Long QT syndrome type 2 (LQT2) is a congenital disease characterized by loss of function mutations in hERG potassium channels (IKr). LQT2 is associated with fatal ventricular arrhythmias promoted by triggered activity in the form of early afterdepolarizations (EADs). We previously demonstrated that intracellular Ca2+ handling is remodeled in LQT2 myocytes. Remodeling leads to aberrant late RyR-mediated Ca2+ releases that drive forward-mode Na+-Ca2+ exchanger (NCX) current and slow repolarization to promote reopening of L-type calcium channels and EADs.
https://ift.tt/2vQkYYc
Τετάρτη 8 Αυγούστου 2018
NCX-mediated subcellular Ca2+ dynamics underlying early afterdepolarizations in LQT2 cardiomyocytes
Percutaneous transluminal plasty: a novel approach for refractory anastomotic stricture after esophagectomy
Abstract
Anastomotic stricture is often observed after esophagectomy. Surgical treatment is considered for refractory stricture to conservative treatments. However, it is not established what type of surgery is safe and effective. In this report, we present a novel approach, percutaneous transluminal plasty, for refractory anastomotic stricture reconstructed via the subcutaneous route in esophagectomy. We believe that the effectiveness and safety of this technique is considerably good and can become a good alternative for refractory stricture after esophagectomy.
https://ift.tt/2OP3e8h
Lactobacilli can attenuate inflammation in mouse macrophages exposed to polyethylene particles in vitro
It is well established that polyethylene (PE) wear particles induce macrophage production of cytokines and mediators associated with the pathogenesis of inflammatory osteolysis. The objective of this study was...
https://ift.tt/2ARskAw
Inotuzumab Ozogamicin: A Review in Relapsed/Refractory B-Cell Acute Lymphoblastic Leukaemia
Abstract
The intravenous CD22-directed antibody drug conjugate inotuzumab ozogamicin (Besponsa®) is approved in several countries including in the USA, EU and Japan, as monotherapy for the treatment of adults with relapsed/refractory B-cell acute lymphoblastic leukaemia (ALL). In adults with relapsed/refractory B-cell ALL who had received one or two prior treatment regimens, inotuzumab ozogamicin was associated with significantly higher rates of complete remission (including complete remission with incomplete haematological recovery) [CR/CRi] than standard therapy in the pivotal INO-VATE ALL trial. Inotuzumab ozogamicin was associated with significantly longer progression-free survival (PFS), duration of remission and higher haematopoietic stem cell transplantation (HSCT) rates than standard therapy. Although there was no significant between-group difference in overall survival duration as per the study design, the 2-year survival probability in the inotuzumab ozogamicin arm was twice that in the control arm. Inotuzumab ozogamicin had an acceptable tolerability profile. Thus, inotuzumab ozogamicin is an important new treatment option for patients with relapsed/refractory CD22-positive B-cell ALL.
https://ift.tt/2MbDS5R
Magnetic resonance imaging as a prognostic disability marker in clinically isolated syndrome: A systematic review
Acta Neurologica Scandinavica, Volume 0, Issue ja, -Not available-.
https://ift.tt/2vrTSY4
Is Polonium-210 a Good Indicator for Anthropogenic Radioactivity?
Cancer Biotherapy and Radiopharmaceuticals, Ahead of Print.
https://ift.tt/2ARKPEE
Comprehensive Ara-C SNP score predicts leukemic cell intracellular ara-CTP levels in pediatric acute myeloid leukemia patients
Pharmacogenomics, Ahead of Print.
https://ift.tt/2ARfLVS
Challenges in ALK inhibition of ALK-positive non-small-cell lung cancer: from ALK positivity detection to treatment strategies after relapse
Future Oncology, Ahead of Print.
https://ift.tt/2M8GmTC
Survival analysis for male ductal and lobular breast cancer patients with different stages
Future Oncology, Ahead of Print.
https://ift.tt/2vP3dIQ
Vitamin D Deficiency has a Negative Impact on Cetuximab-Mediated Cellular Cytotoxicity against Human Colon Carcinoma Cells
Abstract
Background
Hypovitaminosis D is associated with an adverse prognosis in colon cancer patients, possibly due to the effects of the vitamin on the immune system. Antibody-dependent cell-mediated cytotoxicity (ADCC) significantly contributes to the anti-tumor effects of monoclonal antibodies, including cetuximab, an epidermal growth factor receptor (EGFR)-targeted monoclonal antibody that is frequently added to chemotherapy in the treatment of colon cancer.
Objective
The present study evaluates the association between vitamin D serum levels and the ability of ex vivo NK cells to support cetuximab-mediated ADCC in colon cancer cell lines.
Methods
Blood samples were obtained from 124 healthy volunteers and serum vitamin D was determined by RIA. NK cells were isolated from each sample and added to human colorectal carcinoma cells with or without cetuximab, and ADCC was assessed using a colorimetric lactate dehydrogenase assay.
Results
Correlation analysis indicates a significant, gender- and age-independent association between vitamin D levels and cetuximab-induced ADCC on HT29 cells, where NK cells from samples with vitamin D < 20 ng/mL are significantly less efficient in inducing ADCC. A confirmatory study on two additional colon cancer cell lines yielded similar results.
Conclusions
These data suggest that vitamin D supplementation in vitamin-deficient/insufficient colorectal cancer patients could improve cetuximab-induced ADCC.
https://ift.tt/2MrVJSX
FDA Approves Poteligeo for Rare Types of Non-Hodgkin Lymphoma
WEDNESDAY, Aug. 8, 2018 -- Poteligeo (mogamulizumab) injection has been approved by the U.S. Food and Drug Administration to treat adults with two rare types of non-Hodgkin lymphoma. The drug was approved to treat relapsed or refractory mycosis...
https://ift.tt/2KDjExh
Measles Case Reported in Minnesota
WEDNESDAY, Aug. 8, 2018 -- A Somali-American child in Minnesota has been diagnosed with the measles after returning from a trip to Africa, state health officials said Tuesday, adding that the unidentified 5-year-old in Hennepin County was not...
https://ift.tt/2MbKPEe
Most Antipsychotics Prescribed in Nursing Homes Initiated There
WEDNESDAY, Aug. 8, 2018 -- Antipsychotic therapy prescribed to nursing home residents is mostly initiated in nursing homes rather than hospitals or outpatient settings, according to a study published in the June issue of the Journal of the American...
https://ift.tt/2KzEOfD
Cyber Insurance Recommended for All Physician Practices
WEDNESDAY, Aug. 8, 2018 -- The growing threat of hacking is increasing the number of physicians buying cyber insurance, according to an article published in Medical Economics. According to the article, cyber insurance covers losses and damages...
https://ift.tt/2OUi1yk
Inducing Labor at Term Appears to Reduce Cesarean Risk
WEDNESDAY, Aug. 8, 2018 -- Inducing labor at 39 weeks may decrease the risk of cesarean section, according to a study published in the Aug. 9 issue of the New England Journal of Medicine. William A. Grobman, M.D., from Northwestern University in...
https://ift.tt/2KDvzLj
ASHP national survey of pharmacy practice in hospital settings: Dispensing and administration--2017 [Practice Research Reports]
Purpose
The results of the 2017 ASHP national survey of pharmacy practice in hospital settings are described.
MethodsPharmacy directors at 4,828 general and children's medical–surgical hospitals in the United States were surveyed using a mixed-mode method of contact by mail and e-mail. Survey completion was online, using Qualtrics (Qualtrics, Provo, UT). IMS Health supplied data on hospital characteristics; the survey sample was drawn from the IMS hospital database (IMS Health, Yardley, PA).
ResultsThe response rate was 14.4%. Drug distribution systems have evolved from centralized unit dose programs to decentralized programs based on the use of automated dispensing cabinets (ADCs). These systems have been made safer by the use of lidded pockets, by the use of machine-readable coding during ADC stocking, and by linking access to medications to results of pharmacist order review. Health-system pharmacists continue to improve quality practices for compounding sterile preparations, including the use of safeguards in handling hazardous drugs. While some hospitals are prepared for more stringent standards, including United States Pharmacopeia chapter 800 requirements, much still needs to be done to meet these standards. Pharmacists are taking an active role in improving the responsible use of medications through antimicrobial stewardship and controlled-substance diversion prevention programs. The quality of the pharmacy workforce continues to be improved through the increased credentialing of both pharmacists and pharmacy technicians.
ConclusionHealth-system pharmacists continue to have a positive impact on improving healthcare through programs that improve efficiency, safety, and clinical outcomes of medication use in health systems.
https://ift.tt/2M8ZW10
Implementation of patient-centered prescription labeling in a safety-net ambulatory care network [Patient-Centered Prescription Labeling]
Purpose
An initiative to implement patient-centered medication labeling at 4 pharmacies within a publicly funded safety-net healthcare system is described.
SummaryMedication nonadherence negatively affects patient outcomes and safety. Nonadherence has been attributed to poor understanding of instructions on medication labels. Research has demonstrated that patient-centered labeling (PCL) can improve adherence and produce safer medication-taking practices. As part of a mixed-methods study by a safety-net health system, audits of nearly 9,000 prescription labels generated at 4 pharmacy sites, as well as interviews with 6 stakeholder informants, were conducted to determine PCL adoption rates and factors contributing to success. Descriptive statistics were used to analyze audit data; constructs of the Consolidated Framework for Implementation Research were used to analyze interview data. Among the 4 sites, 3 pharmacies successfully converted more than 85% of audited prescriptions to a PCL format; 1 pharmacy converted less than 25% of prescriptions. Barriers to implementation included pharmacists' reluctance to modify prescriber instructions and inadequate real-time data on conversion rates. Interviewees perceived that leadership and policy directives promoted PCL conversion efforts. Successful pharmacies used adaptable software, had closer communication networks with prescribers, and/or used automation to facilitate PCL conversion.
ConclusionThree pharmacies successfully converted more than 85% of labels for audited prescriptions to a PCL format; 1 pharmacy converted less than 25% of prescriptions. Barriers to implementation included pharmacists' reluctance to modify prescriber instructions, inadequate real-time data on conversation rates, and lack of customizable software to automate changes.
https://ift.tt/2OT1Dy0
Construction sites as an important driver of dengue transmission: implications for disease control
In 2013 and 2014, Singapore experienced its worst dengue outbreak known-to-date. Mosquito breeding in construction sites stood out as a probable risk factor due to its association with major dengue clusters in...
https://ift.tt/2vB1esn
[18F]THK-5351 PET imaging in early-stage semantic variant primary progressive aphasia: a report of two cases and a literature review
Semantic variant primary progressive aphasia (svPPA) is a subtype of primary progressive aphasia characterized by two-way anomia and disturbance in word comprehension, with focal atrophy in the left temporal l...
https://ift.tt/2OmEYsV
A review of documents prepared by international organizations about influenza pandemics, including the 2009 pandemic: a bibliometric analysis
World Health Organization (WHO), the World Bank, UN System Influenza Coordination (UNSIC) and other international organizations released a series of documents to fight against the influenza pandemic. Those doc...
https://ift.tt/2B5039N
Fixed-dose combination associated with faster time to smear conversion compared to separate tablets of anti-tuberculosis drugs in patients with poorly controlled diabetes and pulmonary tuberculosis in Qatar
Diabetes is associated with increased risk of tuberculosis (TB) treatment failure, death, and relapse compared to patients without diabetes. Current TB regimens are available as fixed dose combination (FDC) an...
https://ift.tt/2B4ZVXR
Unintended harm? Race differences in the relationship between advance care planning and psychological distress at the end-of-life
Research has revealed racial disparities in advance care planning and intensity of end-of-life care. Studies of the relationship between advance care planning and sadness and anxiety at the end-of-life are inconclusive.
https://ift.tt/2Md1qHt
Young Adults Help Parents Instead of Friends When Forced to Choose
When forced to make a decision that benefits either a parent or a close friend, young adults are more likely to choose the parent, according to findings published in Psychological Science, a journal of the Association for Psychological Science.
"Our study suggests mom still matters," said Jennifer Silvers, assistant professor of psychology at the University of California, Los Angeles (UCLA) and senior author of the study. "Parents continue to have an enduring impact on their children as they become adults — and on their decision-making."
The study involved 174 people between the ages of 18 and 30. Each was asked to play a series of games that forced them to choose between the interests of a parent and a friend they chose. Each subject began with either $5 or 50 points, and was told to play as if the points could be redeemed for prizes, and the choices they made would increase or decrease their winnings. In half the rounds, all of the player's gains went to the parent and all of the losses went to the friend. In the other rounds, all gains went to the friend and all losses to the parent.
In each round, participants were shown 16 cards on a computer monitor, with the cards "face down." On the side that was hidden, each card indicated that the subject had either won or lost a certain amount of money or a certain number of points.
Participants could choose to turn over as many cards as they wanted until they chose to stop or until a card revealed they had lost cash or points. Most of the cards provided money or points, but a few resulted in losses. This meant the longer each participant chose to play each round, the more they helped one person they love and put the other person at risk. Each participant played 48 rounds.
Before playing, each participant completed a 28-item questionnaire that gauged their feelings toward the parent and friend they chose. Overall, the surveys suggested the participants had strong, positive feelings toward both, but on average, the participants felt their relationships with friends were stronger.
The experiment with the cards, however, revealed something different: When they knew they were playing the card game to benefit their parents, the participants were more than 25 percent more likely to turn over additional cards. In other words, they were substantially more likely to make choices to benefit their parents. (Researchers controlled for important variables, such as age, gender and the quality of the participants' relationships.)
"When push came to shove, they prioritized their parents," Silvers said. "Even though not much was at stake, the preferences were quite consistent."
The researchers expected the bias toward parents would occur more among older subjects than younger ones, but the study found it occurred equally regardless of age. Results also were consistent between men and women.
Interviewed after the game, participants expressed ambivalence about the task they performed.
"Many of them seemed conflicted," said Joao Guassi Moreira, a doctoral student in Silvers' laboratory and the study's lead author. "Several said slight variations of, 'Even though it was hard to not pay as much attention to my friend, I felt like I owed it to my parent, who has helped me so much.'"
The researchers are interested in studying why young adults prioritized their parents over their closest friends and whether the phenomenon would be the same among young teenagers as well.
Co-authors of the study are Sarah Tashjian, a UCLA doctoral student in psychology; and Adriana Galván, a UCLA associate professor of psychology.
All data and materials have been made publicly available and the design and analysis plans for the experiments were preregistered via the Open Science Framework (OSF). The complete Open Practices Disclosure for this article is available online. This article has received badges for Open Data, Open Materials, and Preregistration.
https://ift.tt/2KDQQES
Risks Associated with Use of Rupture of Membranes Tests - Letter to Health Care Providers
[Posted 08/08/2018] AUDIENCE: OBGYN, Risk Manager, Health Professional ISSUE: The FDA is reminding health care providers that tests to detect rupture of the amniotic membranes should not be used without other clinical assessments to make critical...
https://ift.tt/2M31jPr
The pattern of idiopathic isolated teres minor atrophy with regard to its two-bundle anatomy
Abstract
Objective
We aimed to analyze the pattern of teres minor atrophy with regard to its two-bundle anatomy and to assess its association with clinical factors.
Materials and methods
Shoulder MRIs performed between January and December 2016 were retrospectively reviewed. Images were evaluated for the presence and pattern of isolated teres minor atrophy. Isolated teres minor atrophy was categorized into complete or partial pattern, and partial pattern was further classified according to the portion of the muscle that was predominantly affected. The medical records were reviewed to identify clinical factors associated with teres minor atrophy.
Results
Seventy-eight shoulders out of 1,264 (6.2%) showed isolated teres minor atrophy; complete pattern in 41.0%, and partial pattern in 59.0%. Most cases of partial pattern had predominant involvement of the medial–dorsal component (82.6%). There was no significant association between teres minor atrophy and previous trauma, shoulder instability, osteoarthritis, and previous operation. The history of shoulder instability was more frequently found in patients with isolated teres minor atrophy (6.4%), compared with the control group (2.6%), although the difference was not statistically significant.
Conclusion
Isolated teres minor atrophy may be either complete or partial, and the partial pattern may involve either the medial–dorsal or the lateral–ventral component of the muscle. The imaging findings of partial pattern teres minor atrophy indicate that the two muscle components may have separate innervation.
https://ift.tt/2MvlPVd
The Claudin-like Protein HPO-30 Is Required to Maintain LAChRs at the C. elegans Neuromuscular Junction
Communications across chemical synapses are primarily mediated by neurotransmitters and their postsynaptic receptors. There are diverse molecular systems to localize and regulate the receptors at the synapse. Here, we identify HPO-30, a member of the claudin superfamily of membrane proteins, as a positive regulator for synaptic localization of levamisole-dependent AChRs (LAChRs) at the Caenorhabditis elegans neuromuscular junction (NMJ). The HPO-30 protein localizes at the NMJ and shows genetic and physical association with the LAChR subunits LEV-8, UNC-29, and UNC-38. Using genetic and electrophysiological assays in the hermaphrodite C. elegans, we demonstrate that HPO-30 functions through Neuroligin at the NMJ to maintain postsynaptic LAChR levels at the synapse. Together, this work suggests a novel function for a tight junction protein in maintaining normal receptor levels at the NMJ.
SIGNIFICANCE STATEMENT Claudins are a large superfamily of membrane proteins. Their role in maintaining the functional integrity of tight junctions has been widely explored. Our experiments suggest a critical role for the claudin-like protein, HPO-30, in maintaining synaptic levamisole-dependent AChR (LAChR) levels. LAChRs contribute to <20% of the acetylcholine-mediated conductance in adult Caenorhabditis elegans; however, they play a significant functional role in worm locomotion. This study provides a new perspective in the study of LAChR physiology.
https://ift.tt/2M6A2Mg
Regional Distribution of CNS Antigens Differentially Determines T-Cell Mediated Neuroinflammation in a CX3CR1-Dependent Manner
T cells continuously sample CNS-derived antigens in the periphery, yet it is unknown how they sample and respond to CNS antigens derived from distinct brain areas. We expressed ovalbumin (OVA) neoepitopes in regionally distinct CNS areas (Cnp-OVA and Nes-OVA mice) to test peripheral antigen sampling by OVA-specific T cells under homeostatic and neuroinflammatory conditions. We show that antigen sampling in the periphery is independent of regional origin of CNS antigens in both male and female mice. However, experimental autoimmune encephalomyelitis (EAE) is differentially influenced in Cnp-OVA and Nes-OVA female mice. Although there is the same frequency of CD45high CD11b+ CD11c+ CX3CL1+ myeloid cell–T-cell clusters in neoepitope-expressing areas, EAE is inhibited in Nes-OVA female mice and accelerated in CNP-OVA female mice. Accumulation of OVA-specific T cells and their immunomodulatory effects on EAE are CX3C chemokine receptor 1 (CX3CR1) dependent. These data show that despite similar levels of peripheral antigen sampling, CNS antigen-specific T cells differentially influence neuroinflammatory disease depending on the location of cognate antigens and the presence of CX3CL1/CX3CR1 signaling.
SIGNIFICANCE STATEMENT Our data show that peripheral T cells similarly recognize neoepitopes independent of their origin within the CNS under homeostatic conditions. Contrastingly, during ongoing autoimmune neuroinflammation, neoepitope-specific T cells differentially influence clinical score and pathology based on the CNS regional location of the neoepitopes in a CX3CR1-dependent manner. Altogether, we propose a novel mechanism for how T cells respond to regionally distinct CNS derived antigens and contribute to CNS autoimmune pathology.
https://ift.tt/2vWVzw7
Selective Role of RGS9-2 in Regulating Retrograde Synaptic Signaling of Indirect Pathway Medium Spiny Neurons in Dorsal Striatum
In the striatum, medium spiny neurons (MSNs) are heavily involved in controlling movement and reward. MSNs form two distinct populations expressing either dopamine receptor 1 (D1-MSN) or dopamine receptor 2 (D2-MSN), which differ in their projection targets and neurochemical composition. The activity of both types of MSNs is shaped by multiple neuromodulatory inputs processed by GPCRs that fundamentally impact their synaptic properties biasing behavioral outcomes. How these GPCR signaling cascades are regulated and what downstream targets they recruit in D1-MSN and D2-MSN populations are incompletely understood. In this study, we examined the cellular and molecular mechanisms underlying the action of RGS9–2, a key GPCR regulator in MSNs implicated in both movement control and actions of addictive drugs. Imaging cultured striatal neurons, we found that ablation of RGS9–2 significantly reduced calcium influx through NMDARs. Electrophysiological recordings in slices confirmed inhibition of NMDAR function in MSNs, resulting in enhanced AMPAR/NMDAR ratio. Accordingly, male mice lacking RGS9–2 displayed behavioral hypersensitivity to NMDAR blockade by MK-801 or ketamine. Recordings from genetically identified populations of striatal neurons revealed that these changes were selective to D2-MSNs. Surprisingly, we found that these postsynaptic effects resulted in remodeling of presynaptic inputs to D2-MSNs increasing the frequency of mEPSC and inhibiting paired-pulse ratio. Pharmacological dissection revealed that these adaptations were mediated by the NMDAR-dependent inhibition of retrograde endocannabinoid signaling from D2-MSNs to CB1 receptor on presynaptic terminals. Together, these data demonstrate a novel mechanism for pathway selective regulation of synaptic plasticity in MSNs controlled by GPCR signaling.
SIGNIFICANCE STATEMENT This study identifies a role for a major G-protein regulator in controlling synaptic properties of striatal neurons in a pathway selective fashion.
https://ift.tt/2M6oV5R
Angiotensin II Triggers Peripheral Macrophage-to-Sensory Neuron Redox Crosstalk to Elicit Pain
Injury, inflammation, and nerve damage initiate a wide variety of cellular and molecular processes that culminate in hyperexcitation of sensory nerves, which underlies chronic inflammatory and neuropathic pain. Using behavioral readouts of pain hypersensitivity induced by angiotensin II (Ang II) injection into mouse hindpaws, our study shows that activation of the type 2 Ang II receptor (AT2R) and the cell-damage-sensing ion channel TRPA1 are required for peripheral mechanical pain sensitization induced by Ang II in male and female mice. However, we show that AT2R is not expressed in mouse and human dorsal root ganglia (DRG) sensory neurons. Instead, expression/activation of AT2R on peripheral/skin macrophages (Ms) constitutes a critical trigger of mouse and human DRG sensory neuron excitation. Ang II-induced peripheral mechanical pain hypersensitivity can be attenuated by chemogenetic depletion of peripheral Ms. Furthermore, AT2R activation in Ms triggers production of reactive oxygen/nitrogen species, which trans-activate TRPA1 on mouse and human DRG sensory neurons via cysteine modification of the channel. Our study thus identifies a translatable immune cell-to-sensory neuron signaling crosstalk underlying peripheral nociceptor sensitization. This form of cell-to-cell signaling represents a critical peripheral mechanism for chronic pain and thus identifies multiple druggable analgesic targets.
SIGNIFICANCE STATEMENT Pain is a widespread health problem that is undermanaged by currently available analgesics. Findings from a recent clinical trial on a type II angiotensin II receptor (AT2R) antagonist showed effective analgesia for neuropathic pain. AT2R antagonists have been shown to reduce neuropathy-, inflammation- and bone cancer-associated pain in rodents. We report that activation of AT2R in macrophages (Ms) that infiltrate the site of injury, but not in sensory neurons, triggers an intercellular redox communication with sensory neurons via activation of the cell damage/pain-sensing ion channel TRPA1. This M-to-sensory neuron crosstalk results in peripheral pain sensitization. Our findings provide an evidence-based mechanism underlying the analgesic action of AT2R antagonists, which could accelerate the development of efficacious non-opioid analgesic drugs for multiple pain conditions.
https://ift.tt/2nlS4eA
The Transmembrane Domain of Synaptobrevin Influences Neurotransmitter Flux through Synaptic Fusion Pores
The soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins synaptobrevin (Syb), syntaxin, and SNAP-25 function in Ca2+-triggered exocytosis in both endocrine cells and neurons. The transmembrane domains (TMDs) of Syb and syntaxin span the vesicle and plasma membrane, respectively, and influence flux through fusion pores in endocrine cells as well as fusion pores formed during SNARE-mediated fusion of reconstituted membranes. These results support a model for exocytosis in which SNARE TMDs form the initial fusion pore. The present study sought to test this model in synaptic terminals. Patch-clamp recordings of miniature EPSCs (mEPSCs) were used to probe fusion pore properties in cultured hippocampal neurons from mice of both sexes. Mutants harboring tryptophan at four different sites in the Syb TMD reduced the rate-of-rise of mEPSCs. A computer model that simulates glutamate diffusion and receptor activation kinetics could account for this reduction in mEPSC rise rate by slowing the flux of glutamate through synaptic fusion pores. TMD mutations introducing positive charge also reduced the mEPSC rise rate, but negatively charged residues and glycine, which should have done the opposite, had no effect. The sensitivity of mEPSCs to pharmacological blockade of receptor desensitization was enhanced by a mutation that slowed the mEPSC rate-of-rise, suggesting that the mutation prolonged the residence of glutamate in the synaptic cleft. The same four Syb TMD residues found here to influence synaptic release were found previously to influence endocrine release, leading us to propose that a similar TMD-lined fusion pore functions widely in Ca2+-triggered exocytosis in mammalian cells.
SIGNIFICANCE STATEMENT SNARE proteins function broadly in biological membrane fusion. Evidence from non-neuronal systems suggests that SNARE proteins initiate fusion by forming a fusion pore lined by transmembrane domains, but this model has not yet been tested in synapses. The present study addressed this question by testing mutations in the synaptic vesicle SNARE synaptobrevin for an influence on the rise rate of miniature synaptic currents. These results indicate that synaptobrevin's transmembrane domain interacts with glutamate as it passes through the fusion pore. The sites in synaptobrevin that influence this flux are identical to those shown previously to influence flux through endocrine fusion pores. Thus, SNARE transmembrane domains may function in the fusion pores of Ca2+-triggered exocytosis of both neurotransmitters and hormones.
https://ift.tt/2vRNadf
Drug Refraining and Seeking Potentiate Synapses on Distinct Populations of Accumbens Medium Spiny Neurons
Cocaine-associated cues and contexts can precipitate drug seeking in humans and in experimental animals. Glutamatergic synapses in the core subcompartment of the nucleus accumbens (NAcore) undergo transient potentiation in response to presenting drug-associated cues. The NAcore contains two populations of medium spiny neurons (MSNs) that differentially express D1 or D2 dopamine receptors. By recording the ratio of AMPA and NMDA glutamate receptor currents (AMPA/NMDA ratio) from MSNs in NAcore tissue slices, we endeavored to understand which subpopulation of MSNs was undergoing transient potentiation. Transgenic female and male mice differentially expressing fluorescent reporters in D1 or D2 MSNs were withdrawn for 2–3 weeks after being trained to self-administer cocaine. In some mice, discrete cocaine-conditioned cues were isolated from the drug-associated context via extinction training, which causes rodents to refrain from drug seeking in the extinguished context. By measuring AMPA/NMDA ratios in the drug context with or without contextual or discrete cues, and with or without extinction training, we made the following three discoveries: (1) mice refraining from cocaine seeking in the extinguished context showed selective elevation in AMPA/NMDA ratios in D2 MSNs; (2) without extinction training, the drug-associated context selectively increased AMPA/NMDA ratios in D1 MSNs; (3) mice undergoing cue-induced cocaine seeking after extinction training in the drug-associated context showed AMPA/NMDA ratio increases in both D1 and D2 MSNs. These findings reveal that the NAcore codes drug seeking through transient potentiation of D1 MSNs, and that refraining from cocaine seeking in an extinguished context is coded through transient potentiation of D2 MSNs.
SIGNIFICANCE STATEMENT Relapse is a primary symptom of addiction that can involve competition between the desire to use drugs and the desire to refrain from using drugs. Drug-associated cues induce relapse, which is correlated with transiently potentiated glutamatergic synapses in the nucleus accumbens core. We determined which of two cell populations in the accumbens core, D1-expressing or D2-expressing neurons, undergo transient synaptic potentiation. After being trained to self-administer cocaine, mice underwent withdrawal, some with and others without extinguishing responding in the drug-associated context. Extinguished mice showed transient potentiation in D2-expressing neurons in the extinguished environment, and all mice engaged in context-induced or cue-induced drug seeking showed transient potentiation of D1-expressing neurons. A simple binary engram in accumbens for seeking drugs and refraining from drugs offers opportunities for cell-specific therapies.
https://ift.tt/2M2sGJz
Risks Associated with Use of Rupture of Membranes Tests - Letter to Health Care Providers
[Posted 08/08/2018] AUDIENCE: OBGYN, Risk Manager, Health Professional ISSUE: The FDA is reminding health care providers that tests to detect rupture of the amniotic membranes should not be used without other clinical assessments to make critical...
https://ift.tt/2M31jPr
How much personal liability do individual EMS providers bear?
Our co-hosts discuss a recent article that raises the question of personal liability for EMS workers
https://ift.tt/2M4VvVU
An Experimental Protocol for Studying Mineral Effects on Organic Hydrothermal Transformations
Earth-abundant minerals play important roles in the natural hydrothermal systems. Here, we describe a reliable and cost-effective method for the experimental investigation of organic-mineral interactions under hydrothermal conditions.
https://ift.tt/2vvjpzp
High-Fat Diet or Diabetes Drug May Enhance Response to Targeted Cancer Drug
A study in mice may have identified a way to help overcome resistance to targeted cancer drugs known as PI3K inhibitors. The approach appears to work by reducing insulin levels in patients receiving these drugs.
https://ift.tt/2OOIQE6
How much personal liability do individual EMS providers bear?
Our co-hosts discuss a recent article that raises the question of personal liability for EMS workers
https://ift.tt/2OVzdU2
APTA National Student Conclave and President Sharon Dunn
Learn why APTA President Dunn attends NSC every year and why you should too.
https://www.youtube.com/watch?v=zR6WKFhZ0Ms
The Barnacle Balanus improvisus as a Marine Model - Culturing and Gene Expression
The barnacle Balanus (Amphibalanus) improvisus is a model for studying osmoregulation and antifouling. However, natural seasonal spawning yields an unpredictable supply of cyprid larvae. Here, a protocol for the all-year-round culturing of B. improvisus is described, including the production of larvae. The use of cultured barnacles in gene expression studies is illustrated.
https://ift.tt/2OTLecI
Tumour origin and R1 rates in pancreatic resections: towards consilience in pathology reporting
Abstract
To evaluate differences in the R1 rates of ampullary (AC), pancreatic (PC), and distal bile duct (DBD) cancers in pancreatoduodenectomies (PD) using standardised pathology assessment. Data of PD (2010–2011) analysed in accordance with the Royal College of Pathologists (UK) protocol, were retrieved. Clinicopathologic features, including frequency, topography, and mode of margin involvement in AC (n = 87), PC (n = 18), and DBD (n = 5) cancers were evaluated. The R1 rate was 7%, 67%, and 20% in the AC, PC, and DBD cancers (p < 0.001). Within the PC cohort, R1 rate was heterogeneous (chemo-naïve, 77%; post-neoadjuvant, 40%). Commonest involved margins were as follows: posterior in overall PD (35%), AC (43%), overall PC (33%), and post-neoadjuvant PC (100%); superior mesenteric artery margin in chemo-naïve PC (38%) and common bile duct margin in DBD (100%) cancers. In AC, majority (66%) of R1 were signet ring cell type. Indirect margin involvement due to tumour within lymph node, perineural sheath or lymphovascular space was observed in 26% cases, and altered R1 rate in AC, PC, and DBD cohorts by 1%, 12%, and 0%, respectively. Although not statistically significant, patients with R1 had lower disease-free survival than those with R0 (mean, 25.4 months versus 44.4 months). Tumour origin impacts R1 data in PD necessitating its accurate classification by pathologists. Indirect involvement, histology, and neoadjuvant therapy influence the R1 rate, albeit in a minority of cases. Generating cogent R1 data based on standardised pathology reporting is the foremost need of the hour.
https://ift.tt/2OiSw8T
EMCrit #230 – Resuscitation Communication
Precise Resuscitation Communication is crucial for patient safety
EMCrit Project by Scott Weingart.
https://ift.tt/2vuUSuq
The association of teaching-learning methods and self-confidence of nurse-midwives. A survey from one province in India
Publication date: Available online 8 August 2018
Source: Women and Birth
Author(s): Bharati Sharma, Ingegerd Hildingsson, Kyllike Christensson
Abstract
Background
This study aimed to investigate the association between self-confidence of final-year students in selected midwifery skills and teaching-learning methods used in the two formally recognized education programs for nurse-midwives in India.
Design
A cross-sectional survey
Participants
633 final-year students, from 25 educational institutions randomly selected, stratified by type of program (diploma/bachelor), and ownership (private/government) in Gujarat.
Data collection and analysis
Students assessed their confidence on a 4-point scale, in four midwifery competency domains-antepartum, intrapartum, postpartum, and newborn care recommended by the International Confederation of Midwives (ICM). Explorative factor analysis was used to reduce skill statements into subscales separately for each domain. Odds ratios with 95% CI were calculated for students with high confidence (≥75th percentile on each subscale) and not high confidence (all others) between diploma and bachelor students.
Results
Classroom teaching was the most practiced method. 'Laboratory demonstrations', 'Practice on models', 'Demonstrations at clinical sites', 'Births Attended' (Hands-on clinical practice), and 'Satisfaction with clinical supervision' were practiced less, lesser in the bachelor's compared to the diploma program. High confidence was associated with 'Births Attended' (Hands-on clinical practice), 'Practice on models', and 'Satisfaction with clinical supervision' for all subscales of all four domains of competencies.
Conclusions
Hands on skills practice in the laboratory and supervised clinical practice during clinical placements were associated with high confidence for basic clinical midwifery skills amongst students. The diploma program followed better pedagogoical approaches than the bachelor's program.
https://ift.tt/2M6hfAI
The uptake and implementation of the Baby Friendly Health Initiative in Australia
Publication date: Available online 8 August 2018
Source: Women and Birth
Author(s): Anahita Esbati, Amanda Henderson, Jane Taylor, Margaret Barnes
Abstract
Problem
Despite evidence that implementation of the Initiative has been effective in increasing breastfeeding rates and duration of breastfeeding worldwide; the uptake is low with only 70 Baby Friendly accredited maternity facilities across Australia (approximately 23% of facilities).
Background
The Ten Steps to Successful Breastfeeding and International Code of Marketing of Breastmilk Substitutes shaped the foundation for the Initiative to implement practices that protect, promote and support breastfeeding. There is evidence that implementation of the Initiative is impacted by individual and organisational culture, organisational support, and education. Organisational change is also identified as playing an important role in the successful implementation of the Initiative. Despite policy and guideline support for the Initiative at national and state levels in Australia the uptake of the Initiative is low.
Aim
The aim of this research was to explore health practitioners' perspectives about the uptake and implementation of the Initiative in Australia.
Methods
Semi-structured, face-to-face, telephone and Skype interviews were conducted with 12 health practitioners. Thematic analysis was used to analyse data.
Results
Participants identified that the uptake and implementation of the Initiative in Australia is complex. This complexity was related to six themes: (1) policy and guideline support for the Initiative, (2) leadership support to implement the Initiative, (3) improving breastfeeding and Initiative-related knowledge, (4) improving communication between stakeholders regarding the Initiative, (5) accreditation and reaccreditation processes, and (6) implementation complexity.
Conclusion
Using organisational change theories as a guide to implementation of the Initiative may be useful for facilities intending to become accredited.
https://ift.tt/2KDDyYH
High Expression of PhospholipaseD2 Induced by Hypoxia Promotes Proliferation of Colon Cancer Cells through Activating NF- κ Bp65 Signaling Pathway
Abstract
Hypoxia is a typical feature of colon cancer occurrence and progression. We have reported that high expression and activity of PhospholipaseD2 (PLD2) induced by hypoxia in colon cancer cells. In order to further investigate the role of PLD2 in colon cancer under hypoxic conditions. MTT assay was used to detect the proliferation of human colon cancer cells (SW480 and SW620) under hypoxic conditions by decrease the PLD2 gene expression or inhibit the activity of PLD2. Expression level of p-P65/T-P65 and Cyclin D1 were detected in those cells treated as above through using western blot and RT-PCR analysis. Effect of NF-Bp65 inhibitor (BAY-117082) on the proliferation and expression level of Cyclin D1 and PLD2 of colon cancer cells under hypoxic conditions were further analysised. As a result, decreased the expression of PLD2 or inhibited the activity of PLD2 leaded to the proliferation of hypoxia colon cancer cells reduced, and along with the expression level of p-P65/T-P65 and Cyclin D1 reduced. However, inhibition the expression level of p-P65/T-P65 lead to the proliferation and expression of Cyclin D1 in those hypoxia colon cancer cells also reduced. In vivo growth decreased in response to PLD2 and NF-Bp65 inhibition. Our study indicates that high expression of PLD2 induced by hypoxia promotes the proliferation of colon cancer cells, and it may elevate the expression level of Cyclin D1 through activating NF-Bp65 signaling pathway. Inhibition of the PLD2 expression may provide a new clue for treatment for colon cancer.
https://ift.tt/2nlkmFV
Stroke Transfer and its Organizational Paradigm
Abstract
Since the clinical recognition of endovascular therapy (EVT) for stroke treatment is recent (2015), some organizational issues, such as the "drip and ship (DS) versus mothership (MS)" access to EVT remain unanswered. There is growing pressure to guarantee immediate access to EVT with limited human resources and infrastructures. As results from prospective studies are missing, a review of the existing literature dealing with clinical retrospective studies was carried out. Most of the studies did not report a significant difference with respect to the adverse effects for patients treated by EVT according to the organizational paradigm of care. Several studies did not report a significant difference concerning the 3 months functional outcomes regarding the organizational paradigm. Only two studies built theoretical models of the best outcomes and observed a superiority of the DS only if the door to needle time was less than 30 min. Waiting for the results of ongoing randomized controlled trials, this review of articles presenting patients treated with either MS or DS provides an overview but does not emphasize a superiority of a given paradigm; however, it highlights the inequalities of access to EVT according to the organization of care in different areas.
https://ift.tt/2vOevgd
Optimized Scratch Assay for In Vitro Testing of Cell Migration with an Automated Optical Camera
Here we describe a procedure to test the cell migration in vitro with an automated optical camera microscope. The scratch assay has been widely used where the closure of the scratch is followed for a set period. The optical microscope enables dependable and cheap detection of cell migration.
https://ift.tt/2M4xBtp
Pulsara launches real-time video call capabilities in version 9.0
BOZEMAN, MT — Pulsara announced today the release of app version 9.0. The full release notes sent out by the company are as follows: Have you ever dreamed of a world in which you could tap a button and get any member of your care team on a video call, just like you do with your grandma, or that friend living abroad in Thailand? Wouldn't it make things so much simpler if medics could...
https://ift.tt/2vQv0Z5
Human dignity statement is a good start, but not enough
Position statements from our national leadership are helpful, but we must make culture change ourselves
https://ift.tt/2M1NJMq
Interactive effects of dissolved nitrogen, phosphorus and litter chemistry on stream fungal decomposers
Abstract
The enrichment of ecosystems by nutrients such as nitrogen (N) and phosphorus (P) has important ecological consequences. This includes effects on plant litter decomposition in forest soils and forested headwater streams, where fungi play a pivotal role. However, our understanding of nutrient relationships on fungal communities associated with decomposing litter remains surprisingly incomplete. We conducted a fully factorial microcosm experiment with known communities of fungal decomposers from streams to assess the importance of dissolved N and P supply, as well as the atomic nutrient ratio (N:P), on fungal community succession, diversity, biomass and reproduction on three leaf-litter species differing in nutrient and lignin concentrations. Fungal biomass accrual and spore production were strongly controlled by external N supply, whereas P supply was much less important. The magnitude of these effects was mediated by litter quality, with stronger effects of dissolved N and P on lignin-poor and high N:P litter. N supply also influenced fungal diversity and species composition, acting as a pacemaker of community succession. Collectively, our data indicate that N was in much greater demand than predicted by standard stoichiometric models. The most parsimonious explanation for this deviation relates to the need of litter fungi to invest large amounts of N into degradative exoenzymes.https://ift.tt/2ATGBMX
One-Third of Canadian Patients Get Hip Fx Repair Within 24 Hours
WEDNESDAY, Aug. 8, 2018 -- Only one-third of Canadian patients received hip fracture repair surgery within the desired 24 hours, according to a Canadian study published in the June 11 issue of CMAJ, the journal of the Canadian Medical...
https://ift.tt/2vNBJmJ
Preschooler's Perfectionism May Predict OCD in Adolescence
WEDNESDAY, Aug. 8, 2018 -- Tendencies toward perfectionism and excessive self-control in children are associated with the onset of obsessive-compulsive disorder (OCD) and smaller dorsal anterior cingulate cortex (dACC) volumes in later childhood and...
https://ift.tt/2M4pMnx
Gender Gap for First Authors of Perspectives in Peds Journals
WEDNESDAY, Aug. 8, 2018 -- Women are underrepresented among physician first authors of perspective-type articles in prominent pediatric journals, according to a study published online July 20 in JAMA Network Open. Julie K. Silver, M.D., from Harvard...
https://ift.tt/2vNB3Od
Inverse Link for Mediterranean Diet Score, Severe Psoriasis
WEDNESDAY, Aug. 8, 2018 -- Patients with severe psoriasis have low levels of adherence to the Mediterranean diet (MEDI-LITE), according to a study published online July 25 in JAMA Dermatology. Céline Phan, M.D., from Mondor Hospital in France, and...
https://ift.tt/2nm0NNO
Walking Tied to Better QoL in Those With/at Risk for CVD
THURSDAY, Aug. 8, 2018 -- Walking is associated with improved quality of life (QoL) among those at risk for or living with cardiovascular disease (CVD), according to a study published in PLoS One. Viviane de Menezes Caceres, from the University of...
https://ift.tt/2vNAWSN
Responsive Parent Intervention in Infancy Can Reduce BMI z Score
WEDNESDAY, Aug. 8, 2018 -- A responsive parenting intervention initiated in early infancy can reduce body mass index (BMI) z score; however, a 36-month multicomponent behavioral intervention does not change BMI trajectory, according to two studies...
https://ift.tt/2nkLeGf
Elevated Late Mortality Persists After Blood or Marrow Transplant
WEDNESDAY, Aug. 8, 2018 -- Individuals who underwent allogeneic blood or marrow transplantation (BMT) in childhood have elevated risk of late mortality 25 years or more after transplantation, according to a study published online July 26 in JAMA...
https://ift.tt/2vNQoOY
Unsheltered Homeless Have High Mortality Rates
WEDNESDAY, Aug. 8, 2018 -- Mortality rates for unsheltered homeless adults are higher than those for the general adult population and sheltered homeless adults, according to a study published online July 30 in JAMA Internal Medicine. Jill S....
https://ift.tt/2M4plcT
Resource Use Greater for More Severe Pediatric Appendicitis
WEDNESDAY, Aug. 8, 2018 -- More severe presentations of complicated appendicitis are associated with worse outcomes and greater resource use among pediatric patients, according to a study published online July 25 in JAMA Surgery. Seema P....
https://ift.tt/2vNACDz
Steps Taken to Increase Use of Electronic Tools in Medicine
WEDNESDAY, Aug. 8, 2018 -- Additional codes have been approved by the Current Procedural Terminology (CPT) Editorial Panel for chronic care remote physiologic monitoring and internet consultations, according to a report published by the American...
https://ift.tt/2nljCkn
Facet joint syndrome: from diagnosis to interventional management
Abstract
Low back pain (LBP) is the most common pain syndrome, and is an enormous burden and cost generator for society. Lumbar facet joints (FJ) constitute a common source of pain, accounting for 15–45% of LBP. Facet joint degenerative osteoarthritis is the most frequent form of facet joint pain. History and physical examination may suggest but not confirm facet joint syndrome. Although imaging (radiographs, MRI, CT, SPECT) for back pain syndrome is very commonly performed, there are no effective correlations between clinical symptoms and degenerative spinal changes. Diagnostic positive facet joint block can indicate facet joints as the source of chronic spinal pain. These patients may benefit from specific interventions to eliminate facet joint pain such as neurolysis, by radiofrequency or cryoablation. The purpose of this review is to describe the anatomy, epidemiology, clinical presentation, and radiologic findings of facet joint syndrome. Specific interventional facet joint management will also be described in detail.
Teaching points
• Lumbar facet joints constitute a common source of pain accounting of 15–45%.
• Facet arthrosis is the most frequent form of facet pathology.
• There are no effective correlations between clinical symptoms, physical examination and degenerative spinal changes.
• Diagnostic positive facet joint block can indicate facet joints as the source of pain.
• After selection processing, patients may benefit from facet joint neurolysis, notably by radiofrequency or cryoablation.
https://ift.tt/2nl9Cr5
A prospective phase I study of hypo-fractionated neoadjuvant radiotherapy for locally advanced gastric cancer
Abstract
Background
Previous studies have reported that neoadjuvant chemoradiotherapy can downstage the advanced gastric cancer. However, no studies are available on the application of hypo-radiotherapy to neoadjuvant radiotherapy. This study sought to assess the maximum tolerated dose (MTD) and dose-limited toxicity (DLT) of hypo-fractionated chemoradiotherapy for local advanced gastric cancer.
Method
Patients with cT3–4 and/or lymph node-positive locally advanced gastric cancer or Siewert II/III esophagogastric junction adenocarcinoma were enrolled. Preoperative chemoradiation was followed by 3 cycles of oxaliplatin + S-1 neoadjuvant chemotherapy with an interval duration of 3–4 weeks. D2 resection was performed 2–4 weeks after neoadjuvant therapy. Three cycles of adjuvant chemotherapy were planned after surgery. Intensity-modulated radiotherapy (IMRT) was used. The radiotherapy dose level was defined using three levels, namely, 40.0 Gy/2.5 Gy, 41.6 Gy/2.6 Gy, 43.2 Gy/2.7 Gy delivered concurrently with S-1 at 80 mg/m2.
Results
From May 2016 to Dec 2016, nine patients with a median age of 63 years were enrolled in this study. The most common grade I-III adverse events were leukopenia (88.9%), nausea (88.9%), vomiting (77.8%) and weight loss (66.7%). Grade III adverse events consisted of vomiting and weight loss.
Conclusion
The MTD of hypo-fractionated radiotherapy for locally advanced gastric cancer was 40.0 Gy/2.5 Gy, and the DLTs were vomiting and weight loss.
Trial registration
Clinicaltrials.gov ID: NCT03427684 (Retrospectively registered on February 9, 2018).
https://ift.tt/2OmPa4H
Clinical outcome of primary giant cell tumor of bone after curettage with or without perioperative denosumab in Japan: from a questionnaire for JCOG 1610 study
Abstract
Background
Giant cell tumor of bone (GCTB) is an intermediate tumor known to be locally aggressive, but rarely metastasizing. To plan a prospective study of GCTB, we performed a questionnaire survey for institutions participating in the Bone and Soft Tissue Tumor Study Group (BSTTSG) in the Japan Clinical Oncology Group (JCOG) in 2015.
Methods
We reviewed 158 consecutive patients with primary GCTB treated with curettage without perioperative denosumab from 2008 to 2010 in Japan. We investigated local and distant recurrence rates after definitive curettage. We also investigated the recurrence rate after treatment with preoperative and/or postoperative denosumab with curettage in recent years. There were 40 patients treated with perioperative denosumab, and the factors affecting recurrence in them were investigated.
Results
Answers were available from 24 of 30 institutions (80.0%) participating in JCOG BSTTSG. Thirty (19.0%) and 4 (2.5%) of 158 patients developed local and distant recurrence after curettage without perioperative denosumab from 2008 to 2010, respectively. Campanacci grade and embolization before surgery were significantly associated with increasing incidence of local recurrence after curettage (p = 0.034 and p = 0.022, respectively). In patients treated with perioperative desnosumab, 120 mg denosumab was administered subcutaneously for a median 6 (2–41) and 6 (1–14) times in preoperative and postoperative settings, respectively. The recurrence rates were 6 of 21 (28.6%), 2 of 9 (22.2%), and 0 of 10 (0.0%) in the preoperative, postoperative, and both pre- and postoperative denosumab treatment groups, respectively. With all of the preoperative treatments, administration exceeding five times was significantly associated with a decreased incidence of local recurrence after curettage (p < 0.001).
Conclusion
The recurrence rate of GCTB was still high after curettage, especially in Campanacci grade III, and improvements in the therapeutic strategy are needed in this cohort. There is a possibility that a sufficient dose of preoperative denosumab can reduce recurrence after curettage. Recently, we have started a clinical trial, JCOG1610, to investigate the efficacy of preoperative denosumab in patients who can be treated with curettage in GCTB.
https://ift.tt/2OTZPoD
Gastric inflammatory myofibroblastic tumor treated with combined laparoscopic and endoscopic gastric wedge resection: a case report
Abstract
Background
Inflammatory myofibroblastic tumor is an uncommon soft tissue neoplasm rarely reported in the stomach.
Case presentation
We identified a tumor highly suggestive of poorly differentiated gastric adenocarcinoma in the lesser curvature of the stomach of a 53-year-old female during screening endoscopy. Although the patient's gastric biopsy did not reveal cancer, the tumor configuration was strongly suspicious for malignancy, and we performed a gastric wedge resection using a combined laparoscopic and endoscopic method. The lesion was diagnosed as inflammatory myofibroblastic tumor based on its morphological and immunohistological features.
Conclusions
Inflammatory myofibroblastic tumor should be considered in the differential diagnosis of soft tissue tumors in the stomach. We present a case of inflammatory myofibroblastic tumor safely treated with combined laparoscopic and endoscopic gastric wedge resection.
https://ift.tt/2ASFdtV
3 metrics to track in your EMS operations
EMS, like any other aspect of healthcare, is data driven, and tracking, measuring and reporting the right data can improve operations and patient care
https://ift.tt/2M7nOTK
Recent advances in development of cell-free protein synthesis systems for fast and efficient production of recombinant proteins
Abstract
Cell-free protein synthesis has emerged in recent years as a powerful tool that can potentially transform the production of recombinant proteins. Cell-free protein synthesis harnesses the synthetic power of living cells while eliminating many of the constraints of traditional cell-based gene expression methods. Due to the lack of physical barriers separating the protein synthesis machinery from the surrounding environment, a cell-free protein synthesis reaction mixture can be directly programmed using diverse genetic material for the instant production of recombinant proteins without complicated cloning procedures. However, a number of issues must be addressed for this technology to be widely accepted as an alternative platform for protein production, including quality-control of translation machinery preparations, and high reagent cost. This review describes recent efforts to make cell-free protein synthesis more affordable and more easily accessible for generic applications.https://ift.tt/2M5ZNfG
Role of tyrosine residue (Y213) in nuclear retention of PCNA1 in human malaria parasite Plasmodium falciparum
Abstract
Proliferating Cell Nuclear Antigen (PCNA) undergoes several post-translational modifications including phosphorylation leading to its regulation in mammalian and yeast systems. Plasmodium falciparum possesses two PCNAs (PCNA1 & PCNA2) with an edge of PfPCNA1 over PfPCNA2 for DNA replication. Recent phospho-proteome data report phosphorylation of S191 residue without its functional implication. In mammalian cells, phosphorylation of HsPCNA at Y211 stabilizes chromatin bound PCNA. We find tyrosine (but not S191) to be conserved in PfPCNAs and it is important for its nuclear localization and foci formation of PfPCNA1. Further, a Y213F mutation in PfPCNA1 leads to its functional loss both in yeast and parasite. We highlight the importance of evolutionarily conserved tyrosine in PCNA from parasite to mammal linked with DNA replication and cell proliferation.https://ift.tt/2vMexW1
3 metrics to track in your EMS operations
EMS, like any other aspect of healthcare, is data driven, and tracking, measuring and reporting the right data can improve operations and patient care
https://ift.tt/2OStyyc
Airway management: Bi-PAP vs. CPAP
While indications for BiPAP and CPAP ventilation differ in the field, both allow EMS to splint broken airways
https://ift.tt/2NLb0ia
Cancers, Vol. 10, Pages 264: The SUMO System and TGFβ Signaling Interplay in Regulation of Epithelial-Mesenchymal Transition: Implications for Cancer Progression
Cancers, Vol. 10, Pages 264: The SUMO System and TGFβ Signaling Interplay in Regulation of Epithelial-Mesenchymal Transition: Implications for Cancer Progression
Cancers doi: 10.3390/cancers10080264
Authors: Ayan Chanda Anusi Sarkar Shirin Bonni
Protein post-translational modification by the small ubiquitin-like modifier (SUMO), or SUMOylation, can regulate the stability, subcellular localization or interactome of a protein substrate with key consequences for cellular processes including the Epithelial-Mesenchymal Transition (EMT). The secreted protein Transforming Growth Factor beta (TGFβ) is a potent inducer of EMT in development and homeostasis. Importantly, the ability of TGFβ to induce EMT has been implicated in promoting cancer invasion and metastasis, resistance to chemo/radio therapy, and maintenance of cancer stem cells. Interestingly, TGFβ-induced EMT and the SUMO system intersect with important implications for cancer formation and progression, and novel therapeutics identification.
https://ift.tt/2vqtE8m
Efficient formation of inert Bi-213 chelates by tetraphosphorus acid analogues of DOTA: towards improved alpha-therapeutics
Abstract
Background
The recently growing interest in targeted alpha-therapy (TAT) calls for improvement of the labelling chemistry of the corresponding radionuclides. 213BiIII is a short-lived alpha emitter which emits only one alpha particle in its decay chain. Hence, it might be safer in application than other respective nuclides, such as 223Ra or 225Ac, because no alpha-emitting daughters are released upon recoil. We investigated cyclen derivatives with phosphorus-containing pendant arms regarding their suitability for 213Bi labelling.
Results
The concentration dependency of 213Bi labelling at 25 °C and 95 °C was determined for DOTP, DOTPH, DOTPEt, and DOTPI, as well as for DOTA and CHX-A"-DTPA for comparison. The labelling efficiency of the phosphorus-containing ligands was at least comparable to CHX-A"-DTPA and exceeded that of DOTA. DOTP was most efficient, requiring chelator concentrations for labelling which were approx. two orders of magnitude lower than those required for CHX-A"-DTPA, both at 25 °C and 95 °C. The 213Bi complexes of phosphorus ligands furthermore showed a higher stability against demetallation (> 96% of intact complex after 120-min incubation in plasma were found for DOTP, DOTPH, and DOTPEt, compared to 85% for DOTA and 76% for CHX-A"-DTPA).
Conclusion
Cyclen derivatives bearing four N-methylenephosphonic or -phosphinic acid substituents, e.g., DOTP, are capable of complexing the alpha-emitting radionuclide 213BiIII with higher efficiency and in-vitro stability than the current gold standards DOTA and CHX-A"-DTPA.
https://ift.tt/2AQMiuZ
Tox and Hound – Dependence Isn’t Addiction, But It’s Still A Problem
by David Juurlink We need to talk about dependence—specifically, what it is, what it isn't, and why it matters. Dependence isn't the same as addiction Dependence is a special type of drug-related harm. It's an adaptive phenomenon resulting from exposure to a centrally-active drug and defined by the development of withdrawal symptoms […]
EMCrit Project by Tox & Hound.
https://ift.tt/2AYdXtU
Second primary cancer after primary peritoneal, epithelial ovarian, and fallopian tubal cancer: a retrospective study
Abstract
Background
In this retrospective study, data from patients listed in the Korea Central Cancer Registry during 1993–2014 were analysed, to investigate the incidence and survival of second primary cancers (SPCs) after a diagnosis of primary peritoneal, epithelial ovarian, and fallopian tubal (POFT) cancer.
Methods
The standardised incidence ratio (SIR) and survival outcomes of patients with SPCs among POFT cancer survivors were analysed.
Results
Among 20,738 POFT cancer survivors, 798 (3.84%) developed SPCs, at an average interval of 5.50 years. SPC risk in POFT survivors (SIR, 1.29) was higher compared to the general population. The most high-risk type of SPC was leukaemia (3.07) followed by the lung and bronchus (1.80), colon (1.58), rectum and rectosigmoid junction (1.42), thyroid (1.34), and breast (1.26). In women aged < 60 years, cancer of the breast (1.30), ascending colon (2.26), and transverse colon (4.07) as SPCs increased. Up to 10 years after POFT cancer treatment, leukaemia risk increased, especially in those < 60 years, with serous histology, and with distant stage, which required aggressive chemotherapy. The median overall survival time was 12.8 years and 14.3 years in women with POFT cancer and SPCs, respectively. Thyroid and breast cancers were favourable prognostic markers among SPCs.
Conclusions
The overall SPC risk increases in POFT cancer survivors, especially in those < 60 years. The cancer risk of breast and the proximal colon increase based on hereditary predisposition, while leukaemia likely develops from aggressive treatment. The median overall survival is favourable in POFT cancer survivors with SPCs.
https://ift.tt/2noelbI
LC-MS based sphingolipidomic study on A549 human lung adenocarcinoma cell line and its taxol-resistant strain
Abstract
Background
Resistance to chemotherapy drugs (e.g. taxol) has been a major obstacle in successful cancer treatment. In A549 human lung adenocarcinoma, acquired resistance to the first-line chemotherapy taxol has been a critical problem in clinics. Sphingolipid (SPL) controls various aspects of cell growth, survival, adhesion, and motility in cancer, and has been gradually regarded as a key factor in drug resistance. To better understand the taxol-resistant mechanism, a comprehensive sphingolipidomic approach was carried out to investigate the sphingolipid metabolism in taxol-resistant strain of A549 cell (A549T).
Methods
A549 and A549T cells were extracted according to the procedure with optimal condition for SPLs. Sphingolipidomic analysis was carried out by using an UHPLC coupled with quadrupole time-of-flight (Q-TOF) MS system for qualitative profiling and an UHPLC coupled with triple quadrupole (QQQ) MS system for quantitative analysis. The differentially expressed sphingolipids between taxol-sensitive and -resistant cells were explored by using multivariate analysis.
Results
Based on accurate mass and characteristic fragment ions, 114 SPLs, including 4 new species, were clearly identified. Under the multiple reaction monitoring (MRM) mode of QQQ MS, 75 SPLs were further quantified in both A549 and A549T. Multivariate analysis explored that the levels of 57 sphingolipids significantly altered in A549T comparing to those of A549 (p < 0.001 and VIP > 1), including 35 sphingomyelins (SMs), 14 ceramides (Cers), 3 hexosylceramides (HexCers), 4 lactosylceramides (LacCers) and 1 sphingosine. A significant decrease of SM and Cer levels and overall increase of HexCer and LacCer represent the major SPL metabolic characteristic in A549T.
Conclusions
This study investigated sphingolipid profiles in human lung adenocarcinoma cell lines, which is the most comprehensive sphingolipidomic analysis of A549 and A549T. To some extent, the mechanism of taxol-resistance could be attributed to the aberrant sphingolipid metabolism, "inhibition of the de novo synthesis pathway" and "activation of glycosphingolipid pathway" may play the dominant role for taxol-resistance in A549T. This study provides insights into the strategy for clinical diagnosis and treatment of taxol resistant lung cancer.
https://ift.tt/2M1uVg9
Diffuse parenchymal pulmonary amyloidosis associated with multiple myeloma: a case report and systematic review of the literature
Abstract
Background
Pulmonary is an uncommon site of extramedullary involvement in multiple myeloma (MM). Diffuse parenchymal amyloidosis as pulmonary manifestation of MM is even rarer. We report a rare case of diffuse parenchymal pulmonary amyloidosis associated with MM diagnosed by video-assisted thoracoscopic lung biopsy (VATLB).
Case presentation
A 58-year-old woman complained of cough and shortness of breath. HRCT disclosed diffuse ground-glass opacifications with interlobular septal thickening in bilateral lungs. A lung-biopsy sample obtained by VATLB revealed Congo Red-positive amorphous eosinophilic deposits in the alveolar septa. Surgical biopsy of abdominal wall skin and subcutaneous fat was also performed, which showed the apple-green birefringence with polarized light on Congo red stain was demonstrated in dermis. The serum immunoelectrophoresis showed monoclonal lambda light chains. A bone marrow biopsy specimen comprised 11.5% plasma cells. She was therefore diagnosed with diffuse parenchymal pulmonary amyloidosis accompanied by MM. The patient was referred to the hematology department for further chemotherapy.
Conclusions
It is important to recognize diffuse parenchymal pulmonary amyloidosis to avoid misdiagnosis.
https://ift.tt/2KCdq0s
Improved outcome in patients following autologous stem cell transplantation for multiple myeloma in south eastern Norway 2001–2010: a retrospective, population based analysis
Abstract
Background
With the advent of novel drugs improved overall survival in patients with multiple myeloma, including patients who received up-front autologous stem cell transplantation (ASCT), has been reported from several centers. Here we report on overall survival in a population-based cohort of patients receiving ASCT as first line treatment and in whom novel agents were an option for second and later lines of treatment.
Methods
Patients with multiple myeloma ≤ 65 years of age who were considered for ASCT from 01.01.2001–31.06.2005 (period 1) and from 01.07.2005 until 31.12.2009 (period 2) at Oslo University Hospital (OUH) were identified. Relevant data were collected from the patients' medical records.
Results
Altogether, 293/355 patients received ASCT. In all, median OS was 82.9 months in patients ≤ 60 years of age and 59.0 months in patients 61–65 years. For patients ≤ 60 years of age median OS increased from 70.6 months to 87.7 months (p = 0. 22) and median survival after start of second line therapy increased from 34.5 months to 46.5 months (p = 0.015) between the two periods. For patients 61–65 years of age median OS increased from 57.3 months to 61.2 months (p = 0. 87) and median survival after start of second line therapy was practically unchanged (32.6 months vs. 33.1 months (p = 0.97) between the periods. In patients ≤ 60 years of age salvage ASCT was used in 34% of the patients while in patients 61–65 years of age salvage ASCT was used in 7.3% of the patients. The use of salvage ASCT and novel drugs, as well as the number of treatment lines, were higher in patients ≤ 60 years of age and increased during the study period.
Conclusion
In patients ≤ 60 years of age an increased median OS of 17 months between the two periods were noted, but the difference failed to reach statistical significance. However, a statistically significant difference in median survival of 12 months after start of second line therapy was found in this age group, which may be explained by a more active second line treatment. In patients 61–65 years only a slight increase of survival, not statistically significant, was noted between the periods.
https://ift.tt/2KBQPBh
In Vitro Antidiabetic Effects of Isolated Triterpene Glycoside Fraction from Gymnema sylvestre
A triterpene glycoside (TG) fraction isolated and purified from ethanolic extract of Gymnema sylvestre (EEGS) was investigated for blood glucose control benefit using in vitro methods. The HPLC purified active fraction TG was characterized using FTIR, LC-MS, and NMR. The purified fraction (TG) exhibited effective inhibition of yeast α-glucosidase, sucrase, maltase, and pancreatic α-amylase with IC50 values 3.16 ± 0.05 μg/mL, 74.07 ± 0.51, 5.69 ± 0.02, and 1.17 ± 0.24 μg/mL, respectively, compared to control. TG was characterized to be a mixture of triterpene glycosides: gymnemic acids I, IV, and VII and gymnemagenin. In vitro studies were performed using mouse pancreatic β-cell lines (MIN6). TG did not exhibit any toxic effects on β-cell viability and showed protection against H2O2 induced ROS generation. There was up to 1.34-fold increase in glucose stimulated insulin secretion (p
https://ift.tt/2M1qVfD
The Chinese Medicine, Jiedu Recipe, Inhibits the Epithelial Mesenchymal Transition of Hepatocellular Carcinoma via the Regulation of Smad2/3 Dependent and Independent Pathways
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. In China, traditional Chinese herb medicine has been widely used in the treatment of HCC. Jiedu Recipe (JR) is a common used prescription which has shown good results against HCC. However, the exact mechanisms of JR are still unknown. Therefore, we investigated the efficacy of JR on HCC in the current study. JR inhibited the cell viability of both SMMC-7721 and Huh7 cells in both time- and dose-dependent manners. Transwell assay revealed that JR decreased the number of migrated cells of SMMC-7721 cells. JR treatment increased the E-cadherin expression level and decreased the levels of p-Smad2/3 and Smad2/3. Further study showed that JR reversed the effect of TGFβ1 on the expression of E-cadherin, vimentin, N-cadherin, and MMP2/9. JR also significantly inhibited TGFβ1-induced migration and invasion of SMMC-7721 and Huh7 cells determined by wound healing assay and transwell assay. TGFβ1 treatment increased the phosphorylation of Smad2/3, p38 MAPK, JNK, ERK1/2, and Akt in SMMC-7721 cells and pretreatment with JR blocked TGFβ1-induced activation of Smad2/3 and Akt and MAPKs. In conclusion, JR inhibits liver cancer cells migration and invasion through epithelial mesenchymal transition (EMT) inhibition via Smad2/3 dependent and independent pathways, suggesting it is an effective therapeutic strategy against HCC metastasis.
https://ift.tt/2KEaLUd
Aqueous Extract of Glucoraphanin-Rich Broccoli Sprouts Inhibits Formation of Advanced Glycation End Products and Attenuates Inflammatory Reactions in Endothelial Cells
We have previously shown that sulforaphane not only inhibits formation of advanced glycation end products (AGEs) but also exerts anti-inflammatory effects on AGE-exposed human umbilical vein endothelial cells (HUVECs) and AGE-injected rat aortae. Here we examined the effects of aqueous extract of glucoraphanin-rich broccoli sprouts on formation of AGEs and then investigated whether the extract could attenuate inflammatory or oxidative stress reactions in tumor necrosis factor-alpha (TNF-α)- or AGE-exposed HUVECs. Fresh broccoli sprouts were homogenized in phosphate-buffered saline and filtered through a gauze. After centrifugation, clear extract was obtained. AGE formation was measured by enzyme-linked immunosorbent assay. Gene expression was evaluated by real-time reverse transcription-polymerase chain reaction. Reactive oxygen species (ROS) generation were measured using a fluorescent dye. Five percent broccoli sprout extract inhibited the formation of AGEs, reduced basal gene expressions of monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1,) and receptor for AGEs (RAGE), and upregulated endothelial nitric oxide synthase (eNOS) mRNA levels in HUVECs. TNF-α upregulated MCP-1, ICAM-1, and RAGE mRNA levels in HUVECs, all of which were attenuated by the treatment with 1% broccoli sprout extract. Pretreatment of 1% broccoli sprout extract prevented the ROS generation in HUVECs evoked by AGEs. The present study demonstrates that sulforaphane-rich broccoli sprout extract could inhibit the AGE-RAGE axis and exhibit anti-inflammatory actions in HUVECs. Supplementation of sulforaphane-rich broccoli sprout extract may play a protective role against vascular injury.
https://ift.tt/2nnjvVa
A novel AXIN2 gene mutation in sagittal synostosis
American Journal of Medical Genetics Part A, EarlyView.
https://ift.tt/2ASdiu7
Translational Insights into Gastrointestinal Stromal Tumor and Current Clinical Advances
Abstract
Gastrointestinal stromal tumor (GIST) is the most common soft tissue sarcoma of the gastrointestinal tract and, in the vast majority of cases, is characterized by activating mutations in KIT or, less commonly, PDGFRA. Mutations in these type III receptor tyrosine kinases (RTKs) account for over 85% of GIST cases, and the majority of KIT primary mutations respond to treatment with the tyrosine kinase inhibitor (TKI) imatinib. However, drug resistance develops over time, most commonly due to secondary kinase mutations. Sunitinib and regorafenib are approved for the treatment of imatinib-resistant GIST in the second and third lines, respectively. However, resistance to these agents also develops and new therapeutic options are needed. In addition, a small number of GISTs harbor primary activating mutations that are resistant to currently available TKIs, highlighting an additional unmet medical need. Several novel and selective TKIs that overcome known mechanisms of resistance in GIST have been developed and show promise in early clinical trials. Additional emerging targeted therapies in GIST include modulation of cellular signaling pathways downstream of KIT, antibodies targeting KIT and PDGFRA and immune checkpoint inhibitors. These advancements highlight the rapid evolution in the understanding of this malignancy and provide perspective on the encouraging horizon of current and forthcoming therapeutic strategies for GIST.https://ift.tt/2nktY3L
Freshwater copepod carcasses as pelagic microsites of dissimilatory nitrate reduction to ammonium
ABSTRACT
A considerable fraction of freshwater zooplankton was recently found to consist of dead specimens that sink to the lake bottom. Such carcasses host intense microbial activities that may promote oxygen depletion at the microscale. Therefore, we tested the hypothesis that sinking zooplankton carcasses are microsites of anaerobic nitrogen cycling that contribute to pelagic fixed-nitrogen loss even in the presence of ambient oxygen. Incubation experiments were performed with the ubiquitous copepods Eudiaptomus sp. and Megacyclops gigas at different ambient oxygen levels that sinking carcasses encounter during their descent in stratified lakes. 15N-stable-isotope incubations revealed intense carcass-associated anaerobic nitrogen cycling only at low ambient oxygen levels (<25% air saturation). Dissimilatory nitrate reduction to ammonium (DNRA) dominated over denitrification and thus the potential for fixed-nitrogen loss was low. Consistent with this partitioning of anaerobic nitrogen cycling, the relative abundance of the carcass-associated marker gene for DNRA (nrfA) was ∼20–400 times higher than that for denitrification (nirS). Additionally, the relative nrfA and nirS abundances were ∼90–180 times higher on copepod carcasses than in lake water. This functional distinctiveness of carcass-associated bacterial communities was further substantiated by 16S rDNA-based fingerprinting. We conclude that the unique bacterial communities and microenvironments provided by zooplankton carcasses influence pelagic nitrogen cycling in lakes, but mainly at seasonally low ambient O2 levels in the bottom water.https://ift.tt/2ORBuzC
Bacterial community assemblages in the rhizosphere soil, root endosphere and cyst of soybean cyst nematode-suppressive soil challenged with nematodes
Abstract
In disease-suppressive soil, plants rely upon mutualistic associations between roots and specific microbes for nutrient acquisition and disease suppression. Notably, the transmission of suppressiveness by the cysts of sugar beet cyst nematode from suppressive to conducive soils has been previously observed in greenhouse trials. However, our current understanding of the bacterial assemblages in the cyst, root endosphere and rhizosphere soil is still limited. To obtain insights into these bacterial microbiota assemblages, the bacterial communities inhabiting the plant-associated microhabitats and cysts in soybean cyst nematode (SCN)-suppressive soil were characterized by deep sequencing, using soybean grown under growth room conditions with additional SCN challenge. Clustering analysis revealed that the cyst bacterial community was closer to the root endosphere community than to the rhizosphere and bulk soil communities. Interestingly, the cyst bacterial community was initially established by the consecutive selection of bacterial taxa from the soybean root endosphere. We found a set of potential microbial consortia, such as Pasteuria, Pseudomonas, Rhizobium, and other taxa, that were consistently enriched in the rhizocompartments under SCN challenge, and more abundant in the cysts than in the bulk soil. Our results suggest that the soybean root-associated and cyst microbiota may cause the suppressiveness of SCN in suppressive soil.https://ift.tt/2ASu0tm
Thiosulfate- and hydrogen-driven autotrophic denitrification by a microbial consortium enriched from groundwater of an oligotrophic limestone aquifer
ABSTRACT
Despite its potentially high relevance for nitrate removal in freshwater environments limited in organic carbon, chemolithoautotrophic denitrification has rarely been studied in oligotrophic groundwater. Using thiosulfate and H2 as electron donors, we established a chemolithoautotrophic enrichment culture from groundwater of a carbonate-rock aquifer to get more insight into the metabolic repertoire, substrate turnover, and transcriptional activity of subsurface denitrifying consortia. The enriched consortium was dominated by representatives of the genus Thiobacillus along with denitrifiers related to Sulfuritalea hydrogenivorans, Sulfuricella denitrificans, Dechloromonas sp. and Hydrogenophaga sp., representing the consortium's capacity to use multiple inorganic electron donors. Microcosm experiments coupled with Raman gas spectroscopy demonstrated complete denitrification driven by reduced sulfur compounds and hydrogen without formation of N2O. The initial nitrate/thiosulfate ratio had a strong effect on nosZ transcriptional activity and on N2 formation, suggesting similar patterns of the regulation of gene expression as in heterotrophic denitrifiers. Sequence analysis targeting nirS and nosZ transcripts identified Thiobacillus denitrificans-related organisms as the dominant active nirS-type denitrifiers in the consortium. An additional assessment of the nirS-type denitrifier community in the groundwaterclearly confirmed the potential for sulfur- and hydrogen-dependent chemolithoautotrophic denitrification as important metabolic feature widely spread among subsurface denitrifiers at the Hainich Critical Zone Exploratory.https://ift.tt/2vulHyN
Utilization of urea and cyanate in waters overlying and within the eastern tropical north Pacific oxygen deficient zone
Abstract
In marine oxygen deficient zones (ODZs), which contribute up to half of marine N loss, microbes use nitrogen (N) for assimilatory and dissimilatory processes. Here, we examine N utilization above and within the ODZ of the Eastern Tropical North Pacific Ocean, focusing on distribution, uptake and genes for the utilization of two simple organic N compounds, urea and cyanate. Ammonium, urea and cyanate concentrations generally peaked in the oxycline while uptake rates were highest in the surface. Within the ODZ, concentrations were lower, but urea N and C and cyanate C were taken up. All identified autotrophs had an N assimilation pathway that did not require external ammonium: ODZ Prochlorococcus possessed genes to assimilate nitrate, nitrite and urea; nitrite oxidizers (Nitrospina) possessed genes to assimilate nitrite, urea and cyanate; anammox bacteria (Scalindua) possessed genes to utilize cyanate; and ammonia-oxidizing Thaumarchaeota possessed genes to utilize urea. Urease genes were present in 20% of microbes, including SAR11, suggesting the urea utilization capacity was widespread. In the ODZ core, cyanate genes were largely (∼95%) associated with Scalindua, suggesting that, within this ODZ, cyanate N is primarily used for N loss via anammox (cyanammox), and that anammox does not require ammonium for N loss.https://ift.tt/2ASAdFN
Active bacterioplankton community response to dissolved ‘free’ deoxyribonucleic acid (dDNA) in surface coastal marine waters
ABSTRACT
Seawater contains dissolved 'free' DNA (dDNA) that is part of a larger <0.2 µm pool of DNA (D-DNA) including viruses and uncharacterised bound DNA. Previous studies have shown that bacterioplankton readily degrade dDNA, and culture-based approaches have identified several potential dDNA-utilising taxa. This study characterised the seasonal variation in D-DNA concentrations at Station L4, a coastal marine observatory in the Western English Channel, and linked changes in concentration to cognate physicochemical and biological factors. The impact of dDNA addition on active bacterioplankton communities at Station L4 was then determined using 16S rRNA high-throughput sequencing and RNA Stable Isotope Probing (RNA SIP) with 13C-labelled diatom-derived dDNA. Compared to other major bacterioplankton orders, the Rhodobacterales actively responded to dDNA additions in amended microcosms and RNA SIP identified two Rhodobacterales populations most closely associated with the genera Halocynthiibacter and Sulfitobacter that assimilated the 13C-labelled dDNA. Here we demonstrate that dDNA is a source of dissolved organic carbon for some members of the major bacterioplankton group the Marine Roseobacter Clade. This study enhances our understanding of roles of specific bacterioplankton taxa in dissolved organic matter cycling in coastal waters with potential implications for nitrogen and phosphorus regeneration processes.https://ift.tt/2ORBvna
The MRI Sepsis Score: An Innovative Tool for the Evaluation of Septic Peritonitis in Mice Using 7-Tesla Small Animal MRI
Background: Magnetic resonance imaging (MRI) techniques are rarely used in the context of abdominal sepsis and in sepsis research. This study investigates the impact of MRI for monitoring septic peritonitis in an animal model (colon ascendens stent-induced peritonitis, CASP). The CASP model closely mimics that of human disease and is highly standardized. The most frequently employed readout parameter in mouse CASP studies is prolonged or decreased rate of survival. Monitoring the progression of peritonitis via MRI could provide a helpful tool in the evaluation of severity. The use of alternative readout systems could very well reduce the number of research animals. Perspectively, clinical improvement after certain treatment could be classified. Methods: This study describes for the first time MRI findings following the induction of septic peritonitis in mice using the CASP model. Two sublethal groups of mice with septic peritonitis were investigated. Each had received one of two differing stent diameters in order to control the leakage of feces into the abdominal cavity. Each mouse served as its own control. Imaging and analyses were performed blinded. Gut diameters, stomach volume, abdominal organ wall diameters, and volume of the adrenal glands were measured. Serum corticosterone levels were detected using ELISA. Serum IL-6, TNF-α, IL-1β, and IL-10 levels were screened by cytometric bead array. Statistical analysis was performed using the Mann-Whitney U test for nonparametric probes and the Kruskal-Wallis and t tests. Results: Using a 7-tesla MRI scanner 24 and 48 h after induction of septic peritonitis, interenteric fluid, organ swelling of spleen and adrenal glands, as well as dilatation of the stomach were compared to nonseptic conditions. Swelling of adrenal glands resulted in an increased serum corticosterone level. In addition, the wall of the intestine bowel was thickened. Based upon these findings, an MRI score (MRI sepsis score, MSS) for abdominal sepsis in mice was established. Reduced stent sizes led to reduced severity of the abdominal sepsis, which could be reproduced in the MSS, which is described here for the first time. Conclusions: Intraabdominal variations during septic peritonitis are detectable by MRI techniques. MRI methods should become a more important tool for the evaluation of abdominal peritonitis. MSS could provide an interesting tool for the evaluation of therapeutic strategies.
Eur Surg Res 2018;59:126–142
https://ift.tt/2KBii68
Eur Surg Res 2018;59:126–142
https://ift.tt/2KBii68
Glycocalyx Degradation after Pulmonary Transplantation Surgery
Purpose: Ischaemia-reperfusion injury (IRI) is a main cause of morbidity after pulmonary resection surgery. The degradation of glycocalyx, a dynamic layer of macromolecules at the luminal surface of the endothelium, seems to participate in tissue dysfunction after IRI. Lidocaine has a proven anti-inflammatory activity in several tissues but its modulation of glycocalyx has not been investigated. This work aimed to investigate the potential involvement of glycocalyx in lung IRI in a lung auto-transplantation model and the possible effect of lidocaine in modulating IRI. Methods: Three groups (sham-operated, control, and lidocaine), each consisting of 6 Large White pigs, were subjected to lung auto-transplantation. All groups received the same anaesthesia. In addition, the lidocaine group received a continuous IV administration of lidocaine (1.5 mg/kg/h). Lung tissue and plasma samples were taken before pulmonary artery clamp, before reperfusion, and 30 and 60 min post-reperfusion in order to analyse pulmonary oedema, glycocalyx components, adhesion molecules, and myeloperoxidase level. Results: Ischaemia caused pulmonary oedema, which was greater after reperfusion. This effect was accompanied by decreased levels of syndecan-1 and heparan sulphate in the lung samples, together with increased levels of both glycocalyx components in the plasma samples. After reperfusion, neutrophil activation and the expression of adhesion molecules were increased. All these alterations were significantly lower or absent in the lidocaine group. Conclusion: Lung IRI caused glycocalyx degradation that contributed to neutrophil activation and adhesion. The administration of lidocaine was able to protect the lung from glycocalyx degradation.
Eur Surg Res 2018;59:115–125
https://ift.tt/2OTDess
Eur Surg Res 2018;59:115–125
https://ift.tt/2OTDess
Efficient SSA-mediated precise genome editing using CRISPR/Cas9.
Efficient SSA-mediated precise genome editing using CRISPR/Cas9.
FEBS J. 2018 Aug 07;:
Authors: Li X, Bai Y, Cheng X, Kalds PGT, Sun B, Wu Y, Lyu H, Xu K, Zhang Z
Abstract
CRISPR/Cas9 has been emerging as a main player in genome editing field since its advent. However, CRISPR/Cas9-induced precise gene editing remains challenging since it requires no scar left after editing. Among the few reports regarding two-step 'pop in & out' technologies for precise gene editing, the combination of CRISPR/Cas9 with Cre/LoxP demonstrates a higher efficiency, but leaves behind a 34 base pair of tag sequence due to its inherent property. Another method utilizes piggyBac transposon for removing the selection cassette, and its disadvantage is the difficulty in controlling its random reintegration after releasing. Here, we report a novel two-step precise gene editing method by leveraging the SSA-mediated repair mechanism into the CRISPR/Cas9 mediated gene editing system. An integrating cassette was developed with positive and negative selection markers, which was flanked by direct repeat sequences with desired mutations as SSA arms. After the targeted integration of the cassette mediated by CRISPR/Cas9-induced homologous-directed repair, cell clones were firstly selected through the positive selection. In the second round targeting, the selection cassette was removed by the SSA-mediated DNA double strand break (DSB) repair without any scar left behind. The novel seamless genome editing technique was tested on CCR5 and APP loci, and finally demonstrated respectively up to 45.83% and 68% of precise genome editing efficiency. This study provides a new efficient approach for precise genome editing and gene correction. This article is protected by copyright. All rights reserved.
PMID: 30085411 [PubMed - as supplied by publisher]
https://ift.tt/2MrYZ0E
Investigational CHK1 inhibitors in early stage clinical trials for acute myeloid leukemia.
Investigational CHK1 inhibitors in early stage clinical trials for acute myeloid leukemia.
Expert Opin Investig Drugs. 2018 Aug 07;:1-6
Authors: Chamoun K, Borthakur G
Abstract
INTRODUCTION: Acute myeloid leukemia (AML) is the most common myeloid malignancy in adults. Despite recent discoveries of targeted therapies, the frontline therapy consisting of chemotherapy remains unchanged for the past four decades. Like other cancers, AML is characterized by deranged DNA damage repair (DDR) pathway. Although impaired DDR may contribute to the pathogenesis of AML it also allows leukemia cells with damaged DNA to attempt repair resulting in resistance. CHK1 inhibitors reverse the cell cycle arrest, disallowing the cell to repair the chemotherapy-induced DNA damage, driving the cell to enter into mitotic catastrophe. Areas covered: This paper reviews the preclinical and clinical development of CHK1 inhibitors and we discussed their promising role as a potential addition to the therapeutic arsenal of AML. Expert opinion: Targeting the cell cycle checkpoints is an intriguing approach to treat cancer in general and AML in particular. CHK1 inhibitors in combination with chemotherapy have the potential of improving outcome in high-risk AML characterized by DDR activation.
PMID: 30084282 [PubMed - as supplied by publisher]
https://ift.tt/2MbgG7O
Influences of nanocarrier morphology on therapeutic immunomodulation.
Influences of nanocarrier morphology on therapeutic immunomodulation.
Nanomedicine (Lond). 2018 Aug 07;:
Authors: Frey M, Bobbala S, Karabin N, Scott E
Abstract
Nanomaterials provide numerous advantages for the administration of therapeutics, particularly as carriers of immunomodulatory agents targeting specific immune cell populations during immunotherapy. While the physicochemical characteristics of nanocarriers have long been linked to their therapeutic efficacy and applications, focus has primarily been placed on assessing influences of size and surface chemistry. In addition to these materials properties, the nanostructure morphology, in other words, shape and aspect ratio, has emerged as an equally important feature of nanocarriers that can dictate mechanisms of endocytosis, biodistribution and degree of cytotoxicity. In this review, we will highlight how the morphological features of nanostructures influence the immune responses elicited during therapeutic immunomodulation.
PMID: 30084296 [PubMed - as supplied by publisher]
https://ift.tt/2MhhDM9
Complementary vaccination protocol with dendritic cells pulsed with autologous tumour lysate in patients with resected stage III or IV melanoma: protocol for a phase II randomised trial (ACDC Adjuvant Trial).
| Related Articles |
Complementary vaccination protocol with dendritic cells pulsed with autologous tumour lysate in patients with resected stage III or IV melanoma: protocol for a phase II randomised trial (ACDC Adjuvant Trial).
BMJ Open. 2018 Aug 05;8(8):e021701
Authors: Ridolfi L, de Rosa F, Fiammenghi L, Petrini M, Granato AM, Ancarani V, Pancisi E, Soldati V, Cassan S, Bulgarelli J, Riccobon A, Gentili G, Nanni O, Framarini M, Tauceri F, Guidoboni M
Abstract
INTRODUCTION: Surgery is one of the treatments of choice for patients with a single metastasis from melanoma but is rarely curative. Such patients could potentially benefit from consolidation immunotherapy. Vaccination with dendritic cells (DCs) loaded with tumour antigens elicits a tumour-specific immune response. In our experience, patients who developed delayed type hypersensitivity (DTH) after DC vaccination showed a median overall survival (OS) of 22.9 monthsvs4.8 months for DTH-negative cases. A phase II randomised trial showed an advantage OS of a DC vaccine over a tumour cell-based vaccine (2-year OS 72% vs31%, respectively). Given that there is no standard therapy after surgical resection of single metastases, we planned a study to compare vaccination with DCs pulsed with autologous tumour lysate versus follow-up.
METHODS AND ANALYSIS: This is a randomised phase II trial in patients with resected stage III/IV melanoma. Assuming a median relapse-free survival (RFS) of 7.0 months for the standard group and 11.7 months for the experimental arm (HR 0.60), with a two-sided tailed alpha of 0.10, 60 patients per arm must be recruited. An interim futility analysis will be performed at 18 months. The DC vaccine, produced in accordance with Good Manufacturing Practice guidelines, consists of autologous DCs loaded with autologous tumour lysate and injected intradermally near lymph nodes. Vaccine doses will be administered every 4 weeks for six vaccinations and will be followed by 3 million unit /day of interleukin-2 for 5 days. Tumour restaging, blood sampling for immunological biomarkers and DTH testing will be performed every 12 weeks.
ETHICS AND DISSEMINATION: The protocol, informed consent and accompanying material given to patients were submitted by the investigator to the Ethics Committee for review. The local Ethics Committee and the Italian Medicines Agency approved the protocol (EudraCT code no.2014-005123-27). Results will be published in a peer-reviewed international scientific journal.
TRIAL REGISTRATION NUMBER: 2014-005123-27.
PMID: 30082356 [PubMed - in process]
https://ift.tt/2ONsmvY
Epilepsyecosystem.org: crowd-sourcing reproducible seizure prediction with long-term human intracranial EEG
Abstract
Accurate seizure prediction will transform epilepsy management by offering warnings to patients or triggering interventions. However, state-of-the-art algorithm design relies on accessing adequate long-term data. Crowd-sourcing ecosystems leverage quality data to enable cost-effective, rapid development of predictive algorithms. A crowd-sourcing ecosystem for seizure prediction is presented involving an international competition, a follow-up held-out data evaluation, and an online platform, Epilepsyecosystem.org, for yielding further improvements in prediction performance. Crowd-sourced algorithms were obtained via the 'Melbourne-University AES-MathWorks-NIH Seizure Prediction Challenge' conducted at kaggle.com. Long-term continuous intracranial electroencephalography (iEEG) data (442 days of recordings and 211 lead seizures per patient) from prediction-resistant patients who had the lowest seizure prediction performances from the NeuroVista Seizure Advisory System clinical trial were analysed. Contestants (646 individuals in 478 teams) from around the world developed algorithms to distinguish between 10-min inter-seizure versus pre-seizure data clips. Over 10 000 algorithms were submitted. The top algorithms as determined by using the contest data were evaluated on a much larger held-out dataset. The data and top algorithms are available online for further investigation and development. The top performing contest entry scored 0.81 area under the classification curve. The performance reduced by only 6.7% on held-out data. Many other teams also showed high prediction reproducibility. Pseudo-prospective evaluation demonstrated that many algorithms, when used alone or weighted by circadian information, performed better than the benchmarks, including an average increase in sensitivity of 1.9 times the original clinical trial sensitivity for matched time in warning. These results indicate that clinically-relevant seizure prediction is possible in a wider range of patients than previously thought possible. Moreover, different algorithms performed best for different patients, supporting the use of patient-specific algorithms and long-term monitoring. The crowd-sourcing ecosystem for seizure prediction will enable further worldwide community study of the data to yield greater improvements in prediction performance by way of competition, collaboration and synergism.10.1093/brain/awy210_video1awy210media15817489051001https://ift.tt/2ATixtH
Cancers, Vol. 10, Pages 263: Real-World Implications of Nonbiological Factors with Staging, Prognosis and Clinical Management in Colon Cancer
Cancers, Vol. 10, Pages 263: Real-World Implications of Nonbiological Factors with Staging, Prognosis and Clinical Management in Colon Cancer
Cancers doi: 10.3390/cancers10080263
Authors: Qi Liu Dakui Luo Sanjun Cai Qingguo Li Xinxiang Li
Background: The present study analyzed the nonbiological factors (NBFs) together with the American Joint Committee on Cancer (AJCC) Tumor-Node-Metastasis (TNM) staging system to generate a refined, risk-adapted stage for the clinical treatment of colon cancer. Methods: Eligible patients (N = 28,818) with colon cancer between 1 January 2010 and 31 December 2014, were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier curves and Cox proportional hazards regression, analyzed the probabilities of cancer-specific survival (CSS) in patients with colon cancer, with different NBF-TNM stages. Results: Insurance status, marital status, and median household income were significant prognostic NBFs in the current study (p < 0.05). The concordance index of NBF-TNM stage was 0.857 (95% confidence interval (CI) = 0.8472–0.8668). Multivariate Cox analyses, indicated that NBF1-stage was independently associated with a 50.4% increased risk of cancer-specific mortality in colon cancer (p < 0.001), which increased to 77.1% in non-metastatic colon cancer. NBF0-stage improved in CSS as compared to the NBF1-stage in the respective stages (p < 0.05). Conclusions: The new proposed NBF-stage was an independent prognostic factor in colon cancer. Effect of NBFs on the survival of colon cancer necessitates further clinical attention. Moreover, the incorporation of NBF-stage into the AJCC TNM staging system is essential for prognostic prediction, and clinical guidance of adjuvant chemotherapy in stage II and III colon cancer.
https://ift.tt/2nmkYvb
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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...
