cues that is not understood. Cells may stiffen as well as soften, depending on the exact type of stimulus. Here we apply large-amplitude oscillatory shear to a monolayer of separated fibroblast cells suspended between two plates. Although we apply identical steady-state excitations, in response we observe different typical regimes that exhibit cell softening or cell stiffening to varying degrees.

http://ift.tt/2g7jv8Q

Issue Information – TOC

http://ift.tt/2xYFWXm

Long-term antibiotic use associated with cancer causing polyps

http://ift.tt/2xYFNTO

Some stage III colon cancer patients may need only half of the standard chemotherapy course

http://ift.tt/2fOiG81

Global tobacco problem far from solved, new report indicates

http://ift.tt/2xYsHWL

Recent Developments for Remediating Acidic Mine Waters Using Sulfidogenic Bacteria

Acidic mine drainage (AMD) is regarded as a pollutant and considered as potential source of valuable metals. With diminishing metal resources and ever-increasing demand on industry, recovering AMD metals is a sustainable initiative, despite facing major challenges. AMD refers to effluents draining from abandoned mines and mine wastes usually highly acidic that contain a variety of dissolved metals (Fe, Mn, Cu, Ni, and Zn) in much greater concentration than what is found in natural water bodies. There are numerous remediation treatments including chemical (lime treatment) or biological methods (aerobic wetlands and compost bioreactors) used for metal precipitation and removal from AMD. However, controlled biomineralization and selective recovering of metals using sulfidogenic bacteria are advantageous, reducing costs and environmental risks of sludge disposal. The increased understanding of the microbiology of acid-tolerant sulfidogenic bacteria will lead to the development of novel approaches to AMD treatment. We present and discuss several important recent approaches using low sulfidogenic bioreactors to both remediate and selectively recover metal sulfides from AMD. This work also highlights the efficiency and drawbacks of these types of treatments for metal recovery and points to future research for enhancing the use of novel acidophilic and acid-tolerant sulfidogenic microorganisms in AMD treatment.

http://ift.tt/2fPDj3v

The Brain as an Input–Output Model of the World

Abstract

An underlying assumption in computational approaches in cognitive and brain sciences is that the nervous system is an input–output model of the world: Its input–output functions mirror certain relations in the target domains. I argue that the input–output modelling assumption plays distinct methodological and explanatory roles. Methodologically, input–output modelling serves to discover the computed function from environmental cues. Explanatorily, input–output modelling serves to account for the appropriateness of the computed function to the explanandum information-processing task. I compare very briefly the modelling explanation to mechanistic and optimality explanations, noting that in both cases the explanations can be seen as complementary rather than contrastive or competing.

http://ift.tt/2kjx5ul

Habitual exercise is associated with cognitive control and cognitive reappraisal success

Abstract

Habitual exercise is associated with enhanced domain-general cognitive control, such as inhibitory control, selective attention, and working memory, all of which rely on the frontal cortex. However, whether regular exercise is associated with more specific aspects of cognitive control, such as the cognitive control of emotion, remains relatively unexplored. The present study employed a correlational design to determine whether level of habitual exercise was related to performance on the Stroop test measuring selective attention and response inhibition, the cognitive reappraisal task measuring cognitive reappraisal success, and associated changes in prefrontal cortex (PFC) oxygenation using functional near-infrared spectroscopy. 74 individuals (24 men, 50 women, age 18–32 years) participated. Higher habitual physical activity was associated with lower Stroop interference (indicating greater inhibitory control) and enhanced cognitive reappraisal success. Higher habitual exercise was also associated with lower oxygenated hemoglobin (O₂Hb) in the PFC in response to emotional information. However, NIRS data indicated that exercise was not associated with cognitive control-associated O₂Hb in the PFC. Behaviorally, the findings support and extend the previous findings that habitual exercise relates to more successful cognitive control of neutral information and cognitive reappraisal of emotional information. Future research should explore whether habitual exercise exerts causal benefits to cognitive control and PFC oxygenation, as well as isolate specific cognitive control processes sensitive to change through habitual exercise.

http://ift.tt/2hIUg0g