Πέμπτη 20 Ιουλίου 2017
Microfibers: Bioinspired Composite Microfibers for Skin Adhesion and Signal Amplification of Wearable Sensors (Adv. Mater. 28/2017)
In article number 1701353, Metin Sitti and co-workers develop bioinspired skin-adhesives composed of microfibrills decorated with conformal and mushroom-shaped tips for strong attachment to dry and wet skin. A high skin-adhesion strength of 18 kPa, along with highly enhanced signal-to-noise quality of integrated wearable strain sensors are achieved by excellent shape adaptation and microfibrillar design of skin-adhesive films.
http://ift.tt/2tvJfnO
Biomaterials: Self-Adjusting, Polymeric Multilayered Roll that can Keep the Shapes of the Blood Vessel Scaffolds during Biodegradation (Adv. Mater. 28/2017)
A self-adjusting, blood vessel-mimicking, multilayered tubular structure with two polymers, which can keep the shape of the scaffold during biodegradation, is described in article number 1700171 by Wei Bai, Wenfu Zheng, Xingyu Jiang, and co-workers. The inner layer of the tube can expand whereas the outer layers shrink to maintain the stability of the shape and the inner space of the tubular shape. This approach is useful for making scaffolds that require the maintenance of a defined shape, based on FDA-approved materials.
http://ift.tt/2tvEryQ
Nanomedicine: Enhancing Photodynamic Therapy through Resonance Energy Transfer Constructed Near-Infrared Photosensitized Nanoparticles (Adv. Mater. 28/2017)
In article number 1604789, Gang Han and co-workers utilize a resonance energy transfer mechanism to develop a novel dyad photosensitizer which dramatically boosts NIR photon utility and shows superb tumor-targeted photodynamic therapeutic (PDT) effects with an exceptionally low-power NIR LED. This study offers a new method for designing NIR-absorbing PDT drugs for clinical cancer treatments.
http://ift.tt/2ugKAMN
Nanofilms: Biphasic Supramolecular Self-Assembly of Ferric Ions and Tannic Acid across Interfaces for Nanofilm Formation (Adv. Mater. 28/2017)
Nanofilm formation of supramolecular ferric ion (FeIII)-tannic acid (TA) complexes across interfaces is reported by Insung S. Choi and co-workers in article number 1700784. FeIII (red sphere) in one phase makes a contact with TA (blue drop) in the other phase and rapidly forms the FeIII-TA film (violet layer) at the interface of the two immiscible phases.
http://ift.tt/2ug0uqx
Gas Purification: Ultrahigh and Selective SO2 Uptake in Inorganic Anion-Pillared Hybrid Porous Materials (Adv. Mater. 28/2017)
Selective recognition and dense packing of SO2 clusters is achieved through multiple synergistic host-guest/guest-guest interactions within SiF62- anion-pillared hybrid porous materials in article number 1606929, by Qiwei Yang, Banglin Chen, Huabin Xing, and co-workers. The binding sites of anions and aromatic rings on the pore surface grasp every atom of SO2 via Sδ+⋯Fδ– and Oδ–⋯Hδ+ interactions, while the interactions between SO2 molecules further promote the gas trapping.
http://ift.tt/2uglYUc
Electrocatalysis: Hierarchical Co(OH)F Superstructure Built by Low-Dimensional Substructures for Electrocatalytic Water Oxidation (Adv. Mater. 28/2017)
A novel superstructure of Co(OH)F has been developed for efficient electrocatalytic water oxidation, as described in article number 1700286, by Wei Zhang, Rui Cao, and co-workers. The as-prepared 3D Co(OH)F microsphere superstructures are built using 2D nanoflake building blocks, which are further woven by 1D nanorod foundations. The hierarchical structure of this Co(OH)F material combines the merits of all material dimensions in heterogeneous catalysis.
http://ift.tt/2uglFsB
Concurrent electrical cervicomedullary stimulation and cervical transcutaneous spinal direct current stimulation results in a stimulus interaction
Abstract
Transcutaneous spinal direct current stimulation (tsDCS) can modulate neuronal excitability within the human spinal cord; however few studies have used tsDCS at a cervical level. This study aimed to further characterise cervical tsDCS by observing its acute effects on motor responses to transcranial magnetic stimulation (TMS) and cervicomedullary stimulation. In both Study 1 and 2, participants (Study 1: n = 8, 4F; Study 2: n = 8, 3F) received two periods of 10 min, 3 mA cervical tsDCS on the same day through electrodes placed in an anterior-posterior configuration over the neck; one period with the cathode posterior (c-tsDCS) and the other with the anode posterior (a-tsDCS). In Study 1, electrically-elicited cervicomedullary motor evoked potentials (eCMEPs) and TMS-elicited motor evoked potentials (MEPs) were measured in biceps brachii and flexor carpi radialis (FCR) before, during and after each tsDCS period. In Study 2, eCMEPs and magnetically-elicited CMEPs (mCMEPs) were measured before, during and after each tsDCS period. For Study 3, computational modelling was used to observe possible interactions of cervical tsDCS and electrical cervicomedullary stimulation. Study 1 and 2 revealed that eCMEPs were larger during c-tsDCS and smaller during a-tsDCS compared to those elicited when tsDCS was off (P < 0.05), with no changes in MEPs or mCMEPs. Modelling revealed that eCMEP changes may result from modifications of electrical field direction and magnitude when combined with cervical tsDCS. Bidirectional eCMEP changes are likely caused by an interaction between cervical tsDCS and electrical cervicomedullary stimulation, thus care should be taken when combining such electrical stimuli in close proximity.
This article is protected by copyright. All rights reserved
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New Genes Causing Hereditary Parkinson’s Disease or Parkinsonism
Abstract
Purpose of Review
This article reviews was to review genes where putative or confirmed pathogenic mutations causing Parkinson's disease or Parkinsonism have been identified since 2012, and summarizes the clinical and pathological picture of the associated disease subtypes.
Recent Findings
Newly reported genes for dominant Parkinson's disease are DNAJC13, CHCHD2, and TMEM230. However, the evidence for a disease-causing role is not conclusive, and further genetic and functional studies are warranted. RIC3 mutations have been reported from one family but not yet encountered in other patients. New genes for autosomal recessive disease include SYNJ1, DNAJC6, VPS13C, and PTRHD1. Deletions of a region on chromosome 22 (22q11.2del) are also associated with early-onset PD, but the mode of inheritance and the underlying causative gene remain unclear. PODXL mutations were reported in autosomal recessive PD, but their roles remain to be confirmed. Mutations in RAB39B cause an X-linked Parkinsonian disorder.
Summary
Mutations in the new dominant PD genes have generally been found in medium- to late-onset Parkinson's disease. Many mutations in the new recessive and X-chromosomal genes cause severe atypical juvenile Parkinsonism, but less devastating mutations in these genes may cause PD.
http://ift.tt/2vqx2yg
Identification of biosynthetic gene clusters from metagenomic libraries using PPTase complementation in a Streptomyces host
Abstract
The majority of environmental bacteria are not readily cultured in the lab, leaving the natural products they make inaccessible using culture-dependent discovery methods. Cloning and heterologous expression of DNA extracted from environmental samples (environmental DNA, eDNA), provides a means of circumventing this discovery bottleneck. To facilitate the identification of clones containing biosynthetic gene clusters, we developed a model heterologous expression reporter strain Streptomyces albus::bpsA ΔPPTase. This strain carries a 4'-phosphopantetheinyl transferase (PPTase) dependent blue pigment synthase A gene, bpsA, in a PPTase deletion background. eDNA clones that express a functional PPTase restore production of the blue pigment, indigoidine. As PPTase genes often occur in biosynthetic gene clusters (BGCs), indigoidine production can be used to identify eDNA clones containing BGCs. We screened a soil eDNA library hosted in S. albus::bpsA ΔPPTase and identified clones containing non-ribosomal peptide synthetase (NRPS), polyketide synthase (PKS) and mixed NRPS/PKS biosynthetic gene clusters. One NRPS gene cluster was shown to confer the production of myxochelin A to S. albus::bpsA ΔPPTase.http://ift.tt/2tvkloH
Role of PatS and cell type on the heterocyst spacing pattern in a filamentous branching cyanobacterium
Abstract
Cell differentiation is one of the marks of multicellular organisms. Terminally specialized nitrogen-fixing cells, termed heterocysts, evolved in filamentous cyanobacteria more than 2 Gya. The development of their spacing pattern has been thoroughly investigated in model organisms such as Anabaena sp. PCC 7120. This paper focuses on the more complex, branching cyanobacterium Mastigocladus laminosus (Stigonematales). Contrary to what has been previously published, a heterocyst spacing pattern is present in M. laminosus but it varies with the age of the culture and the morphology of the cells. Heterocysts in young, narrow trichomes were more widely spaced (∼14.8 cells) than those in old, wide trichomes (∼9.4 cells). Biochemical and transgenic experiments reveal that the heterocyst spacing pattern is affected by the heterocyst inhibitor PatS. Addition of the pentapeptide RGSGR (PatS-5) to the growth medium and overexpression of patS from Anabaena sp. PCC 7120 in M. laminosus resulted in the loss of heterocyst differentiation under nitrogen deprivation. Bioinformatics investigations indicated that putative PatS sequences within cyanobacteria are highly diverse, and fall into two main clades. Both are present in most branching cyanobacteria. Despite its more complex, branching phenotype, M. laminosus appears to use a PatS-based pathway for heterocyst differentiation, a property shared by Anabaena/Nostoc.http://ift.tt/2tMbU3v
Targeted Nanotherapeutics Encapsulating Liver X Receptor Agonist GW3965 Enhance Antiatherogenic Effects without Adverse Effects on Hepatic Lipid Metabolism in Ldlr−/− Mice
The pharmacological manipulation of liver X receptors (LXRs) has been an attractive therapeutic strategy for atherosclerosis treatment as they control reverse cholesterol transport and inflammatory response. This study presents the development and efficacy of nanoparticles (NPs) incorporating the synthetic LXR agonist GW3965 (GW) in targeting atherosclerotic lesions. Collagen IV (Col IV) targeting ligands are employed to functionalize the NPs to improve targeting to the atherosclerotic plaque, and formulation parameters such as the length of the polyethylene glycol (PEG) coating molecules are systematically optimized. In vitro studies indicate that the GW-encapsulated NPs upregulate the LXR target genes and downregulate proinflammatory mediator in macrophages. The Col IV-targeted NPs encapsulating GW (Col IV–GW–NPs) successfully reaches atherosclerotic lesions when administered for 5 weeks to mice with preexisting lesions, substantially reducing macrophage content (≈30%) compared to the PBS group, which is with greater efficacy versus nontargeting NPs encapsulating GW (GW–NPs) (≈18%). In addition, mice administered the Col IV–GW–NPs do not demonstrate increased hepatic lipid biosynthesis or hyperlipidemia during the treatment period, unlike mice injected with the free GW. These findings suggest a new form of LXR-based therapeutics capable of enhanced delivery of the LXR agonist to atherosclerotic lesions without altering hepatic lipid metabolism.
A new form of liver X receptor-based therapeutics based on the nanoparticles (NPs) decorated with collagen IV targeting ligands is generated. The NPs with optimal polyethylene glycol density can successfully reach atherosclerotic lesions and enhance therapeutic efficacy of GW3965 while maintaining hepatic lipid metabolism. This targeted NP system suggests a new modality for combating inflammation in advanced atherosclerosis.
http://ift.tt/2ugq7r6
Dual MET and ERBB inhibition overcomes intra-tumor plasticity in osimertinib resistant advanced non-small cell lung cancer (NSCLC)
Abstract
BackgroundThird-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as osimertinib are the last line of targeted treatment for metastatic non-small cell lung cancer (NSCLC) EGFR-mutant harboring T790M. Different mechanisms of acquired resistance to third-generation EGFR-TKIs have been proposed. It is therefore crucial to identify new and effective strategies to overcome successive acquired mechanisms of resistance.MethodsFor Amplicon-seq analysis, samples from the index patient (primary and metastasis lesions at different timepoints) as well as the patient derived orthotopic xenograft (PDOX) tumors corresponding to the different treatment arms were used. All samples were formalin-fixed paraffin-embedded (FFPE), selected and evaluated by a pathologist. For ddPCR, twenty patients diagnosed with NSCLC at baseline or progression to different lines of TKI therapies were selected. FFPE blocks corresponding to either primary tumor or metastasis specimens were used for analysis. For single cell analysis orthotopically grown metastases were dissected from the brain of an athymic nu/nu mouse and cryopreserved at -80 °C.ResultsIn a brain metastasis lesion from a NSCLC patient presenting an EGFR T790M mutation we detected MET gene amplification after prolonged treatment with osimertinib. Importantly, the combination of capmatinib (c-MET inhibitor) and afatinib (ErbB-1/2/4 inhibitor) completely suppressed tumor growth in mice orthotopically injected with cells derived from this brain metastasis. In those mice treated with capmatinib or afatinib as monotherapy we observed the emergence of KRAS G12C clones. Single cell gene expression analyses also revealed intratumor heterogeneity, indicating the presence of a KRAS-driven subclone. We also detected low frequent KRAS G12C alleles in patients treated with various EGFR-TKIs.ConclusionAcquired resistance to subsequent EGFR TKI treatment lines in EGFR-mutant lung cancer patients may induce genetic plasticity. We assess the biological insights of tumor heterogeneity in an osimertinib-resistant tumor with acquired MET-amplification and propose new treatment strategies in this situation.http://ift.tt/2tvL5p6
Open access to journal articles in oncology: Current situation and citation impact
Abstract
Background:Recent years have seen numerous efforts and resources devoted to the development of open access (OA), but the current OA situation of the oncology literature remains unknown. We conducted this cross-sectional study to determine the current share and provision methods of OA in the field of oncology, identify predictors of OA status (OA vs. non-OA), and study the association between OA and citation counts.Materials and Methods:PubMed was searched for oncology-related, peer-reviewed journal articles published in December 2014. Google, Google Scholar, PubMed, ResearchGate, OpenDOAR and OAIster were manually checked to assess the OA status of each included article. Citation data were extracted from Web of Science, Scopus and Google Scholar. Descriptive statistics were used to summarise the OA proportion (primary outcome) and OA provision methods. Multivariable logistic regression and multilevel generalised linear model analyses were performed to study predictors of OA status and the association between OA and citation counts, respectively.Results:In a random sample of 1000 articles, 912 were deemed eligible and therefore included. Of these, the full-texts of 530 articles (58.1%; 95% CI: 54.9 to 61.3) were freely available online: 314 (34.4%) were available from publishers ("Gold road" to OA), 424 (46.5%) were available via self-archiving ("Green road" to OA). According to multivariable regression analyses, impact factor, publisher type, language, research type, number of authors, continent of origin, and country income were significant predictors of articles' OA status; OA articles received a citation rate 1.24 times the incidence rate for non-OA articles (95% CI: 1.05 to 1.47; P=0.012).Conclusions:Based on our sample, in the field of oncology, 42% of recent journal articles are behind the pay-wall (non-OA) one year after publication; the "Green road" of providing OA is more common than the "Gold road"; OA is associated with higher citation counts.http://ift.tt/2ug9Jac
BET inhibitors: A Novel Epigenetic Approach
Abstract
Epigenetics has been defined as "the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states." Currently, several classes of anticancer drugs function at the epigenetic level, including inhibitors of DNA methyltransferase, histone deacetylase (HDAC), lysine-specific demethylase 1 (LSD1), zeste homolog 2 (EZH2), and bromodomain and extra-terminal motif (BET) proteins.BET proteins have multiple functions, including the initiation and elongation of transcription and cell cycle regulation. In recent years, inhibitors of BET proteins have been developed as anticancer agents. These inhibitors exhibit selectivity for tumor cells by preferentially binding to superenhancers, noncoding regions of DNA critical for the transcription of genes which determine a cell's identity. Preclinical research on BET inhibitors has identified them as a potential means of targeting MYC.Early clinical trials with BET inhibitors have had mixed results, with few responses in both hematologic and solid tumors that tend to be short-lived. Toxicities have included severe, thrombocytopenia, fatigue, nausea, vomiting, and diarrhea; GI side effects, fatigue, and low grade dysgeusia have limited compliance. However, preclinical data suggests that BET inhibitors may have a promising future in combination with other agents. They appear to be able to overcome resistance to targeted agents and have strong synergy with immune checkpoint inhibitors as well as with multiple epigenetic agents, particularly HDAC inhibitors. In many instances, BET and HDAC inhibitors were synergistic at reduced doses, suggesting a potential means of avoiding the overlapping toxicities of the two drug classes.BET inhibitors provide a novel approach to epigenetic anticancer therapy. However, to date they appear to have limited efficacy as single agents. A focus on BET inhibitors in combination with other drugs such as targeted and/or as other epigenetic agents is warranted, due to limited monotherapy activity, including pharmacodynamic correlatives differential activity amongst select drug combinations.http://ift.tt/2tvD7Mk
Interview with Thomas Powles: The use of durvalumab in urothelial cancer - the latest strides in immuno-oncology
Future Oncology, Ahead of Print.
http://ift.tt/2ugrp7o
Necrotizing eosinophilic granulomatous lymphadenitis with ring- and C-shaped granulomas—an underrecognized specific manifestation of nodal Churg-Strauss syndrome
Abstract
Nodal involvement as the main or prominent clinical manifestation of Churg-Strauss Syndrome (CSS) is uncommon but is being recognized with increasing frequency. Lymph node biopsies are only obtained in CSS cases in which the classic clinical and serologic manifestations of the disease are not clear, and thus the nodal biopsy becomes crucial for recognizing a disorder associated with severe morbidity and mortality. Unfortunately, lymph node pathologists are rarely confronted with this disease, and detailed descriptions of pathologic findings in nodal CSS are scant, with only one previous detailed report. We confirmed the specificity of the findings described in the previous report, and expanded the morphologic and immunophenotypic features of nodal CSS, including a possible pathogenetic role of IgG4. The diagnosis allowed successful treatment of symptoms that had plagued the patient for over 2 years and allowed the rapid recognition of a potentially fatal acute alveolar hemorrhage that occurred after the patient underwent an aortic valve replacement for bacterial endocarditis. Treatment with anti-interleukin-5 humanized monoclonal antibody mepolizumab allowed decreasing the risk of infection and poor healing associated with high-dose steroids and cyclophosphamide.
http://ift.tt/2ugaShS
CD8+ T cell programming by cytomegalovirus vectors: applications in prophylactic and therapeutic vaccination
Klaus Früh | Louis Picker
http://ift.tt/2uFdPeJ
Cancer immunotherapy: moving forward with peptide T cell vaccines
Takumi Kumai | Aaron Fan | Yasuaki Harabuchi | Esteban Celis
http://ift.tt/2ufFRuF
Turbocharging vaccines: emerging adjuvants for dendritic cell based therapeutic cancer vaccines
Mansi Saxena | Nina Bhardwaj
http://ift.tt/2uEMqte
No pain no gain? Adjuvant effects of alum and monophosphoryl lipid A in pertussis and HPV vaccines
Thomas C Mitchell | Carolyn R Casella
http://ift.tt/2ufMo8J
Immunological tolerance as a barrier to protective HIV humoral immunity
Kristin MS Schroeder | Amanda Agazio | Raul M Torres
http://ift.tt/2ug85p1
Insurance Clearance for Early-Phase Oncology Clinical Trials Following the Affordable Care Act
Purpose: The Affordable Care Act (ACA) required that private insurance plans allow clinical trial participation and cover standard-of-care costs, but the impact of this provision has not been well-characterized. We assessed rates of insurance clearance for trial participation within our large early-phase clinical trials program, before and after implementation of the requirement.
Experimental Design: We analyzed the departmental database for the Clinical Center for Targeted Therapy (CCTT) at MD Anderson Cancer Center (Houston, TX). Among patients referred for sponsored trials, we described rates of insurance clearance and prolonged time to clearance (at least 14 days) from July 2012 to June 2013 (baseline), July 2013–December 2013 (following CCTT staffing changes in July 2103), and January 2014–June 2015 (following implementation of the ACA). We used multivariable logistic regression models to compare rates across these time periods.
Results: We identified 2,404 referrals for insurance clearance. Among privately insured patients, insurance clearance rates were higher for those referred from January 2014 to June 2015 than for those referred from July 2012 to June 2013 (OR, 4.72; 95% CI, 2.96–7.51). There was no association between referral period and clearance rates for Medicare/Medicaid patients (P = 0.25). Referral from January 2014 to June 2015 was associated with lower rates of prolonged clearance among both privately insured (OR 0.57; 95% CI, 0.38–0.86) and Medicare/Medicaid patients (OR 0.39; 95% CI, 0.19–0.83).
Conclusion: Within our large early-phase clinical trials program, insurance clearance rates among privately insured patients improved following implementation of the ACA's requirement for coverage of standard-of-care costs. Clin Cancer Res; 23(15); 1–8. ©2017 AACR.
http://ift.tt/2tl8sxl
Surveying the expanding prokaryotic Rubisco multiverse
Abstract
The universal, but catalytically modest, CO2-fixing enzyme Rubisco is currently experiencing intense interest by researchers aiming to enhance crop photosynthesis. These efforts are mostly focused on the highly conserved hexadecameric enzyme found in land plants. In comparison prokaryotic organisms harbor a far greater diversity in Rubisco forms. Recent work towards improving our appreciation of microbial Rubisco properties and harnessing their potential is surveyed. New structural models are providing informative glimpses into catalytic subtleties and diverse oligomeric states. Ongoing characterization is informing us about the conservation of constraints, such as sugar phosphate inhibition and the associated dependence on Rubisco activase helper proteins. Prokaryotic Rubiscos operate under a far wider range of metabolic contexts than the photosynthetic function of higher plant enzymes. Relaxed selection pressures may have resulted in the exploration of a larger volume of sequence space than permitted in organisms performing oxygenic photosynthesis. To tap into the potential of microbial Rubiscos in vivo selection systems are being used to discover functional metagenomic Rubiscos. Various directed evolution systems to optimize their function have been developed. It is anticipated that this approach will provide access to biotechnologically valuable enzymes that cannot be encountered in the higher plant Rubisco space.http://ift.tt/2uO2KIR
Effect of the RNA pyrophosphohydrolase RppH on envelope integrity in Escherichia coli
Abstract
The bacterial enzyme RppH initiates mRNA decay by removing pyrophosphate from 5'-triphosphorylated mRNA. Escherichia coli RppH has promiscuous substrate specificity, but relatively few transcripts are affected by loss of RppH. The phenotypic analysis of the rppH mutant is required for understanding the physiological role of RppH, but the phenotype of the rppH mutant has not yet been determined. In this study, we provide several phenotypes of the rppH mutant associated with envelope integrity. Through phenotype analysis and drug susceptibility testing, we found that the rppH mutant is sensitive to a variety of chemicals including antibiotics, and is also significantly sensitive to envelope stresses, such as osmotic stress, ethanol, and sodium dodecyl sulfate. All phenotypes of the rppH mutant were caused by loss of its enzymatic activity. The rppH mutant exhibited increased envelope permeability, compared to wild-type cells. In contrast, an increase of RppH activity significantly inhibited the growth of wild-type cells under low temperature conditions. In conclusion, various phenotypes of the rppH mutant propose that RppH is associated with regulation of envelope integrity.http://ift.tt/2ufUiyH
Pseudomonas aeruginosa Trent and zinc homeostasis
Abstract
Pseudomonas aeruginosa is a Gram-negative pathogen and the major cause of mortality in patients with cystic fibrosis. The mechanisms that P. aeruginosa strains use to regulate intracellular zinc have an effect on infection, antibiotic resistance, and the propensity to form biofilms. However, zinc homeostasis in P. aeruginosa strains of variable infectivity has not been compared. In the present study, zinc homeostasis in P. aeruginosa Trent, a highly infectious clinical strain, was compared to that of a laboratory P. aeruginosa strain, ATCC27853. Trent was able to tolerate higher concentrations of additional zinc in rich media than ATCC27853. Further, pre-adaptation to additional zinc enhanced the growth of Trent at non-inhibitory concentrations but the impact of pre-adaption in on the growth of ATCC27853 under the same conditions was minimal. The results establish clear differences in zinc-induced responses in Trent and ATCC27853, and how zinc homeostasis can be a promising target for the development of novel antimicrobial strategies for P. aeruginosa infection in cystic fibrosis patients.http://ift.tt/2uOAdCJ
Autophagy participates in the unfolded protein response in Toxoplasma gondii
Abstract
Environmental and genetic perturbations of endoplasmic reticulum (ER) function can lead to the accumulation of unfolded proteins. In these conditions, eukaryotic cells can activate a complex signaling network called the unfolded protein response (UPR) to reduce ER stress and restore cellular homeostasis. Autophagy, a degradation and recycling process, is part of this response. The parasitic protist Toxoplasma gondii is known to be able to activate the UPR upon ER stress, and we now show this pathway leads to autophagy activation, supporting the idea of a regulated function for canonical autophagy as part of an integrated stress response in the parasites.http://ift.tt/2ug2ork
MYC-regulated Mevalonate Metabolism Maintains Brain Tumor Initiating Cells
Metabolic dysregulation drives tumor initiation in a subset of glioblastomas harboring isocitrate dehydrogenase (IDH) mutations, but metabolic alterations in glioblastomas with wildtype IDH are poorly understood. MYC promotes metabolic reprogramming in cancer, but targeting MYC has proven notoriously challenging. Here, we link metabolic dysregulation in patient-derived brain tumor initiating cells (BTICs) to a nexus between MYC and mevalonate signaling, which can be inhibited by statin or 6-fluoromevalonate treatment. BTICs preferentially express mevalonate pathway enzymes, which we find regulated by novel MYC binding sites, validating an additional transcriptional activation role of MYC in cancer metabolism. Targeting mevalonate activity attenuated RAS-ERK-dependent BTIC growth and self-renewal. In turn, mevalonate created a positive feed-forward loop to activate MYC signaling via induction of miR-33b. Collectively, our results argue that MYC mediates its oncogenic effects in part by altering mevalonate metabolism in gloma cells, suggesting a therapeutic strategy in this setting.
http://ift.tt/2uEGnVK
Mathematical modeling of tumor-tumor distant interactions supports a systemic control of tumor growth
Interactions between different tumors within the same organism have major clinical implications, especially in the context of surgery and metastatic disease. Three main explanatory theories (competition, angiogenesis inhibition and proliferation inhibition) have been proposed but precise determinants of the phenomenon remain poorly understood. Here we formalized these theories into mathematical models and performed biological experiments to test them with empirical data. In syngeneic mice bearing two simultaneously implanted tumors, growth of only one of the tumors was significantly suppressed (61% size reduction at day 15, pMajor findings In mice bearing two tumors implanted simultaneously, tumor growth was suppressed in one of the two tumors. Three theories of this phenomenon were advanced and assessed against the data. As formalized, a model of competition for nutrients was not able to explain the growth behavior as well as indirect, angiogenesis-regulated inhibition or a third model based on direct systemic inhibition. This last model offers a depiction of concomitant resistance that provides an improved theoretical basis for tumor growth control and may also find utility in therapeutic planning to avoid post-surgery metastatic acceleration.
http://ift.tt/2vGIAg6
Methods of Academic Course Planning for Cancer Biology Ph.D. Students to Enhance Knowledge of Clinical Oncology
Little is known about how clinical oncology concepts are taught to Ph.D. students or the most effective methods of doing so. In this study, electronic surveys were sent to faculty and students at Ph.D. training programs, assessing their institution's methods of clinical oncology education and their perspective on optimal approaches to clinical oncology education. Only 40.0% of students reported any clinical oncology component to their institution's training, and only 26.5% had a clinician on their graduate advisory committee. Forty-three percent of students believed that they had a good understanding for translating basic science research into clinical practice, and 77.2% of all participants believed dual degree M.D./Ph.D. students were superior to Ph.D. students in this regard. Lectures on clinical oncology research topics were the most valuable type of experience for all participants, and was also the most common type of experience utilized. Working with a clinician to develop a clinical trial with correlative endpoints was also highly valued, but was only utilized by approximately 10% of programs. Faculty rated the value of nearly all types of clinical oncology exposure significantly lower than did students. Inclusion of the approaches identified in this study is likely to enhance Ph.D. training in oncology-related disciplines.
http://ift.tt/2uF6hJ0
CIB2 negatively regulates oncogenic signaling in ovarian cancer via sphingosine kinase 1
Sphingosine kinase 1 (SK1) is a key regulator of the cellular balance between pro-apoptotic and pro-survival sphingolipids. Oncogenic signaling by SK1 relies on its localization to the plasma membrane, which is mediated by the calcium and integrin binding protein CIB1 via its Ca2+-myristoyl switch function. Here we show that another member of the CIB family, CIB2, plays a surprisingly opposite role to CIB1 in the regulation of SK1 signalling. CIB2 bound SK1 on the same site as CIB1, yet it lacks the Ca2+-myristoyl switch function. As a result, CIB2 blocked translocation of SK1 to the plasma membrane and inhibited its subsequent signaling, which included sensitization to TNFα-induced apoptosis and inhibition of Ras-induced neoplastic transformation. CIB2 was significantly down-regulated in ovarian cancer and low CIB2 expression was associated with poor prognosis in ovarian cancer patients. Notably, reintroduction of CIB2 in ovarian cancer cells blocked plasma membrane localization of endogenous SK1, reduces in vitro neoplastic growth and tumour growth in mice, and supressed cell motility and invasiveness both in vitro and in vivo. Consistent with the in vitro synergistic effects between the SK1 specific inhibitor SK1-I and standard chemotherapeutics, expression of CIB2 also sensitized ovarian cancer cells to carboplatin. Together, these findings identify CIB2 as a novel endogenous suppressor of SK1 signaling and potential prognostic marker and demonstrate the therapeutic potential of SK1 in this gynaecological malignancy.
http://ift.tt/2vH7lJg
An essential role for the tumor suppressor Merlin in regulating fatty acid synthesis
Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterized by the development of multiple tumors in the central nervous system, most notably schwannomas and meningiomas. Mutational inactivation of the NF2 gene encoding the protein Merlin is found in most sporadic and inherited schwannomas, but the molecular mechanisms underlying neoplastic changes in schwannoma cells remain unclear. We report here that NF2-deficient cells display elevated expression levels of key enzymes involved in lipogenesis and that this upregulation is caused by increased activity of Torc1. Inhibition or knockdown of fatty acid synthase (FASN), the enzyme that catalyzes the formation of palmitic acid from malonyl-CoA, drove NF2-deficient cells into apoptosis. Treatment of NF2-mutant cells with agents that inhibit the production of malonyl-CoA reduced their sensitivity to FASN inhibitors. Collectively, these results suggest that the altered lipid metabolism found in NF2-mutant cells renders them sensitive to elevated levels of malonyl-CoA, as occurs following blockade of fatty acid synthase, suggesting new targeted strategies in the treatment of NF2-deficient tumors.
http://ift.tt/2uEO0eH
Breast cancer suppression by progesterone receptors is mediated by their modulation of estrogen receptors and RNA polymerase III
Greater than 50% of estrogen receptor (ER)-positive breast cancers co-express the progesterone receptor (PR), which can directly and globally modify ER action to attenuate tumor growth. However, whether this attenuation is mediated only through PR-ER interaction remains unknown. To address this question, we assessed tumor growth in ER/PR-positive PDX models of breast cancer where both natural and synthetic progestins were found to antagonize the mitogenic effects of estrogens. Probing the genome-wide mechanisms by which this occurs, we documented that chronic progestin treatment blunted ER-mediated gene expression up to 2-fold at the level of mRNA transcripts. Unexpectedly, <25% of all ER DNA binding events were affected by the same treatment. The PR cistrome displayed a bimodal distribution. In one group, >50% of PR binding sites were co-occupied by ER, with a propensity for both receptors to coordinately gain or lose binding in the presence of progesterone. In the second group, PR but not ER was associated with a large fraction of RNA polymerase III (Pol III)-transcribed tRNA genes, independent of hormone treatment. Notably, we discovered that PR physically associated with the Pol III holoenzyme. Select pre-tRNA and mature tRNA that colocalized with PR and POLR3A at their promoters were relatively decreased in estrogen+progestin treated tumors. Our results illuminate how PR may indirectly impede ER action by reducing the bioavailability of translational molecules needed for tumor growth.
http://ift.tt/2uFrWR4
Tumor Evolution as a Therapeutic Target [Reviews]
Recent technological advances in the field of molecular diagnostics (including blood-based tumor genotyping) allow the measurement of clonal evolution in patients with cancer, thus adding a new dimension to precision medicine: time. The translation of this new knowledge into clinical benefit implies rethinking therapeutic strategies. In essence, it means considering as a target not only individual oncogenes but also the evolving nature of human tumors. Here, we analyze the limitations of targeted therapies and propose approaches for treatment within an evolutionary framework.
Significance: Precision cancer medicine relies on the possibility to match, in daily medical practice, detailed genomic profiles of a patient's disease with a portfolio of drugs targeted against tumor-specific alterations. Clinical blockade of oncogenes is effective but only transiently; an approach to monitor clonal evolution in patients and develop therapies that also evolve over time may result in improved therapeutic control and survival outcomes. Cancer Discov; 7(8); 1–13. ©2017 AACR.
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Super-Enhancer Analysis Defines Novel Epigenomic Subtypes of Non-APL AML Including an RAR{alpha} Dependency Targetable by SY-1425, a Potent and Selective RAR{alpha} Agonist [Research Articles]
We characterized the enhancer landscape of 66 AML patients, identifying 6 novel subgroups and their associated regulatory loci. These subgroups are defined by their super-enhancer (SE) maps, orthogonal to somatic mutations, and are associated with distinct leukemic cell states. Examination of transcriptional drivers for these epigenomic subtypes uncovers a subset of patients with a particularly strong super-enhancer at the retinoic acid receptor alpha (RARA) gene locus. Presence of a RARA SE and concomitant high levels of RARA mRNA predisposes cell lines and ex vivo models to exquisite sensitivity to a selective agonist of RARα, SY-1425 (tamibarotene). Furthermore, only AML patient-derived xenograft (PDX) models with high RARA mRNA were found to respond to SY-1425. Mechanistically, we show that the response to SY-1425 in RARA-high AML cells is similar to that of APL treated with retinoids, characterized by the induction of known retinoic acid response genes, increased differentiation, and loss of proliferation.
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Effect of scheduled second-look endoscopy on peptic ulcer bleeding: a prospective randomized multicenter trial
This study aimed to investigate the effectiveness of scheduled second-look EGD with endoscopic hemostasis on peptic ulcer rebleeding and sought to identify the risk factors related to the need for second-look EGD.
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Role of Thyroid Deficiency on Adiponectin, Leptin, and Metabolic Status in Visceral Obesity: A Cross-Sectional Study
Horm Metab Res
DOI: 10.1055/s-0043-115532
Hypothyroidism results in disturbances of metabolism influencing many regulatory systems and active molecules as adipocytokines. Objective of the study was to investigate leptin and adiponectin in patients with visceral obesity and hypothyroidism in relation to metabolic status, insulin resistance and systemic inflammation. A total of 118 patients (59 hypothyroid and 59 euthyroid) were enrolled divided into four age-matched groups according to body wеight (BMI) and thyroid function. Laboratory panel includes TSH, FT4, FT3 (CMIA), adiponectin and leptin (ELISA), IL- 6 (ECLIA), CRP, insulin, glucose, apolipoprotein B and lipoprotein (a) - Lp(a). Hypothyroid patients revealed significant positive correlations of TSH, adiponectin and Lp(a). Their medians of 10.4 mU/l, 12.5 µg/ml and 116.3 mg/l respectively were significantly higher than in euthyroid patients- 1.5 mU/l, 6.26 µg/ml and 32.0 mU/l (p < 0.0001). Leptin in both obese groups was significantly higher than in patients with normal weight. Leptin in hypothyroid patients was lower but not significant to euthyroid ones (9.7 ng/ml vs 13.4 ng/ml respectively, p = 0.16), correlated negatively to TSH and positively to CRP, IL-6, ApoB, Lp(a) and BMI. HOMA-IR and serum insulin at 120 min in OGTT were significantly higher in hypothyroid than in euthyroid patients independent of BMI (p < 0.001). Adiponectin, insulin resistance and chronic inflammation indices in hypothyroid patients correlated positively to TSH, BMI and atherogenic lipoproteins subclasses ApoB/Lp(a). Increased adiponectin in thyroid deficiency could be due to secondary resistance of adiponectin receptors or appeared as a compensatory pathogenetic factor in hypothyroidism.
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© Georg Thieme Verlag KG Stuttgart · New York
Article in Thieme eJournals:
Table of contents | Abstract | Full text
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Full title: Policy measures to support palliative care at home: a cross-country case comparison in three European countries
The proportion of people in need of palliative care worldwide is rising, and the majority wish to receive this care at home. Many countries have created policy measures to support palliative care at home.
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What Impact Do Chaplains Have? A Pilot Study of Spiritual AIM for Advanced Cancer Patients in Outpatient Palliative Care
Spiritual care is integral to quality palliative care. Although chaplains are uniquely trained to provide spiritual care, studies evaluating chaplains' work in palliative care are scarce.
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Opioid-Induced Constipation Relief of Fixed-Ratio Combination Prolonged-Release Oxycodone/Naloxone Compared with Oxycodone and Morphine for Chronic Non-malignant Pain: A Systematic Review and Meta-analysis of Randomized Controlled Trials
Opioid-induced constipation (OIC) is one of the most frequent and severe adverse events (AEs) following treatment with opioids. Recent studies have indicated that fixed-ratio combination prolonged-release oxycodone/naloxone (OXN PR) could decrease OIC with similar pain relief compared with other opioids.
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Preoperative Chemoradiation Therapy Does Not Increase Risk of Anastomotic Leak in Patients with Gastric Cancer
In this single institutional retrospective cohort study of 346 patients who underwent gastrectomy at our institution 2001-2016, anastomotic leak and intra-abdominal fluid collection were diagnosed in 3.5% and 7.5% of patients, respectively. Multivariable analysis revealed that concomitant organ resection was the only significant risk factor for anastomotic leak or intra-abdominal fluid collection (p = 0.014). Preoperative chemoradiation therapy was not a risk factor for anastomotic leak or intra-abdominal fluid collection.
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Spectrum of lesions derived from branchial arches occurring in the thyroid: from solid cell nests to tumors
Abstract
There is a group of lesions in the head and neck region derived from branchial arches and related structures which, when inflamed, are characterized by the formation of cysts lined by squamous or glandular epithelium and surrounded by a heavy inflammatory infiltrate rich in germinal centers. In the thyroid, the main source of various structures which may cause diagnostic dilemma is the ultimobranchial body. To investigate the spectrum of such thyroid lesions, the consultation files were reviewed for thyroid samples containing pathological structures regarded to arise from the ultimobranchial body. Positive reaction with antibodies against CK5/6, p63, galectin 3, and CEA, and negative reaction with antibodies against thyroglobulin, TTF-1, and calcitonin were used to confirm the diagnosis. The specific subtype of the ultimobranchial body-derived lesion was then determined based on histological examination of H&E-stained slides. Twenty-one cases of ultimobranchial body-derived lesions were retrieved from the consultation files, 20 of them along with clinical information (M/F = 6/14, mean age 55 years, range 36–68 years). Lesions derived from the ultimobranchial body were classified as follows: (hyperplastic) solid cell nests (nine cases), solid cell nests with focal cystic change (five cases), cystic solid cell nests (two cases), branchial cleft-like cyst (four cases), and finally a peculiar Warthin tumor-like lesion (one case). We suggest that the common denominator of these structures is that they all arise due to activation of inflammatory cells around the vestigial structures, which leads to cystic dilatation and proliferation of the epithelial component.
http://ift.tt/2ufUS1d
Ventilator-Induced Hiccups
A male infant born at 36 weeks of gestation with cervical lymphangioma was admitted to the pediatric intensive care unit. He was mechanically ventilated while awaiting elective tracheostomy. Two days after birth, he was found to have hiccups, with each one occurring invariably at the end of inspiration (Figure). Neither sedatives nor decompressing the stomach by nasogastric tube suppressed the hiccups. They continued for an hour until the pressure control (PC) of the ventilator was decreased from 12 to 10 cm H2O, which immediately terminated the hiccups After cessation, increasing the PC instantaneously triggered hiccups; they were again terminated by dropping the PC to the baseline (Video; available at www.jpeds.com).
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Using Functional Magnetic Resonance Imaging to Detect Preserved Function in a Preterm Infant with Brain Injury
We studied developmental plasticity using functional magnetic resonance imaging (fMRI) in a preterm infant with brain injury on structural MRI. fMRI showed preserved brain function and subsequent neurodevelopment was within the normal range. Multimodal neuroimaging including fMRI can improve understanding of neural plasticity after preterm birth and brain injury.
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Autoimmune Liver Disease in Children with Sickle Cell Disease
To assess the incidence, clinical features, and outcome of autoimmune liver disease (AILD) in patients with sickle cell disease (SCD).
http://ift.tt/2uGNDzM
Amoxicillin Is the Most Cost-Effective Therapy for Acute Otitis Media: The Culmination of 40 Years of Research
In this volume of The Journal, Shaikh et al1 report "bang for the buck" rankings for 5 management options for acute otitis media (AOM). Two aspects should interest readers: (1) "cost-utility analysis," a complex but increasingly used method to judge whether the balance between benefits and adverse events justify the overall socioeconomic and treatment costs, and (2) confirmation of AOM guideline recommendations based on decades of increasingly rigorous science.
http://ift.tt/2tkAKrL
Cardiovascular Effects of High-Molecular-Weight Compounds of Humic Nature
The active ingredient extracted from the peat humic substances was characterized by physicochemical parameters evaluated by UV- and IR-spectroscopy, titration, and elemental (C, H, N) analysis. The cardiovascular effects of this ingredient were examined on isolated Langendorff-perfused rat heart. It was found that the active substance in a concentration range of 0.01-0.1 mg/ml produced a vasodilating effect; in addition, it decreased the end-diastolic and left-ventricular developed pressures.
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Assessment of Oxidative Status of the Brain and Blood Plasma in Rats with Modeled Focal Cerebral Ischemia/Reperfusion Injury
Parameters of the oxidative status of the brain and blood plasma were measured in rats 24 h after 1-h focal cerebral ischemia. In the brain of rats exposed to cerebral ischemia, activities of superoxide dismutase and catalase were elevated. Ischemia reduced the total antioxidant activity of the brain and the levels of malonic dialdehyde and protein carbonyl derivatives. In the blood plasma of experimental rats, superoxide dismutase activity and malonic dialdehyde level increased and total antioxidant activity decreased, i.e. the shifts were similar to those in the brain. The ischemia-induced changes in the brain and blood were not always co-directed.
http://ift.tt/2voNsai
Dynamics of the Pro-Oxidant/Antioxidant System Parameters in Wound Discharge and Plasma in Experimental Purulent Wound during Its Technological Liquid Phase Treatment
The dynamics of the pro-oxidant/antioxidant system of rabbits was studied at the local (in exudate) and systemic (blood) levels during therapy of purulent wounds in liquid medium with the use of a programmed device and the efficiency of the proposed technological method was compared with that of classical methods for the treatment of these wounds. More rapid recovery of the indicators of the pro-oxidant/antioxidant system to physiological values in the postoperative period was observed after treatment by the proposed method (7 days vs. 10 days after standard treatment), these results attest to strengthening of the adaptation potential in laboratory animals. The intensity of free radical oxidation in the exudate decreased by 26.6% in animals treated by the technological method. These data indicated acceleration of the regenerative processes at the local level.
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Modeling RNA Secondary Structure with Sequence Comparison and Experimental Mapping Data
Secondary structure prediction is an important problem in RNA bioinformatics because knowledge of structure is critical to understanding the functions of RNA sequences. Significant improvements in prediction accuracy have recently been demonstrated though the incorporation of experimentally obtained structural information, for instance using selective 2′-hydroxyl acylation analyzed by primer extension (SHAPE) mapping. However, such mapping data is currently available only for a limited number of RNA sequences.
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Inside EMS Podcast: The EMS system of the future
Download this podcast on iTunes, SoundCloud or via RSS feed In this Inside EMS Podcast episode, co-hosts Chris Cebollero and Kelly Grayson discuss the EMS system of the future. Is it time to respond with BLS units and have paramedic intercept" If so, what additional training do we need to give our BLS providers to prepare for 911 response" Learn more about the EMS1 Academy and schedule a free demo ...
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Modeling RNA Secondary Structure with Sequence Comparison and Experimental Mapping Data
Secondary structure prediction is an important problem in RNA bioinformatics because knowledge of structure is critical to understanding the functions of RNA sequences. Significant improvements in prediction accuracy have recently been demonstrated though the incorporation of experimentally obtained structural information, for instance using selective 2′-hydroxyl acylation analyzed by primer extension (SHAPE) mapping. However, such mapping data is currently available only for a limited number of RNA sequences.
http://ift.tt/2uE2ETt
Blood donation practice and its associated factors among health professionals of University of Gondar Hospital, Northwest Ethiopia: a cross sectional study
Blood donation has remained a challenge in developing countries, like Ethiopia. In Ethiopia there is a high reliance on family surrogate and waged blood donors which carries an attendant increased risk of tran...
http://ift.tt/2ufAUnl
Clinical predictors of survival in patients with castration-resistant prostate cancer receiving sipuleucel-T cellular immunotherapy
Abstract
Background
We evaluated the patterns of progression and determined clinical predictors of survival in patients with castration-resistant prostate cancer (CRPCa) who received sipuleucel-T.
Methods
We retrospectively analyzed 56 consecutive patients with asymptomatic or minimally symptomatic CRPCa treated with sipuleucel-T. Age, number of bone metastases, history of prior systemic treatment, and alkaline phosphatase level (ALP) were tested as predictors of survival in a multivariate Cox proportional hazards regression model. The Kaplan–Meier method was used to estimate event-free probabilities.
Results
The 56 patients were a median age of 67 years (range 51–84 years). After sipuleucel-T treatment, 25 patients developed bone progression after a median of 22 months of follow-up (54% of patients were event free at 2 years) and 10% (6/56 patients) developed rapid progression. Eleven deaths were observed after a median of 28 months of follow-up. Forty-eight patients were included in the multivariate analysis for overall survival. The analysis showed that age >70 years (p = 0.012), number of bone metastases >20 (p = 0.018), prior systemic treatment (p = 0.018), and ALP level >90 IU/L (p = 0.010) significantly predicted worse overall survival. Two-year overall survival was 36% among the 16 patients with two or more of these factors and was 93% among the 32 patients with one or none of these factors (p = 0.0004).
Conclusions
CRPCa patients with age (>70 years), increased tumor burden in bone (>20 metastases and/or elevated ALP level), and/or prior systemic treatment are more likely to experience rapid deterioration after sipuleucel-T. These results need to be prospectively validated.
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Image-based Lagrangian Particle Tracking in Bed-load Experiments
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Severe Respiratory Failure, Extracorporeal Membrane Oxygenation, and Intracranial Hemorrhage.
Objectives: For patients supported with veno-venous extracorporeal membrane oxygenation, the occurrence of intracranial hemorrhage is associated with a high mortality. It is unclear whether intracranial hemorrhage is a consequence of the extracorporeal intervention or of the underlying severe respiratory pathology. In a cohort of patients transferred to a regional severe respiratory failure center that routinely employs admission brain imaging, we sought 1) the prevalence of intracranial hemorrhage; 2) survival and neurologic outcomes; and 3) factors associated with intracranial hemorrhage. Design: A single-center, retrospective, observational cohort study. Setting: Tertiary referral severe respiratory failure center, university teaching hospital. Patients: Patients admitted between December 2011 and February 2016. Intervention: None. Measurements and Main Results: Three hundred forty-two patients were identified: 250 managed with extracorporeal support and 92 managed using conventional ventilation. The prevalence of intracranial hemorrhage was 16.4% in extracorporeal membrane oxygenation patients and 7.6% in conventionally managed patients (p = 0.04). Multivariate analysis revealed factors independently associated with intracranial hemorrhage to be duration of ventilation (d) (odds ratio, 1.13 [95% CI, 1.03-1.23]; p = 0.011) and admission fibrinogen (g/L) (odds ratio, 0.73 [0.57-0.91]; p = 0.009); extracorporeal membrane oxygenation was not an independent risk factor (odds ratio, 3.29 [0.96-15.99]; p = 0.088). In patients who received veno-venous extracorporeal membrane oxygenation, there was no significant difference in 6-month survival between patients with and without intracranial hemorrhage (68.3% vs 76.0%; p = 0.350). Good neurologic function was observed in 92%. Conclusions: We report a higher prevalence of intracranial hemorrhage than has previously been described with high level of neurologically intact survival. Duration of mechanical ventilation and admission fibrinogen, but not exposure to extracorporeal support, are independently associated with intracranial hemorrhage. Copyright (C) by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.
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http://ift.tt/2ufySn7
Increase in intracranial pressure by application of a rigid cervical collar: a pilot study in healthy volunteers.
Objectives: Rigid cervical collars are known to increase intracranial pressure (ICP) in severe traumatic brain injury (TBI). Cerebral blood flow might decrease according to the Kellie Monroe doctrine. For this reason, the use of the collar in patients with severe TBI has been abandoned from several trauma protocols in the Netherlands. There is no evidence on the effect of a rigid collar on ICP in patients with mild or moderate TBI or indeed patients with no TBI. As a first step we tested the effect in healthy volunteers with normal ICPs and intact autoregulation of the brain. Methods: In this prospective blinded cross-over study, we evaluated the effect of application of a rigid cervical collar in 45 healthy volunteers by measuring their optical nerve sheath diameter (ONSD) by transocular sonography. Sonographic measurement of the ONSD behind the eye is an indirect noninvasive method to estimate ICP and pressure changes. Results: We included 22 male and 23 female volunteers. In total 360 ONSD measurements were performed in these 45 volunteers. Application of a collar resulted in a significant increase in ONSD in both the left ([beta]=0.06, 95% confidence interval: 0.05-0.07, P
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http://ift.tt/2uNpcl4
Enhanced anticancer efficacy of histone deacetyl inhibitor, suberoylanilide hydroxamic acid, in combination with a phosphodiesterase inhibitor, pentoxifylline, in human cancer cell lines and in-vivo tumor xenografts.
Vorinostat [suberoylanilide hydroxamic acid (SAHA)], a histone deacetylase inhibitor, shows limited clinical activity against solid tumors when used alone. The methyl xanthine drug, pentoxifylline (PENT), has been described to have antitumor properties. The aim of this study was to look for the enhanced anticancer activities of both agents when used in combination at doses lower than their respective efficacy dose when used alone. We investigated the antitumor potential of this novel combination in vitro and in vivo. The combination index was assessed for these two drugs to look for synergistic antiproliferative activity against a broad spectrum of human cancer cell lines. Consistent additive to synergistic interactions were observed in HCT116 cells when PENT was combined with SAHA at all drug tested concentrations. The combination of SAHA and PENT induces chromatin condensation and apoptosis downstream of the pan histone deacetylase inhibition and phosphodiesterase regulation, leading to subsequent cell cycle arrest at their lower tested concentrations. Further, the ability of this combination to inhibit angiogenesis, both in vitro and in vivo, was examined and a significant inhibition in tube formation in HUVEC cells and neovascularization of Matrigel plug was observed. A significant inhibition in tumor growth was observed in severe combined immunodeficient mice bearing HCT116 (colon) and PC3 (prostate) human xenografts treated with SAHA (30 mg/kg, intraperitoneal) in combination with PENT (60 mg/kg, intraperitoneal), with no loss in body weight and 100% survival. In conclusion, these findings indicate the enhanced anticancer activity of SAHA in combination with PENT both in vitro and in vivo. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.
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http://ift.tt/2tjEYQu
Examination of the gait pattern based on adjusting and resulting components of the stride-to-stride variability: proof of concept
Stride-to-stride variability may be used as an indicator in the assessment of gait performance, but the evaluation of this parameter is not trivial. In the gait pattern, a deviation in one stride must be corre...
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Genomic fingerprints of Escherichia coli strains isolated from surface water in Alborz province, Iran
Consistent use of suitable diagnostic methods is essential to evaluate the genomic diversity of E. coli strains. Advance of efficient methods to discriminate the causes of E. coli in aquatic environments is impor...
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Antimicrobial susceptibility pattern of clinical isolates of Burkholderia pseudomallei in Bangladesh
Melioidosis an infectious disease, caused by a Gram negative bacterium called Burkholderia pseudomallei, is endemic in Bangladesh. This organism is sensitive to limited number of antimicrobial agents and need pro...
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Effect of electrode position of low intensity neuromuscular electrical stimulation on the evoked force in the quadriceps femoris muscle
The present study aimed to test the effect of the electrode position and inter-electrode distance on the evoked force by neuromuscular electrical stimulation (NMES) with a low current intensity and a single pa...
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Developing HiPSC Derived Serum Free Embryoid Bodies for the Interrogation of 3-D Stem Cell Cultures Using Physiologically Relevant Assays
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Mediastinal injury is the strongest predictor of mortality in mounted blast amongst UK deployed forces
Publication date: Available online 19 July 2017
Source:Injury
Author(s): A. Phillip Pearce, Anthony M.J. Bull, Jonathon C. Clasper
BackgroundBlast injury has been the most common cause of morbidity and mortality encountered by UK forces during recent conflicts. Injuries sustained by blast are categorised by the injuring component of the explosion and depend upon physical surroundings. Previous work has established that head injuries and intra cavity haemorrhage are the major causes of death following exposure to under body (mounted) blast but has failed to explore the precise nature of these torso injuries nor the effect of particular injuries upon survival. This study examines the patterns of torso injury within the mounted blast environment in order to understand the effect of these injuries upon survivability.MethodsThis retrospective study examined the UK Joint Theatre Trauma Registry to determine precise injury patterns of mounted blast casualties within a 13year period of UK military deployments. Survival rates of individual injuries were compared and a multivariable logistic regression model was developed in order to assess the effect that each injury had upon likelihood of death.Results426 mounted casualties were reviewed of whom 129 did not survive. Median NISS and ISS for non-survivors was found to be 75. Torso injuries were significantly more common amongst non-survivors than survivors and high case fatality rates were associated with all haemorrhagic torso injuries. Multivariable analysis shows that mediastinal injuries have the largest odds ratio for mortality (20.4) followed by lung laceration and head injury.ConclusionsNon-compressible torso haemorrhage is associated with mortality amongst mounted blast. Of this group, mediastinal injury is the strongest predictor of death and could be considered as a surrogate marker of lethality. Future work to link blast loading characteristics with specific injury patterns will inform the design of mitigating strategies in order to improve survivability of underbody blast
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Molecular characterization and genetic relatedness of clinically Acinetobacter baumanii isolates conferring increased resistance to the first and second generations of tetracyclines in Iran
The increasing resistance of Acinetobacter baumannii to antibiotics has recently been regarded as a notable therapeutic difficulty. Evaluating resistance rates of some A. baumannii isolates to tetracyclines had a...
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Basic Methods for the Study of Reproductive Ecology of Fish in Aquaria
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Efficacy and safety of taxane monotherapy in advanced gastric cancer refractory to triplet chemotherapy with docetaxel, cisplatin, and S-1: a multicenter retrospective study
Abstract
Purpose
Taxane monotherapy is widely used for advanced gastric cancer (AGC) after failure of standard first-line chemotherapy with fluoropyrimidine and cisplatin. Triplet chemotherapy with docetaxel, cisplatin, and S-1 (DCS) is a promising regimen for first-line chemotherapy of AGC. The aim of this study was to evaluate the efficacy of taxane monotherapy in patients refractory to DCS.
Methods
We retrospectively evaluated the efficacy and safety of taxane monotherapy in patients with AGC refractory to first-line therapy with DCS between January 2010 and April 2015. Selection criteria were as follows: ECOG PS of 0–2, treatment with taxane monotherapy in second-line or third-line therapy after failure of second-line irinotecan, absence of massive ascites, and adequate organ function.
Results
A total of 30 patients were included in this study. Of these, 15 patients received paclitaxel while another 15 received nanoparticle albumin-bound paclitaxel in either second- or third-line treatment. Median age for the second/third-line group was 64.0/62.0 (range 27–75/42–75); 14/13 (93.3/86.7%) had ECOG PS of 0 or 1. No patients achieved complete or partial response and stable disease was observed in 37.5/35.7% of the patients in the second/third line. Median progression-free survival and overall survival were 3.4 and 5.8 months in the second-line group, and 2.0 and 4.5 months in the third-line group, respectively. The incidences of any grade ≥3 adverse events in the second-line group and the third-line group were 60.0 and 33.3%, respectively. There was no treatment-related death.
Conclusions
Taxane monotherapy after DCS failure had acceptable toxicities but was ineffective in AGC patients.
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Lung cancer as a paradigm for precision oncology in solid tumours
Abstract
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in the western world. However, the combination of molecular genotyping and subsequent systematic treatment of decoded target structures is a prime example of precision oncology in solid tumours. In this review, current targets of approved therapeutics and potential targets in clinical and preclinical trials are outlined. Furthermore, immune checkpoint inhibitors, as promising new therapeutic options, which have already been applied successfully in cases of lung cancer, are introduced. A major issue of targeted treatment of lung tumours is the persistent development of resistance. The underlying mechanisms and established and potentially applicable alternative therapeutic approaches are described. In this process of precision oncology, immunohistochemistry, fluorescence in situ hybridization, and parallel sequencing are crucial diagnostic tools.
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Transarterial chemoembolization combined with recombinant human adenovirus type 5 H101 prolongs overall survival of patients with intermediate to advanced hepatocellular carcinoma: a prognostic nomogram study
Patients with intermediate to advanced hepatocellular carcinoma (HCC) are most commonly treated with transarterial chemoembolization (TACE). Previous studies showed that TACE combined with recombinant human ad...
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Pa. councilman saves wife after heart attack with CPR
Thanks to Tony Spadaro's quick thinking, EMTs were able to administer a defibrillator shock and bring back his wife's heartbeat
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Polygenic Risk Score Analysis of Pathologically Confirmed Alzheimer's Disease
Abstract
Previous estimates of the utility of polygenic risk score analysis for the prediction of Alzheimer's disease have given Area Under the Curve estimates of <80%. However, these have been based on the genetic analysis of clinical case control series. Here we apply the same analytic approaches to a pathological case control series and show a predictive AUC of 84%. We suggest that this analysis has clinical utility and that there is limited room for further improvement using genetic data. This article is protected by copyright. All rights reserved.
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A Human Glioblastoma Organotypic Slice Culture Model for Study of Tumor Cell Migration and Patient-specific Effects of Anti-Invasive Drugs
http://ift.tt/2uDw4RQ
Intermittent versus continuous renal replacement therapy in acute methanol poisoning: comparison of clinical effectiveness in mass poisoning outbreaks
Intermittent hemodialysis (IHD) is the modality of choice in the extracorporeal treatment (ECTR) of acute methanol poisoning. However, the comparative clinical effectiveness of intermittent versus continuous m...
http://ift.tt/2uMJScX
Bedside selection of positive end-expiratory pressure by electrical impedance tomography in hypoxemic patients: a feasibility study
Positive end-expiratory pressure (PEEP) is a key element of mechanical ventilation. It should optimize recruitment, without causing excessive overdistension, but controversy exists on the best method to set it...
http://ift.tt/2tKhVxq
Leveraging a Clinical Phase Ib Proof-of-Concept Study for the GPR40 Agonist MK-8666 in Patients With Type 2 Diabetes for Model-Informed Phase II Dose Selection
GPR40 mediates free fatty acid–induced insulin secretion in beta cells. We investigated the safety, pharmacokinetics, and glucose response of MK-8666, a partial GPR40 agonist, after once-daily multiple dosing in type 2 diabetes patients. This double-blind, multisite, parallel-group study randomized 63 patients (placebo, n = 18; 50 mg, n = 9; 150 mg, n = 18; 500 mg, n = 18) for 14-day treatment. The results showed no serious adverse effects or treatment-related hypoglycemia. One patient (150-mg group) showed mild-to-moderate transaminitis at the end of dosing. Median MK-8666 Tmax was 2.0–2.5 h and mean apparent terminal half-life was 22–32 h. On Day 15, MK-8666 reduced fasting plasma glucose by 54.1 mg/dL (500 mg), 36.0 mg/dL (150 mg), and 30.8 mg/dL (50 mg) more than placebo, consistent with translational pharmacokinetic/pharmacodynamic model predictions. Maximal efficacy for longer-term assessment is projected at 500 mg based on exposure–response analysis. In conclusion, MK-8666 was generally well tolerated with robust glucose-lowering efficacy.
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Cerebrospinal fluid drainage options for posthemorrhagic hydrocephalus in premature neonates
ABSTRACT Objective The literature describes various cerebrospinal fluid (CSF) drainage techniques to alleviate posthemorrhagic hydrocephalus in preterm newborns; however, consensus has not been reached. The scope of this study was describing a case series of premature neonates with posthemorrhagic hydrocephalus and assessing the outcomes of different approaches used for CSF diversion. Methods A consecutive review of the medical records of neonates with posthemorrhagic hydrocephalus treated with CSF drainage was conducted. Results Forty premature neonates were included. Serial lumbar puncture, ventriculosubgaleal shunt, and ventriculoperitoneal shunt were the treatments of choice in 25%, 37.5% and 37.5% of the cases, respectively. Conclusion Cerebrospinal fluid diversion should be tailored to each case with preference given to temporary CSF drainage in neonates with lower age and lower birth-weight, while the permanent ventriculoperitoneal shunt should be considered in healthier, higher birth-weight neonates born closer to term.
RESUMO Objetivo A literatura descreve várias opções de drenagem liquórica (DL) para alivio da hidrocefalia pós-hemorrágica (HPH) em neonatos prematuros; contudo, não existe um consenso sobre a melhor abordagem. O escopo deste estudo foi descrever uma série de casos de neonatos prematuros, portadores de HPH, verificando os resultados de diferentes técnicas utilizadas para DL. Métodos Revisão consecutiva dos prontuários de neonatos com diagnostico de HPH submetidos a DL. Resultados Quarenta recém-nascidos prematuros foram incluídos. A punção lombar seriada (PL), a derivação ventriculosubgaleal (VSG) e a derivação ventrículo peritoneal (VP) foram o tratamento escolhido em 25%, 37,5% e 37,5% dos casos, respectivamente. Conclusão As opções de DL devem ser avaliadas caso a caso, sendo dada preferência às drenagens temporária em prematuros com idade e peso mais baixos ao nascer, enquanto o shunt definitivo (derivação VP) pode ser considerado naqueles prematuros mais saudáveis, com idade e peso superiores.
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The intercostobrachial nerve as a sensory donor for hand reinnervation in brachial plexus reconstruction is a feasible technique and may be useful for restoring sensation
ABSTRACT Objective Few donors are available for restoration of sensibility in patients with complete brachial plexus injuries. The objective of our study was to evaluate the anatomical feasibility of using the intercostobrachial nerve (ICBN) as an axon donor to the lateral cord contribution to the median nerve (LCMN). Methods Thirty cadavers were dissected. Data of the ICBN and the LCMN were collected, including diameters, branches and distances. Results The diameters of the ICBN and the LCMN at their point of coaptation were 2.7mm and 3.7mm, respectively. The ICBN originated as a single trunk in 93.3% of the specimens and bifurcated in 73.3%. The distance between the ICBN origin and its point of coaptation to the LCMN was 54mm. All ICBNs had enough extension to reach the LCMN. Conclusion Transfer of the ICBN to the LCMN is anatomically feasible and may be useful for restoring sensation in patients with complete brachial plexus injuries.
RESUMO Objetivo Poucos doadores estão disponíveis para a restauração da sensibilidade em pacientes com lesões completas do plexo braquial (LCPB). O objetivo deste estudo foi avaliar a viabilidade anatômica do uso do nervo intercostobraquial (NICB) como doador de axônios para a contribuição do cordão lateral para o nervo mediano (CLNM). Métodos Trinta cadáveres foram dissecados. Os dados do NICB e do CLNM foram coletados: diâmetros, ramos e distâncias. Resultados Os diâmetros do NICB e da CLNM no ponto de coaptação foram 2,7mm e 3,7mm, respectivamente. O NICB originou-se como um único tronco em 93,3% dos espécimes e bifurcou-se em 73,3%. A distância entre a origem do NICB e seu ponto de coaptação com a CLNM foi de 54mm. Todos os NICBs tiveram extensão suficiente para alcançar a CLNM. Conclusão A transferência do NICB para a CLNM é anatomicamente viável e pode ser útil para restaurar a sensibilidade em pacientes com LCPB.
http://ift.tt/2vFxd8g
Quantitative Myasthenia Gravis Score: a Brazilian multicenter study for translation, cultural adaptation and validation
ABSTRACT Objective To perform the translation, cross-cultural adaptation and validation of the Quantitative Myasthenia Gravis Score (QMGS) to Brazilian Portuguese in accordance with international ethical standards. Methods The following steps were taken: (1) implementation of the translation protocol and transcultural adaptation, (2) validation of the adapted content, and (3) assessment of reliability. To check intra- and inter-observer reproducibility, each patient underwent two interviews with interviewer-A and one with B. The QMGS was compared to the Myasthenia Gravis Composite Scale and Myasthenia-specific Quality of Life Questionnaire. Results Our study group consisted of 30 patients, with a mean age of 47.6±11.4 years and a mean duration of illness of 11.33±8.49 years. Correlation between the QMGS and MGC was very strong (r = 0.928; p < 0.001) and substantial between the QMGS and MG-QOL 15 (r = 0.737; p < 0.001). Conclusion The Brazilian Portuguese translation, and validation of the QMGS was successfully performed.
RESUMO Objetivo O objetivo foi realizar a tradução e validação do teste quantitativo para Miastenia Gravis (QMGS) para Português do Brasil, de acordo com as diretrizes internacionais. Métodos Foram realizadas as etapas de implementação do protocolo de tradução e adaptação transcultural, validação do conteúdo adaptado e avaliação da confiabilidade. Para verificar a reprodutibilidade intra e inter-observador cada paciente foi submetido a duas entrevistas por um entrevistador-A e um B. O QMGS foi comparado ao MG Composite Scale e Myasthenia-specific Quality of Life Questionnaire. Resultados O estudo inclui 30 pacientes, com a média de idade de 47,6±11,4 anos e tempo médio de doença de 11,33±8,49 anos. A correlação entre QMGS e MGC apresentou-se muito forte (r = 0,928; p < 0,001) e substancial entre QMGS e MG-QOL 15 (r = 0,737; p < 0,001). Conclusão A tradução, e validação do QMGS para o português do Brasil foi realizada com sucesso.
http://ift.tt/2ueVog0
Cerebral hemodynamic and metabolic changes in fulminant hepatic failure
ABSTRACT Intracranial hypertension and brain swelling are a major cause of morbidity and mortality of patients suffering from fulminant hepatic failure (FHF). The pathogenesis of these complications has been investigated in man, in experimental models and in isolated cell systems. Currently, the mechanism underlying cerebral edema and intracranial hypertension in the presence of FHF is multi-factorial in etiology and only partially understood. The aim of this paper is to review the pathophysiology of cerebral hemodynamic and metabolism changes in FHF in order to improve understanding of intracranial dynamics complication in FHF.
RESUMO O edema cerebral e a hipertensão intracraniana (HIC) são as principais causas de morbidade e mortalidade de pacientes com insuficiência hepática fulminante (IHF). A patogênese dessas complicações tem sido investigada no homem, em modelos experimentais e em sistemas celulares isolados. Atualmente, o mecanismo subjacente ao edema cerebral e HIC na presença de IHF é multifatorial em etiologia e pouco compreendido na literatura. O objetivo deste trabalho é revisar a fisiopatologia das alterações hemodinâmicas e metabólicas cerebrais na IHF, visando melhorar a compreensão da complicação da hemodinâmica encefálica na IHF.
http://ift.tt/2ueoDPH
Effect of intra-hippocampal injection of human recombinant growth hormone on synaptic plasticity in the nucleus basalis magnocellularis-lesioned aged rats
ABSTRACT In this study, we proposed that administration of hippocampal growth hormone in ageing animals with growth hormone deficiency can compensate long-term potentiation and synaptic plasticity in nucleus basalis magnocellularis (NBM)-lesioned rats. Aged male Wistar rats were randomly divided into six groups (seven in each) of sham-operated healthy rats (Cont); NBM-lesioned rats (L); NBM-lesioned rats and intrahippocampal injection of growth hormone vehicle (L + Veh); NBM-lesioned and intrahippocampal injection of growth hormone (10, 20 and 40 µg.2 µl-1) (L + GH). In vivo electrophysiological recording techniques were used to characterize maintenance of long-term potentiation at distinct times (1, 2, 3, 24 and 48 hours) after high-frequency stimulation. The population spike was enhanced significantly for about 48 hours following tetanic stimulation in rats treated with a dose-dependent growth hormone compared to the vehicle group (p < 0.05), possibly through neuronal plasticity and neurogenesis in affected areas.
RESUMO Neste estudo, propusemos que a administração de hormônio hipocampal do crescimento em animais envelhecidos com deficiência de hormônio do crescimento pode compensar a potencialização em longo prazo e a plasticidade sináptica em ratos lesados do núcleo basalis magnocellularis (NBM). Ratos machos Wistar foram divididos aleatoriamente em seis grupos (sete ratos em cada grupo) de ratos falso-operados saudáveis (Cont); ratos lesados do NBM (L); ratos lesados do NBM e injeção intrahipocampal de veículo de hormônio do crescimento (L + Veh); ratos lesados do NBM e injeção de hormônio do crescimento (10, 20 e 40 μg.2 μl-1) (L + GH). Técnicas de registro eletrofisiológico in vivo foram utilizadas para caracterizar a manutenção da potencialização em longo prazo em momentos distintos (1, 2, 3, 24 e 48 horas) após estimulação de alta frequência. O pico populacional aumentou significativamente cerca de 48 horas após a estimulação tetânica em ratos tratados com um hormônio do crescimento dose-dependente, em comparação com o grupo veículo (p <0,05), possivelmente através da plasticidade neuronal e da neogênese nas áreas afetadas.
http://ift.tt/2vFHyB7
The art and neurology of Paul Richer
ABSTRACT In the 1890s, one of Charcot's most important protégés, Dr. Paul Richer (1849–1933), drew and sculpted a series of representations of the main types of nerve pathology. That series included drawings of pleomorphic hysterical crises and sculptures depicting patients suffering from labio-glosso-laryngeal paralysis and myopathy, as well as Parkinson's disease. Richer was a resident at La Salpêtrière and, in 1882, became head of the Charcot museum. Early in his career, despite having no formal artistic training, he could represent masterfully, in drawings and sculptures, people's tragic suffering from neurological diseases. Later on, with the same tools, he expressed the beauty of human movements in health.
RESUMO Nos anos 1890, um dos mais importantes protegidos de Charcot, o doutor Paul Richer (1849-1933), desenhou e esculpiu uma série de representações figurativas dos principais tipos de patologia nervosa. Essa série incluiu desenhos de crises histéricas pleomórficas e esculturas de bustos representando pacientes que sofriam de doenças tais como: paralisia labio-glosso-laríngea, miopatia e doença de Parkinson. Richer foi residente de La Salpêtrière e, em 1882, foi nomeado chefe do museu de Charcot. Na primeira parte de sua carreira e sem qualquer treinamento artístico formal, ele conseguiu representar, como ninguém, em desenhos e esculturas, o trágico sofrimento das doenças neurológicas. Mais adiante, com as mesmas ferramentas, ele concebeu a beleza do movimento humano na saúde.
http://ift.tt/2ueOuqK
Magnetic resonance findings in subacute combined degeneration
ABSTRACT In the 1890s, one of Charcot's most important protégés, Dr. Paul Richer (1849–1933), drew and sculpted a series of representations of the main types of nerve pathology. That series included drawings of pleomorphic hysterical crises and sculptures depicting patients suffering from labio-glosso-laryngeal paralysis and myopathy, as well as Parkinson's disease. Richer was a resident at La Salpêtrière and, in 1882, became head of the Charcot museum. Early in his career, despite having no formal artistic training, he could represent masterfully, in drawings and sculptures, people's tragic suffering from neurological diseases. Later on, with the same tools, he expressed the beauty of human movements in health.
RESUMO Nos anos 1890, um dos mais importantes protegidos de Charcot, o doutor Paul Richer (1849-1933), desenhou e esculpiu uma série de representações figurativas dos principais tipos de patologia nervosa. Essa série incluiu desenhos de crises histéricas pleomórficas e esculturas de bustos representando pacientes que sofriam de doenças tais como: paralisia labio-glosso-laríngea, miopatia e doença de Parkinson. Richer foi residente de La Salpêtrière e, em 1882, foi nomeado chefe do museu de Charcot. Na primeira parte de sua carreira e sem qualquer treinamento artístico formal, ele conseguiu representar, como ninguém, em desenhos e esculturas, o trágico sofrimento das doenças neurológicas. Mais adiante, com as mesmas ferramentas, ele concebeu a beleza do movimento humano na saúde.
http://ift.tt/2vFI0PT
Acute Epstein-Barr virus encephalitis in an immunocompetent adolescent patient
ABSTRACT In the 1890s, one of Charcot's most important protégés, Dr. Paul Richer (1849–1933), drew and sculpted a series of representations of the main types of nerve pathology. That series included drawings of pleomorphic hysterical crises and sculptures depicting patients suffering from labio-glosso-laryngeal paralysis and myopathy, as well as Parkinson's disease. Richer was a resident at La Salpêtrière and, in 1882, became head of the Charcot museum. Early in his career, despite having no formal artistic training, he could represent masterfully, in drawings and sculptures, people's tragic suffering from neurological diseases. Later on, with the same tools, he expressed the beauty of human movements in health.
RESUMO Nos anos 1890, um dos mais importantes protegidos de Charcot, o doutor Paul Richer (1849-1933), desenhou e esculpiu uma série de representações figurativas dos principais tipos de patologia nervosa. Essa série incluiu desenhos de crises histéricas pleomórficas e esculturas de bustos representando pacientes que sofriam de doenças tais como: paralisia labio-glosso-laríngea, miopatia e doença de Parkinson. Richer foi residente de La Salpêtrière e, em 1882, foi nomeado chefe do museu de Charcot. Na primeira parte de sua carreira e sem qualquer treinamento artístico formal, ele conseguiu representar, como ninguém, em desenhos e esculturas, o trágico sofrimento das doenças neurológicas. Mais adiante, com as mesmas ferramentas, ele concebeu a beleza do movimento humano na saúde.
http://ift.tt/2ueL3QQ
A review of rate control in atrial fibrillation, and the rationale and protocol for the RATE-AF trial
Background and objective
Atrial fibrillation (AF) is common and causes impaired quality of life, an increased risk of stroke and death as well as frequent hospital admissions. The majority of patients with AF require control of heart rate. In this article , we summarise the limited evidence from clinical trials that guides prescription, and present the rationale and protocol for a new randomised trial. As rate control has not yet been shown to reduce mortality, there is a clear need to compare the impact of therapy on quality of life, cardiac function and exercise capacity. Such a trial should concentrate on the long-term effects of treatment in the largest proportion of patients with AF, those with symptomatic permanent AF, with the aim of improving patient well-being.
Design and interventionThe RAte control Therapy Evaluation in permanent Atrial Fibrillation (RATE-AF) trial will enrol 160 participants with a prospective, randomised, open-label, blinded end point design comparing initial rate control with digoxin or bisoprolol. This will be the first head-to-head randomised trial of digoxin and beta-blockers in AF.
ParticipantsRecruited patients will be aged âÂÂ¥60 years with permanent AF and symptoms of breathlessness (equivalent to New York Heart Association class II or above), with few exclusion criteria to maximise generalisability to routine clinical practice.
Outcome measuresThe primary outcome is patient-reported quality of life, with secondary outcomes including echocardiographic ventricular function, exercise capacity and biomarkers of cellular and clinical response. Follow-up will occur at 6 and 12 months, with feasibility components to inform the design of a future trial powered to detect a difference in hospital admission. The RATE-AF trial will underpin an integrated approach to management including biomarkers, functions and symptoms that will guide future research into optimal, personalised rate control in patients with AF.
Ethics and disseminationEast Midlands-Derby Research Ethics Committee (16/EM/0178); peer-reviewed publications.
Trial registrationClinicaltrials.gov: NCT02391337; ISRCTN: 95259705. Pre-results.
http://ift.tt/2uFOosW
Hepatocytes contribute to residual glucose production in a mouse model for glycogen storage disease type Ia
Abstract
It is a longstanding enigma how glycogen storage disease (GSD) type I patients retain a limited capacity for endogenous glucose production (EGP) despite the loss of glucose-6-phosphatase (G6Pase) activity. Insight into the source of residual EGP is of clinical importance given the risk of sudden death in these patients, but so far contradictory mechanisms have been proposed.
We investigated G6Pase-independent EGP in hepatocytes isolated from a liver-specific GSD Ia mouse model (L-G6pc-/- mice), and performed real-time analysis of hepatic glucose fluxes and glycogen metabolism in L-G6pc-/- mice using state-of-the-art stable isotope methodologies.
Here we show that G6pc-deficient hepatocytes are capable of producing glucose. In vivo analysis of hepatic glucose metabolism revealed that the hepatic glucokinase (GCK) flux was decreased by 95% in L-G6pc-/- mice. It also showed increased glycogen phosphorylase flux in L-G6pc-/- mice, which is coupled to the release of free glucose via glycogen debranching. Although the ex vivo activities of debranching enzyme and lysosomal acid maltase, two major hepatic α-glucosidases, were unaltered in L-G6pc-/- mice, pharmacological inhibition of α-glucosidase activity almost completely abolished residual glucose production by G6pc-deficient hepatocytes.
Conclusion. Our data indicate that hepatocytes contribute to residual glucose production in GSD Ia. We show that α-glucosidase activity, i.e. glycogen debranching and/or lysosomal glycogen breakdown, contributes to residual glucose production by GSD Ia hepatocytes. A strong reduction in hepatic GCK flux in L-G6pc-/- mice furthermore limits the phosphorylation of free glucose synthesized by G6pc-deficient hepatocytes, allowing the release of glucose into the circulation. The almost complete abrogation of GCK flux in G6pc-deficient liver also explains the contradictory reports on residual glucose production in GSD Ia patients. This article is protected by copyright. All rights reserved.
http://ift.tt/2ueHKco
Human myiasis caused by the reindeer warble fly, Hypoderma tarandi, case series from Norway, 2011 to 2016
Hypoderma tarandi causes myiasis in reindeer and caribou (Rangifer tarandus spp.) in most northern hemisphere regions where these animals live. We report a series of 39 human myiasis cases caused by H. tarandi in Norway from 2011 to 2016. Thirty-two were residents of Finnmark, the northernmost county of Norway, one a visitor to Finnmark, and six lived in other counties of Norway where reindeer live. Clinical manifestations involved migratory dermal swellings of the face and head, enlargement of regional lymph nodes, and periorbital oedema, with or without eosinophilia. Most cases of human myiasis are seen in tropical and subtropical countries, and in tourists returning from such areas. Our findings demonstrate that myiasis caused by H. tarandi is more common than previously thought. Healthcare professionals in regions where there is a likelihood of human infestation with H. tarandi (regions populated by reindeer), or treating returning travellers, should be aware of the condition. All clinicians are advised to obtain a detailed travel history when assessing patients with migratory dermal swellings. On clinical suspicion, ivermectin should be given to prevent larval invasion of the eye (ophthalmomyiasis). Since H. tarandi oviposits on hair, we suggest wearing a hat as a prevention measure.
http://ift.tt/2uee4MA
Ongoing hepatitis A among men who have sex with men (MSM) linked to outbreaks in Europe in Tel Aviv area, Israel, December 2016 - June 2017
Between December 2016 and June 2017, 19 Hepatitis A virus (HAV)-positive cases, 17 of which were among men who have sex with men (MSM) were identified in the Tel Aviv area. Seven of the 15 sewage samples collected between January and June 2017 were also HAV-positive. All sequences clustered with two of the three strains identified in the current European HAV outbreak. We demonstrate that despite an efficient vaccination programme, HAV can still be transmitted to an unvaccinated high-risk population.
http://ift.tt/2vnAiu3
Are pertussis cases reported too late for public health interventions? Retrospective analysis of cases in London and South East England, 2010 to 2015
In the United Kingdom, pertussis guidance recommends prophylaxis for household contacts within 21 days of case symptom onset if the household includes a vulnerable contact. The aim of our study was to identify characteristics associated with cases reported late for public health action. We reviewed the epidemiology of cases reported in London and South East England for the period 2010 to 2015. We characterised risk factors associated with late reporting of cases and described public health actions taken on timely reported cases. From 2010 to 2015, 9,163 cases of pertussis were reported to health protection teams. Only 11% of cases were reported within 21 days of onset, limiting opportunities for secondary prevention. Timely reporting was associated with younger age groups, pregnancy, being a healthcare worker and being reported by schools or hospital clinicians. Late reporting was associated with older age groups and general practitioner or laboratory reporting. Delays, such as those due to insidious onset and late presentation to healthcare, may be unavoidable; however, delay in reporting once a patient presents can be reduced since cases can be reported before laboratory confirmation. Thus we recommend working with clinicians and laboratories to determine causes and improve early reporting to public health.
http://ift.tt/2uesz33
Firefly at AVMA 2017 – Booth 1301
Firefly will be exhibiting with Henry Schein at the annual American Veterinary Medical Association conference in Indianapolis from July 22nd through the 24th in booth 1301.
- There will be live demonstrations of:
Come by the booth to see a demo!
http://ift.tt/2uezhpM
Next-generation sequencing of cytologic preparations: An analysis of quality metrics
BACKGROUND
Next-generation sequencing (NGS) fails for many small biopsies (BXs) because of a low overall DNA concentration or tumor percentage. Cytology smears and liquid-based preparations (LBPs), or smears/LBPs, often contain abundant tumor cells and may provide adequate material for molecular testing when other materials are insufficient. This study examined the performance of smears/LBPs on a clinical NGS assay.
METHODS
This study retrospectively reviewed quality metrics from consecutive smear/LBP, core BX, and cell block (CB) cases run on a hybrid-capture NGS assay interrogating 309 cancer-related genes. The following quality metrics were compared: adequacy rate, initial DNA concentration, postshearing fragment size, post–library preparation fragment size, fragment size difference, insert size, total reads, passing-filter reads aligned, percent passing-filter unique reads aligned, mean target coverage, percentage of loci with >100× coverage, percent duplication rate, percent selected bases, and percent usable bases on bait.
RESULTS
Twenty-three of 26 smears/LBPs (88%) were successfully sequenced, whereas 77 of 87 core BXs (89%) and 29 of 30 CBs (97%) were. The mean target coverage, median insert size, and percent usable bases were significantly higher in the smear/LBP category. The postshearing fragment size and the percent duplication were significantly lower for smears/LBPs.
CONCLUSIONS
The adequacy rate of cytology smears/LBPs for NGS is comparable to that of core BXs or CBs. Increased values for the mean insert size, mean target coverage, and percent usable bases, along with a lower duplication rate, suggest that smears/LBPs provide higher quality DNA than formalin-fixed material. Cytology smears/LBPs can serve as a valuable source of material for molecular testing. Cancer (Cancer Cytopathol) 2017. © 2017 American Cancer Society.
http://ift.tt/2gNuqqQ
Platelet-rich plasma enhances bone union in posterolateral lumbar fusion: a prospective randomized controlled trial
Publication date: Available online 20 July 2017
Source:The Spine Journal
Author(s): Go Kubota, Hiroto Kamoda, Sumihisa Orita, Kazuyo Yamauchi, Yoshihiro Sakuma, Yasuhiro Oikawa, Kazuhide Inage, Takeshi Sainoh, Jun Sato, Michihiro Ito, Masaomi Yamashita, Junichi Nakamura, Takane Suzuki, Kazuhisa Takahashi, Seiji Ohtori
Background ContextPlatelet-rich plasma (PRP) accelerates bone union in vivo in a rodent model of spinal fusion surgery. However, PRP's effect on bone union after spinal surgery remains unclear.PurposeTo evaluate the efficacy of PRP after posterolateral lumbar fusion (PLF) surgery.Study Design/SettingSingle-center prospective randomized controlled clinical trial with 2-year follow-up.Patient SampleTotal 62 patients (31 patients in PRP group or 31 patients in control groupsOutcome MeasuresBone fusion rate, area of bone fusion mass, duration for bone fusion, and clinical score using visual analog scale (VAS).MethodsWe randomized 62 patients who underwent one- or two-level instrumented PLF for lumbar degenerative spondylosis with instability to either PRP (31 patients) or control (31 patients) groups. PRP-treated patients underwent surgery using an autograft bone chip (local bone) and PRP was prepared from patient blood samples immediately before surgery; patients from the control group underwent PLF without PRP treatment. We assessed platelet counts and growth factor concentrations in PRP prepared immediately before surgery. Duration for bone union, postoperative bone fusion rate, and area of fusion mass were assessed using plain radiography every 3 months after surgery and by computed tomography (CT) at 12 or 24 months. The duration for bone fusion, and clinical scores for low back pain, leg pain, and leg numbness before, and 3, 6, 12, and 24 months after surgery were evaluated using a VAS.ResultsData from 50 patients with complete data were included. Bone union rate at final follow-up was significantly higher in the PRP group (94%) than controls (74%) (P = 0.002). Area of fusion mass was significantly higher in the PRP group (572 mm2) than controls (367 mm2) (P = 0.02). The mean period necessary for union was 7.8 months in the PRP group and 9.8 months in controls (P = 0.013). In the PRP, platelet count was 7.7 times higher and growth factor concentrations were 50 times higher than found in plasma (P < 0.05). There was no significant difference in low back pain, leg pain, and leg numbness in either group at any time evaluated (P > 0.05).ConclusionsPatients treated with PRP showed a higher fusion rate, greater fusion mass, and more rapid bone union after spinal fusion surgery than patients not treated with PRP.
http://ift.tt/2gNqFBK
Respiratory sinus arrhythmia in the fourth decade of life depends on birth weight and the DRD4 gene: Implications for understanding the development of emotion regulation
Abstract
Introduction
The long allele of the DRD4 gene can confer different behavioral and emotional phenotypes depending upon environmental exposure, although the physiological changes underlying these phenotypes are not fully known. We sought to extend this work by assessing the interaction of the DRD4 gene and exposure to perinatal adversity (indexed by extremely low birth weight [ELBW]) on resting respiratory sinus arrhythmia (RSA), a neurophysiological measure of emotion regulation, in adulthood.
Methods
We examined the interaction between the DRD4 gene and perinatal adversity on RSA at age 30–35 in a longitudinal cohort of ELBW survivors (n = 49) and NBW controls (n = 63). Buccal DNA samples were genotyped for short and long carriers of the exon III DRD4 VNTR gene. Resting RSA was assessed by electrocardiogram.
Results
We report an interaction between birth weight status and DRD4 gene (F = 9.42, p = 0.003) in predicting RSA, such that DRD4 long carriers had the highest and lowest resting RSA depending on whether they were born NBW or ELBW, respectively. DRD4 short carriers were less sensitive to birth weight. Additionally, reduced RSA was correlated with a history of major depressive disorder, suggesting it was a reliable index of emotion dysregulation.
Discussion
These results suggest that the perinatal environment influences autonomic nervous system functioning in individuals with genotypes that confer additional sensitivity. Whether the long-term autonomic outcomes of this environmental sensitivity are beneficial or detrimental appears to depend on the quality of the early life environment, and may influence the development of emotion regulatory and psychiatric problems in adulthood.
http://ift.tt/2ucyFPI
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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Alimentary Pharmacology &Therapeutics, EarlyView. https://ift.tt/2qECBIJ
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
