Correction

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Corrections

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Errors in published papers are multifactorial

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How to describe your data – the devil is in the distribution

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Are aviation industry fatigue risk management strategies needed in healthcare?

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EWTD implementation in anaesthesia: effects on training and quality of life

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Iliac artery balloon catheter use in abnormally invasive placental disease management

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Are aviation industry fatigue risk management strategies needed in healthcare? A reply

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Curtailing fabrication in medical literature

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Apnoeic oxygenation with high-flow nasal oxygen for laryngeal surgery: a case series

Summary

Surgery under apnoeic conditions with the use of high-flow nasal oxygen is novel. Between November 2016 and May 2017, 28 patients underwent tubeless laryngeal or tracheal surgery under apnoeic conditions with high-flow nasal oxygen as the sole method of gas exchange. Patients received total intravenous anaesthesia and neuromuscular blocking agents for the duration of their surgery. The median (IQR [range]) apnoea time was 19 (15–24 [9–37]) min. Four patients experienced an episode of oxygen desaturation to a value between 85% and 90%, lasting less than 2 min in each case. Median (IQR [range]) end-tidal carbon dioxide (ETCO₂) level following apnoea was 8.2 (7.2–9.4 [5.8–11.8]) kPa. The mean (SD) rate of ETCO₂ increase was 0.17 (0.07) kPa.min⁻¹ from an approximated baseline value of 5.00 kPa. Venous blood sampling from 19 patients demonstrated a mean (SD) partial pressure of carbon dioxide (P_VCO₂) of 6.29 (0.71) kPa at baseline and 9.44 (1.12) kPa after 15 min of apnoea. This equates to a mean (SD) P_VCO₂ rise of 0.21 (0.08) kPa.min⁻¹ during this period. Mean (SD) pH was 7.40 (0.03) at baseline and 7.23 (0.04) after 15 min of apnoea. Mean (SD) standard bicarbonate was 26.7 (1.8) mmol.l⁻¹ at baseline and 25.4 (1.8) mmol.l⁻¹ at 15 min. We conclude that high-flow nasal oxygen under apnoeic conditions can provide satisfactory gas exchange in order to allow tubeless anaesthesia for laryngeal surgery.

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Suxamethonium or rocuronium for rapid sequence induction of anaesthesia?

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Iliac artery balloon catheter use in abnormally invasive placenta disease management – a reply

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Suxamethonium or rocuronium for rapid sequence induction of anaesthesia? A reply

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The use of activated charcoal filters in anaesthetic circuits in suspected malignant hyperthermia

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Issue Information – Editorial Board

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Improving TIVA safety through measurement of peripheral venous pressure

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When traditional research fails – the case for veno-arterial ECMO in postcardiotomy cardiogenic shock

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Onset of labour epidural analgesia with low-dose bupivacaine and different doses of fentanyl

Summary

This study investigated the effects of different doses of epidural fentanyl on the time to onset of epidural analgesia in women in early labour. We hypothesised that onset of epidural labour analgesia (the primary outcome defined as time in minutes from completion of epidural bolus to the first uterine contraction with a numeric pain rating scale [NPRS] score ≤ 3) would be faster with 100 μg of fentanyl epidural bolus compared with 20 μg or 50 μg. Epidural labour analgesia was initiated with 20 μg of fentanyl (F20 group), 50 μg (F50 group) or 100 μg (F100 group) along with 10 ml bupivacaine 0.08% as the loading dose. We randomly allocated 105 patients, with 35 patients in each group. Median (IQR [range]) time to achieve NPRS ≤ 3 was 18 (11–30 [6–20]) min in F20, 10 (8–19 [4–30]) min in F50 and 10 (6–16 [3–30]) min in F100 groups. There was a significant difference in onset times comparing F100 with F20 (p < 0.001) and F50 with F20 (p = 0.007), but not significantly different comparing F100 with F50 (p = 0.19). The median (IQR [range]) time from the epidural loading dose to first patient controlled epidural analgesia bolus was 61 min (20–165 [20–420]) in F20, 118 min (66–176 [20–396]) in F50 and 150 min (66–214 [30-764]) in F100 groups. This was not statistically significant (p = 0.16) comparing the F20 with the F100 group. There were no significant differences in maternal side-effects, mode of delivery, patient satisfaction scores or neonatal Apgar scores between all groups. We conclude that the 50 μg and 100 μg fentanyl doses were associated with reduced onset times to effective analgesia compared with the 20 μg dose.

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Cohesive properties of the caulobacter crescentus holdfast adhesin are regulated by a novel c-di-GMP effector protein

Many bacteria grow in aquatic environments such as oceans, lakes and rivers. These environments pose special challenges, as nutrient availability is poor and hard to exploit due to constant water flow. Therefore, most bacteria grow on surfaces and have developed mechanisms that anchor them on an adequate nutrient source in the moment of encounter. Yet, they need to effectively disperse when conditions become unfavorable. The switch between motile and sessile lifestyles is controlled by the global second messenger c-di-GMP, which suppresses motility and promotes sessility. Here, we use the aquatic bacterium Caulobacter crescentus as a model to dissect c-di-GMP mediated lifestyle changes and surface attachment. C. crescentus has a biphasic life cycle that comprises both a motile and a sessile phase. A motile swarmer cell can develop into a sessile surface attached stalked cell by expressing a polar exopolysaccharide-based structure called the holdfast that shows remarkably strong adhesive properties. Recent studies have shown that holdfast biogenesis requires c-di-GMP and is initiated either upon surface contact or as part of the developmental program. However, the underlying molecular mechanisms are not understood. In an unbiased screen for c-di-GMP binding proteins in C. crescentus we identified a novel c-di-GMP effector of unknown function and confirmed specific binding to c-di-GMP in vitro. Orthologous genes of this effector were found in different phyla and showed a strong association with exopolysaccharide synthesis genes. Its importance in holdfast biogenesis could be experimentally confirmed and the protein was named HfsK following the terminology used for holdfast synthesis proteins. Cells deficient in HfsK produced holdfast but could not retain the adhesin on the cell envelope, resulting in a strong surface adhesion defect and failure in surface colonization. Furthermore, a strong deformation of the mutant holdfast was observed when it was subject to shear stress, indicating a decrease in holdfast cohesion forces. HfsK is a member of an uncharacterized subclass of Gcn5-related-N-acetyltransferases, a diverse enzyme family that could potentially acylate the holdfast exopolysaccharide. Mutations in genes encoding holdfast anchor proteins that are predicted to form membrane-anchored filaments exhibited a similar phenotype. Based on our findings we propose a model in which the anchor filaments and the holdfast form a strong interaction network that relies on HfsK-mediated chemical modification of the holdfast exopolysaccharide. In accordance with its proposed function in holdfast biogenesis, HfsK predominately localized to the cell membrane. The protein delocalized into the cytosol for a short period during the cell cycle, coinciding with holdfast biogenesis and with an upshift of cellular c-di-GMP levels. HfsK mutants impaired in c-di-GMP binding remained membrane associated throughout the cell cycle indicating that c-di-GMP binding controls the localization of this protein. A role in HfsK control could be attributed to a short stretch of amino acids at the C-terminus. This part of the protein is involved in c-di-GMP binding and is required for HfsK localization and activity. Functional analysis revealed a clear correlation between HfsK activity and subcellular localization. HfsK mutants that remained membrane-associated were mostly found to be active, while variants exclusively localizing to the cytosol failed to support proper holdfast formation. We propose that c-di-GMP binding to the C-terminus of HfsK leads to its delocalization and concomitant inactivation. Finally, we show that overexpression of the glycosyltransferase HfsJ restored holdfast biogenesis in a strain lacking c-di-GMP. This exposed HfsJ as catalyst of the rate-limiting step of holdfast biogenesis when c-di-GMP levels are low. Together with recent findings that HfsJ directly binds c-di-GMP this suggested furthermore that HfsJ is the main effector through which holdfast synthesis is activated upon a cellular upshift of c-di-GMP. This work establishes two pathways through which c-di-GMP can activate and possibly modulate the holdfast adhesin of C. crescentus and provides novel insight into the basis of the holdfast strong adhesive properties.

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Dental firm claimed A 300,000 for treatments never given to patients

Bringing you the best journalism, comment and analysis in Scotland, wherever and whenever you need it, in any format. Faster AD-LIGHT subscriptions now available too.

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Chronic curcumin treatment improves spatial working memory but not recognition memory in middle-aged rhesus monkeys

Abstract

Studies of both humans and non-human primates have demonstrated that aging is typically characterized by a decline in cognition that can occur as early as the fifth decade of life. Age-related changes in working memory are particularly evident and mediated, in part, by the prefrontal cortex, an area known to evidence age-related changes in myelin that is attributed to inflammation. In recent years, several nutraceuticals, including curcumin, by virtue of their anti-inflammatory and antioxidant effects, have received considerable attention as potential treatments for age-related cognitive decline and inflammation. Accordingly, we assessed for the first time in a non-human primate model of normal aging the efficacy of dietary intervention using the natural phenol curcumin to ameliorate the effects of aging on spatial working and recognition memory. Results revealed that monkeys receiving daily administration of curcumin over 14–18 months demonstrated a greater improvement in performance on repeated administration of a task of spatial working memory compared to monkeys that received a control substance.

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Congenital pulmonary airway malformations: state-of-the-art review for pediatrician’s use

Abstract

Congenital pulmonary airway malformations or CPAM are rare developmental lung malformations, leading to cystic and/or adenomatous pulmonary areas. Nowadays, CPAM are diagnosed prenatally, improving the prenatal and immediate postnatal care and ultimately the knowledge on CPAM pathophysiology. CPAM natural evolution can lead to infections or malignancies, whose exact prevalence is still difficult to assess. The aim of this "state-of-the-art" review is to cover the recently published literature on CPAM management whether the pulmonary lesion was detected during pregnancy or after birth, the current indications of surgery or surveillance and finally its potential evolution to pleuro-pulmonary blastoma.

Conclusion: Surgery remains the cornerstone treatment of symptomatic lesions but the postnatal management of asymptomatic CPAM remains controversial. There are pros and cons of surgical resection, as increasing rate of infections over time renders the surgery more difficult after months or years of evolution, as well as risk of malignancy, though exact incidence is still unknown.

What is known:

• Congenital pulmonary airway malformations (CPAM) are rare developmental lung malformations mainly antenatally diagnosed. • While the neonatal management of symptomatic CPAM is clear and includes prompt surgery, controversies remain for asymptomatic CPAM due to risk of infections and malignancies.

What is new:

• Increased rate of infection over time renders the surgery more difficult after months or years of evolution and pushes for recommendation of early elective surgery. • New molecular or pathological pathways may help in the distinction of type 4 CPAM from type I pleuropulmonary blastoma.

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Improving the rates of electronic results acknowledgement at a tertiary eye care centre

Background

Hundreds of thousands of tests are performed annually in hospitals worldwide. Safety Issues arise when abnormal results are not recognized promptly resulting in delayed treatment and increased morbidity and mortality. As a result Singapore's largest healthcare group, Singhealth introduced an electronic result acknowledgement system. This system was adopted by the Singapore National Eye Centre (SNEC) in February 2016. Baseline measurements show that weekly numbers of unacknowledged results ranged from 193 to 617. The current standards of electronic results acknowledgement posts a significant patient safety hazard.

Methods

Root cause analysis was performed to identify contributory factors. Pareto principle was then used by the authors to identify the main contributory factors. We employed the rapid cycle improvement Plan-do-study-act (PDSA) strategy to test and evaluate implemented changes. Changes are implemented for 2 weeks and data collected prospectively. The data is analyzed the week after and the following PDSA actions are decided and instituted the following week. 3 PDSA cycles were undertaken in total.

Results

The first PDSA cycle focused on raising awareness of the problem at hand, the number of unacknowledged results drastically decreased during the 1^stweek of implementation of our PDSA from 617 to 254.The second PDSA cycle targeted the lack of knowledge of doctors involved in the electronic result acknowledgement process. There was a trend downwards near the end of the cycle which continued through the week after.The third PDSA cycle targeted individual doctors and provided individual remedial training. Second line doctors were also equipped to better handle abnormal results. There was significant improvement with the number of unacknowledged abnormal results dropping to <5 a week.

Conclusions

Multiple factors were identified to contribute to the low compliance to electronic acknowledgement of results. The role doctors play in the issue at hand was paramount and required careful handling in a professional manner with multiple reminders and emphasis on the importance of acknowledging and acting on the results.A significant improvement in the rates of acknowledgement of abnormal results was demonstrated with clear benefits to patient safety. Interventions can be replicated when implementing similar systems to other areas of healthcare.

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Improving a process to obtain hepatitis B serology among patients treated with infliximab at a large urban childrens hospital

Background

Hepatitis B infection is a significant public health challenge despite improvements in vaccination efforts. Patients such as those on chronic immunosuppressive therapy for inflammatory bowel disease (IBD) or rheumatic disease may incur greater risk. The risk of reactivation of hepatitis B while on immunosuppressive therapy may have mortality rates up to 25%. These patients should be screened for acute or chronic infection and vaccinated if necessary. Our aim was to reliably complete hepatitis B screenings in patients receiving infliximab at Cincinnati Children's Hospital Medical Center (CCHMC).

Methods

Eligible patients included all patients with gastroenterology (GI) IBD and rheumatology receiving infliximab between October 2015 and March 2016. Using quality improvement methodology and the 'plan–do–study–act' (PDSA) approach, interventions centred around education of clinical providers, previsit planning and the development of 'talking points' for patients.

Results

An initial screen of the IBD population revealed that 48% of the IBD patient population had been screened for anti-HBs alone, but no patients from GI or rheumatology divisions had a complete set of hepatitis B serology prior to the intervention including anti-Hep B Core and Hep B Surface Antigen. Seven PDSA cycles were performed during the 32-week intervention period, resulting in an increase in patients screened from 0% to ~85%. By March 2016, a total of 251 patients (201 GI, 50 rheumatology) had up-to-date hepatitis B serology screening. Automated ordering of the hepatitis B serology and 'talking points' for the provider had the greatest impact on successful screening.

Conclusions

We developed a method to obtain hepatitis B serology on at-risk patients on infliximab within two subspecialty divisions within a large children's hospital. Next steps will be to develop a process to reliably provide vaccines for patients who are seronegative, expand this process to all patients who are identified as immunocompromised within GI and rheumatology and then expand this process to other divisions at the CCHMC.

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Novel Sarcopenia-related Alterations in Sarcomeric Protein Post-translational Modifications in Skeletal Muscles Identified by Top-down Proteomics [Research]

Sarcopenia, the age-related loss of skeletal muscle mass and strength, is a significant cause of morbidity in the elderly and is a major burden on health care systems. Unfortunately, the underlying molecular mechanisms in sarcopenia remain poorly understood. Herein, we utilized top-down proteomics to elucidate sarcopenia-related changes in the fast- and slow-twitch skeletal muscles of aging rats with a focus on the sarcomeric proteome, which includes both myofilament and Z-disc proteins—the proteins that constitute the contractile apparatuses. Top-down quantitative proteomics identified significant changes in the post-translational modifications (PTMs) of critical myofilament proteins in the fast-twitch skeletal muscles of aging rats, in accordance with the vulnerability of fast-twitch muscles to sarcopenia. Surprisingly, age-related alterations in the phosphorylation of Cypher isoforms, proteins that localize to the Z-discs in striated muscles, were also noted in the fast-twitch skeletal muscle of aging rats. This represents the first report of changes in the phosphorylation of Z-disc proteins in skeletal muscle during aging. In addition, increased glutathionylation of slow skeletal troponin I, a novel modification that may help protect against oxidative damage, was observed in slow-twitch skeletal muscles. Furthermore, we have identified and characterized novel muscle type-specific proteoforms of myofilament proteins and Z-disc proteins, including a novel isoform of the Z-disc protein Enigma. The finding that the phosphorylation of Z-disc proteins is altered in response to aging in the fast-twitch skeletal muscles of aging rats opens new avenues for the investigation of the role of Z-discs in age-related muscle dysfunction.

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The antibody repertoire of colorectal cancer [Research]

Immunotherapy is becoming increasingly important in the fight against cancers, utilizing and manipulating the body's immune response to treat tumors. Understanding the immune repertoire – the collection of immunological proteins – of treated and untreated cells is possible at the genomic, but technically difficult at the protein level. Standard protein databases do not include the highly divergent sequences of somatic rearranged immunoglobulin genes, and may lead to missed identifications in a mass spectrometry search. We introduce a novel proteogenomic approach, AbScan, to identify these highly variable antibody peptides, by developing a customized antibody database construction method using RNA-seq reads aligned to immunoglobulin (Ig) genes.<br />AbScan starts by filtering transcript (RNA-seq) reads that match the template for Ig genes. The retained reads are used to construct a repertoire graph using the 'split' de Bruijn graph: a graph structure that improves upon the standard de Bruijn graph to capture the high diversity of Ig genes in a compact manner. AbScan corrects for sequencing errors, and converts the graph to a format suitable for searching with MS/MS search tools. We used AbScan to create an antibody database from 90 RNA-seq colorectal tumor samples. Next, we used proteogenomics analysis to search MS/MS spectra of matched colorectal samples from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) against the AbScan generated database. AbScan identified 1, 940 distinct antibody peptides. Correlating with previously identified Single Amino-Acid Variants (SAAVs) in the tumor samples, we identified 163 pairs (antibody peptide, SAAV) with significant co-occurrence pattern in the 90 samples. The presence of co-expressed antibody and mutated peptides was correlated with survival time of the individuals. Our results suggest that Ab-Scan (http://ift.tt/2wNIsg7) is an effective tool for a proteomic exploration of the immune response in cancers.

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The early dendritic cell signaling induced by virulent Francisella tularensis strain occurs in phases and involves the activation of ERKs and p38 in the later stage. [Research]

Dendritic cells (DCs) infected by Francisella tularensis are poorly activated and do not undergo classical maturation process. While reasons of such unresponsiveness are not fully understood, their impact on the priming of immunity is well appreciated. Previous attempts to explain the behavior of Francisella-infected DCs were hypothesis-driven and focused on events at later stages of infection. Here, we took an alternative unbiased approach by applying methods of global phosphoproteomics to analyze the dynamics of cell signaling in primary DCs during the first hour of infection by Francisella tularensis. Presented results show that the early response of DCs to Francisella occurs in phases and that ERK and p38 signaling modules induced at the later stage are differentially regulated by virulent and attenuated dsbA strain. These findings imply that the temporal orchestration of host pro-inflammatory pathways represents the integral part of Francisella life-cycle inside hijacked DCs.

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Involving Members of the Public in Health Economics Research: Insights from Selecting Health States for Valuation to Estimate Quality-Adjusted Life-Year (QALY) Weights

Abstract

Over recent years, public involvement in health research has expanded considerably. However, public involvement in designing and conducting health economics research is seldom reported. Here we describe the development, delivery and assessment of an approach for involving people in a clearly defined piece of health economics research: selecting health states for valuation in estimating quality-adjusted life-years (QALYs). This involvement formed part of a study to develop a condition-specific preference-based measure of health-related quality of life, the Multiple Sclerosis Impact Scale (MSIS-8D), and the work reported here relates to the identification of plausible, or realistic, health states for valuation. An Expert Panel of three people with multiple sclerosis (MS) was recruited from a local involvement network, and two health economists designed an interactive task that enabled the Panel to identify health states that were implausible, or unlikely to be experienced. Following some initial confusion over terminology, which was resolved by discussion with the Panel, the task worked well and can be adapted to select health states for valuation in the development of any preference-based measure. As part of the involvement process, five themes were identified by the Panel members and the researchers which summarised our experiences of public involvement in this health economics research example: proportionality, task design, prior involvement, protectiveness and partnerships. These are described in the paper, along with their practical implications for involving members of the public in health economics research. Our experience demonstrates how members of the public and health economists can work together to improve the validity of health economics research.

Plain Language Summary It has become commonplace to involve members of the public in health service research. However, published reports of involving people in designing health economics research are rare. We describe how we designed a way of involving people in a particular piece of health economics research.

The aim of the work was to produce descriptions of different states of health experienced by people with multiple sclerosis (MS). These descriptions have since been rated in terms of how good or bad they are in a way that can be used by the National Institute for Health and Care Excellence (NICE) to make decisions about what services to fund on the NHS.

We formed a panel of three people with MS, and designed a task to help the group produce health descriptions likely to be experienced by people with MS. After discussion about jargon, and working together to find more layman's terms, the task worked well, and can be adapted to produce health descriptions for any condition.

We identified some key themes about working together that give insights into how members of the public can be involved in health economics research, and show the importance of their involvement in improving the relevance of this research.

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Do We Need Consent Forms for Everything?

This quick article was inspired by a thread in a dental group (called "The Dental Place") on Facebook.  Some dentists reported that they have a consent form signed for EVERY procedure they do.  For every patient, every time (even repeat … Continue reading →

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Ral signaling pathway in health and cancer

Abstract

The Ral (Ras-Like) signaling pathway plays an important role in the biology of cells. A plethora of effects is regulated by this signaling pathway and its prooncogenic effectors. Our team has demonstrated the overactivation of the RalA signaling pathway in a number of human malignancies including cancers of the liver, ovary, lung, brain, and malignant peripheral nerve sheath tumors. Additionally, we have shown that the activation of RalA in cancer stem cells is higher in comparison with differentiated cancer cells. In this article, we review the role of Ral signaling in health and disease with a focus on the role of this multifunctional protein in the generation of therapies for cancer. An improved understanding of this pathway can lead to development of a novel class of anticancer therapies that functions on the basis of intervention with RalA or its downstream effectors.

Ral signaling pathway as an important effector pathway downstream of Ras plays an important role in health and diseases.

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A comprehensive genome-wide analysis of long noncoding RNA expression profile in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, especially in East Asia and China. Long noncoding RNAs (lncRNAs) are emerging as critical regulators that may be involved in the development and progression of cancers in humans. However, the contributions of lncRNAs to HCC development, metastasis, and recurrence remain largely unknown. In this study, we comprehensively investigated lncRNA expression profile in HCC and normal tissues using TCGA RNA sequencing data, one RNA sequencing dataset, and two microarray datasets from GEO. By analyzing these four datasets, we identified hundreds of expression-dysregulated lncRNAs in HCC tissues compared with normal tissues. Genomic copy number variation analysis showed that many of those lncRNAs disorder are related to the copy number amplification or deletion. Moreover, several lncRNAs expression levels are associated with HCC patients' overall and recurrence-free survival, such as RP1-228H13.5, TMCC1-AS1, LINC00205, and RP11-307C12.11. Furthermore, we identified two lncRNAs termed PVT1 and SNHG7 that may be involved in HCC cells metastasis by comparing lncRNAs expression profiles between early recurrence HCC tissues with metastasis and late recurrence HCC tissues without metastasis. Finally, loss-of-function assays confirmed that knockdown of SNHG7 and PVT1 impaired HCC cells invasion. Taken together, these findings may provide a valuable resource for further identification of novel biomarkers and therapeutic targets for HCC patients.

lncRNAs are emerging as critical regulators that are involved in the development and progression of cancers in humans. We comprehensively investigated lncRNA expression profiling in HCC and normal tissues; these findings may provide a valuable resource to further identify novel biomarkers and therapeutic targets of HCC.

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Macroglossia During Awake Craniotomy: A Near Miss.

No abstract available

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Effects of probiotics on body weight, body mass index, fat mass and fat percentage in subjects with overweight or obesity: a systematic review and meta-analysis of randomized controlled trials

Summary

A systematic review and meta-analysis of randomized controlled trials was conducted to examine the effects of probiotic supplementation on body weight, body mass index (BMI), fat mass and fat percentage in subjects with overweight (BMI 25–29.9 kg m⁻²) or obesity (BMI ≥30 kg m⁻²). MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched for studies published between 1946 and September 2016. A meta-analysis, using a random effects model, was performed to calculate the weighted mean difference between the intervention and control groups. Of 800 studies identified through the literature search, 15 were finally included. The studies comprised a total of 957 subjects (63% women), with the mean BMI being 27.6 kg m⁻² and the duration of the interventions ranging from 3 to 12 weeks. Administration of probiotics resulted in a significantly larger reduction in body weight (weighted mean difference [95% confidence interval]; −0.60 [−1.19, −0.01] kg, I² = 49%), BMI (−0.27 [−0.45, −0.08] kg m⁻², I² = 57%) and fat percentage (−0.60 [−1.20, −0.01] %, I² = 19%), compared with placebo; however, the effect sizes were small. The effect of probiotics on fat mass was non-significant (−0.42 [−1.08, 0.23] kg, I² = 84%).

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Esophageal lesions following button-battery ingestion in children: Analysis of causes and proposals for preventive measures

Publication date: Available online 18 October 2017
Source:European Annals of Otorhinolaryngology, Head and Neck Diseases
Author(s): J. Lahmar, C. Célérier, E.N. Garabédian, V. Couloigner, N. Leboulanger, F. Denoyelle
ObjectivesTo study recent cases of esophageal injury due to button-battery ingestion in children presenting in pediatric ENT emergency departments of the Paris area of France (Île-de-France region), in order to propose appropriate preventive measures.Material and methodA retrospective descriptive single-center study included all children under 15 years of age, presenting in pediatric ENT emergency departments between January 2008 and April 2014 for button-battery ingestion with esophageal impaction requiring emergency removal.ResultsTwenty-two boys and 4 girls, with a median age of 25 months, were included. Twenty-five of the 26 batteries had diameters of 20mm or more. Median esophageal impaction time was 7 hours 30 minutes (range, 2 to 72 hours). The complications rate was 23%. Mean hospital stay cost was €38,751 (range, €5130–119,737). The origin of the battery was known in 23 of the 26 cases: remote control without screw-secured compartment (42.3%), open battery pack (15.4%), children's toy (15.3%), camera (7.7%), watch (1 case) and hearing aid without screw-secured compartment (1 case).ConclusionEsophageal lesions due to ingestion of button-batteries in children are almost always due to batteries larger than 20mm in diameter, mostly from devices with a poorly protected compartment, or batteries that are not individually packaged. These lesions cause serious complications in a quarter of cases and their management entails high health costs. Legislation requiring screw-secured compartments and individual blisters for batteries could have prevented 69.2% of the ingestions.



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Hormones and Migraine: A Case Study

Headaches that occur several days before menses as well as disabling headaches on days unrelated to menses... how would you help this young woman? (Source: CancerNetwork)

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Esophageal lesions following button-battery ingestion in children: Analysis of causes and proposals for preventive measures

Publication date: Available online 18 October 2017
Source:European Annals of Otorhinolaryngology, Head and Neck Diseases
Author(s): J. Lahmar, C. Célérier, E.N. Garabédian, V. Couloigner, N. Leboulanger, F. Denoyelle
ObjectivesTo study recent cases of esophageal injury due to button-battery ingestion in children presenting in pediatric ENT emergency departments of the Paris area of France (Île-de-France region), in order to propose appropriate preventive measures.Material and methodA retrospective descriptive single-center study included all children under 15 years of age, presenting in pediatric ENT emergency departments between January 2008 and April 2014 for button-battery ingestion with esophageal impaction requiring emergency removal.ResultsTwenty-two boys and 4 girls, with a median age of 25 months, were included. Twenty-five of the 26 batteries had diameters of 20mm or more. Median esophageal impaction time was 7 hours 30 minutes (range, 2 to 72 hours). The complications rate was 23%. Mean hospital stay cost was €38,751 (range, €5130–119,737). The origin of the battery was known in 23 of the 26 cases: remote control without screw-secured compartment (42.3%), open battery pack (15.4%), children's toy (15.3%), camera (7.7%), watch (1 case) and hearing aid without screw-secured compartment (1 case).ConclusionEsophageal lesions due to ingestion of button-batteries in children are almost always due to batteries larger than 20mm in diameter, mostly from devices with a poorly protected compartment, or batteries that are not individually packaged. These lesions cause serious complications in a quarter of cases and their management entails high health costs. Legislation requiring screw-secured compartments and individual blisters for batteries could have prevented 69.2% of the ingestions.



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Androgens trigger different growth responses in genetically identical human hair follicles in organ culture that reflect their epigenetic diversity in life [Research]

Male sex hormones—androgens—regulate male physique development. Without androgen signaling, genetic males appear female. During puberty, increasing androgens harness the hair follicle's unique regenerative ability to replace many tiny vellus hairs with larger, darker terminal hairs (e.g., beard). Follicle response is epigenetically varied: some remain unaffected (e.g., eyelashes) or are inhibited, causing balding. How sex steroid hormones alter such developmental processes is unclear, despite high incidences of hormone-driven cancer, hirsutism, and alopecia. Unfortunately, existing development models are not androgen sensitive. Here, we use hair follicles to establish an androgen-responsive human organ culture model. We show that women's intermediate facial follicles respond to men's higher androgen levels by synthesizing more hair over several days, unlike donor-matched, androgen-insensitive, terminal follicles. We demonstrate that androgen receptors—androgen-activated gene transcription regulators—are required and are present in vivo within these follicles. This is the first human organ that involves multiple cell types that responds appropriately to hormones in prolonged culture, in a way which mirrors its natural behavior. Thus, intermediate hair follicles offer a hormone-switchable human model with exceptional, unique availability of genetically identical, but epigenetically hormone-insensitive, terminal follicles. This should enable advances in understanding sex steroid hormone signaling, gene regulation, and developmental and regenerative systems and facilitate better therapies for hormone-dependent disorders.—Miranda, B. H., Charlesworth, M. R., Tobin, D. J., Sharpe, D. T., Randall, V. A. Androgens trigger different growth responses in genetically identical human hair follicles in organ culture that reflect their epigenetic diversity in life.

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Translationally controlled tumor protein is required for the fast growth of Toxoplasma gondii and maintenance of its intracellular development [Research]

Translationally controlled tumor protein (TCTP) is a highly conserved, multifunctional protein that has been implicated in a range of cell physiologic processes, especially cell growth and development. A TCTP-like gene has been identified in the Toxoplasma genome [Toxoplasma gondii TCTP (TgTCTP)], although its function remains unknown. The sequence analysis of TgTCTP indicated that it is a highly conserved protein in eukaryotes. We found that the expression level of TgTCTP in the virulent RH strain was significantly higher than that in the avirulent PLK strain. Indirect immunofluorescence showed that TgTCTP was expressed in the parasite cytoplasm. The localization of TgTCTP was unchanged during the replication of the parasite. We expressed a functional recombinant TgTCTP (rTgTCTP) protein in Escherichia coli and found that the recombinant protein could form a multimer. We then evaluated the function of TgTCTP using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 knockout (KO) system. Phenotypic analysis of the KO strain (TgTCTP) revealed that TgTCTP is required for the robust growth of the parasites. TgTCTP deficiency also led to early egress of the parasites and subsequent impairment in their invasion and attachment abilities. We subsequently found that the multimer form of TgTCTP might not be necessary for the growth and replication of the parasite. Then the expression profiling of genes in the TgTCTP and complement strains were analyzed. The results revealed that 988 genes were regulated in TgTCTP compared with the complement strain. Overall, although not essential, TgTCTP is required for the fast growth of Tg and maintenance of its intracellular development.—Zheng, J., Chen, Y., Li, Z., Cao, S., Zhang, Z., Jia, H. Translationally controlled tumor protein is required for the fast growth of Toxoplasma gondii and maintenance of its intracellular development.

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Trefoil factor family peptides enhance cell migration by increasing cellular osmotic permeability and aquaporin 3 levels [Research]

Trefoil factor family (TFF) peptides are produced rapidly at sites of injury, stimulating epithelial migration, a process involving rapid changes in cell shape and volume, requiring rapid flow of water into and out of the cell. We examined the effect of TFFs on fluidity of cells by measuring their sensitivity to osmotic challenges and cell migration, and determined whether those results were mediated through altering the levels of aquaporins (AQPs), a family of transmembrane water channels involved in cellular water homeostasis. Gastric (AGS) and colonic (Caco-2) cell lines had intrinsic TFF levels determined and the predominant TFF peptide knocked down (RNA interference). Knockdown caused lessened responsiveness to changes in external osmotic challenge (by 51 and 69% in AGS and Caco-2 cells, respectively) and reduced cell migration and transepithelial permeability but did not influence proliferation. Exogenous TFF increased several AQPs, particularly AQP3, and those were reciprocally reduced in knockdown cells. TFF-induced, but not fetal calf serum–induced, cell migration was inhibited by the presence of AQP3 blocker (CuSO₄). We summarize that TFF peptides promptly produced at sites of injury increase AQP levels, most notably AQP3, thereby enhancing the cells' ability to rapidly change their shape as part of the restitutive process. TFF peptides also require functioning AQP3 channels to induce cell migration.—Marchbank, T., Playford, R. J. Trefoil factor family peptides enhance cell migration by increasing cellular osmotic permeability and aquaporin 3 levels.

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A ERK/RSK-mediated negative feedback loop regulates M-CSF-evoked PI3K/AKT activation in macrophages [Research]

Activation of the RAS/ERK and its downstream signaling components is essential for growth factor–induced cell survival, proliferation, and differentiation. The Src homology-2 domain containing protein tyrosine phosphatase 2 (SHP2), encoded by protein tyrosine phosphatase, non-receptor type 11 (Ptpn11), is a positive mediator required for most, if not all, receptor tyrosine kinase–evoked RAS/ERK activation, but differentially regulates the PI3K/AKT signaling cascade in various cellular contexts. The precise mechanisms underlying the differential effects of SHP2 deficiency on the PI3K pathway remain unclear. We found that mice with myelomonocytic cell-specific [Tg(LysM-Cre);Ptpn11^fl/fl mice] Ptpn11 deficiency exhibit mild osteopetrosis. SHP2-deficient bone marrow macrophages (BMMs) showed decreased proliferation in response to M-CSF and decreased osteoclast generation. M-CSF–evoked ERK1/2 activation was decreased, whereas AKT activation was enhanced in SHP2-deficient BMMs. ERK1/2, via its downstream target RSK2, mediates this negative feedback by negatively regulating phosphorylation of M-CSF receptor at Tyr721 and, consequently, its binding to p85 subunit of PI3K and PI3K activation. Pharmacologic inhibition of RSK or ERK phenotypically mimics the signaling defects observed in SHP2-deficient BMMs. Furthermore, this increase in PI3K/AKT activation enables BMM survival in the setting of SHP2 deficiency.—Wang, L., Iorio, C., Yan, K., Yang, H., Takeshita, S., Kang, S., Neel, B.G., Yang, W. An ERK/RSK-mediated negative feedback loop regulates M-CSF-evoked PI3K/AKT activation in macrophages.

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Spatial distributions, fractionation characteristics, and ecological risk assessment of trace elements in sediments of Chaohu Lake, a large eutrophic freshwater lake in eastern China

Abstract

The concentrations, spatial distribution, fractionation characteristics, and potential ecological risks of trace elements (Cu, Pb, Zn, Cr, Ni, and Co) in the surface sediment samples collected from 32 sites in Chaohu Lake were investigated. The improved BCR sequential extraction procedure was applied to analyze the chemical forms of trace elements in sediments. The enrichment factor (EF), sediment quality guidelines (SQGs), potential ecological risk index (PERI), and risk assessment code (RAC) were employed to evaluate the pollution levels and the potential ecological risks. The results found that the concentrations of Cu, Pb, Zn, Cr, Ni, and Co in the surface sediments were 78.59, 36.91, 161.84, 98.87, 38.92, and 10.09 mg kg⁻¹, respectively. The lower concentrations of Cu, Pb, Zn, Cr, and Ni were almost found in the middle part of the lake, while Co increased from the western toward the eastern parts of the lake. Cr, Ni, Co, and Zn predominantly existed in the residual fractions, with the average values of 76.35, 59.22, 45.60, and 44.30%, respectively. Cu and Pb were mainly combined with Fe/Mn oxides in reducible fraction, with the average values of 66.4 and 69.1%, respectively. The pollution levels were different among the selected elements. Cu had the highest potential ecological risk, while Cr had the lowest potential ecological risk.

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Spatial distribution and potential biological risk of some metals in relation to granulometric content in core sediments from Chilika Lake, India

Abstract

The article presents first systematic report on the concentration of selected major elements [iron (Fe) and manganese (Mn)] and minor elements [zinc (Zn), copper (Cu), chromium (Cr), lead (Pb), nickel (Ni), and cobalt (Co)] from the core sediment of Chilika Lake, India. The analyzed samples revealed higher content of Pb than the background levels in the entire study area. The extent of contamination from minor and major elements is expressed by assessing (i) the metal enrichments in the sediment through the calculations of anthropogenic factor (AF), pollution load index (PLI), Enrichment factor (EF), and geoaccumulation index (Igeo) and (ii) potential biological risks by the use of sediment quality guidelines like effect range median (ERM) and effect range low (ERL) benchmarks. The estimated indices indicated that sediment is enriched with Pb, Ni, Cr, Cu and Co. The enrichment of these elements seems to be due to the fine granulometric characteristics of the sediment with Fe and Mn oxyhydroxides being the main metal carriers and fishing boats using low grade paints, fuel, and fishing technology using lead beads fixed to fishing nets. Trace element input to the Chilika lake needs to be monitored with due emphasis on Cr and Pb contaminations since the ERM and ERL benchmarks indicated potential biological risk with these metals.

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First determination of fullerenes in the Austrian market and environment: quantitative analysis and assessment

Abstract

This study forms the first report on analyzing fullerenes in the Austrian environment and cosmetic products available on the Austrian market. We developed, optimized, and validated a novel method for the analysis of C₆₀ and C₇₀ fullerenes and N-methylfulleropyrrolidine C₆₀ (NMFP) for measuring sensitivities in the low nanograms per liter range in order to prove their presence in the environment (12 wastewater- and 12 sewage sludge samples) and in 11 selected fullerene-containing cosmetic products from three different brands. The optimized method relies on a liquid-liquid extraction (LLE) or solid-liquid extraction (SLE) and, for the first time, introduced the Carrez-clarification, followed by liquid chromatography (LC) and coupled to a hybrid triple quadrupole mass spectrometry (MS) quantification. The total variability of the new established LC-MS/MS method based on all the tested matrices was below 10%. We found recoveries generally higher than 70% for both tap water and surface water. The limits of quantitation (LOQ) for the wastewater samples were measured to be from 0.8 to 1.6 ng/L, for the sewage sludge samples, from 1.4 to 2.6 ng/g DM (drymass), and for the cosmetic samples from 0.2 to 0.4 ng/g. None of the analyzed samples of wastewater or sewage sludge samples contained fullerenes. But in 70% of the tested cosmetics, fullerene concentrations between 10 and 340 ng/g were detected. These values were much lower than concentrations causing toxicity in water animals.

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Structural and thermodynamic analyses reveal critical features of glycopeptide recognition by the human PILR{alpha} immune cell receptor [Immunology]

Before entering host cells, herpes simplex virus-1 (HSV-1) uses its envelope glycoprotein B (gB) to bind paired immunoglobulin-like type 2 receptor α (PILRα) on immune cells. PILRα belongs to the Siglec (sialic acid (SA)-binding immunoglobulin-like lectin)-like family, members of which bind SA. PILRα is the only Siglec member to recognize not only the sialylated O-linked sugar T antigen (sTn) but also its attached peptide region. We previously determined the crystal structure of PILRα complexed with the sTn-linked glycopeptide of gB, revealing the simultaneous recognition of sTn and peptide by the receptor. However, the contribution of each glycopeptide component to PILRα binding was largely unclear. Here, we chemically synthesized glycopeptide derivatives and determined the thermodynamic parameters of their interaction with PILRα. We show that glycopeptides with different sugar units linking SA and peptides (i.e. ″GlcNAc type″ and ″Deoxy GlcNAc type″ glycopeptides) have lower affinity and more enthalpic-driven binding than the wildtype (i.e. GalNAc type glycopeptide). The crystal structures of PILRα complexed with these glycopeptides highlighted the importance of stereochemical positioning of the O4 atom of the sugar moiety. These results provide insights both for understanding the unique O-glycosylated peptide recognition by the PILRα and for the rational design of HSV-1 entry inhibitors.

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Evidence for a conserved inhibitory binding mode between the membrane fusion assembly factors Munc18 and syntaxin in animals [Molecular Biophysics]

The membrane fusion necessary for vesicle trafficking is driven by the assembly of heterologous SNARE proteins orchestrated by the binding of Sec1/Munc18 (SM) proteins to specific syntaxin SNARE proteins. However, the precise mode of interaction between SM proteins and SNAREs is debated, as contrasting binding modes have been found for different members of the SM protein family, including the three vertebrate Munc18 isoforms. While different binding modes could be necessary given their roles in different secretory processes in different tissues, the structural similarity of the three isoforms makes this divergence perplexing. Though the neuronal isoform Munc18a is well established to bind tightly to both the closed conformation and the N-peptide of Syntaxin 1a, thereby inhibiting SNARE complex formation, Munc18b and c, which have a more widespread distribution, are reported to mainly interact with the N-peptide of their partnering syntaxins and are thought to instead promote SNARE complex formation. We have re-investigated the interaction between Munc18c and Syntaxin 4 (Syx4). Using isothermal titration calorimetry, we found that Munc18c, like Munc18a, binds to both the closed conformation and the N-peptide of Syx4. Furtermore, using a novel kinetic approach, we found that Munc18c, like Munc18a, slows down SNARE complex formation through high-affinity binding to syntaxin. This strongly suggests that secretory Munc18s in general control the accessibility of the bound syntaxin, probably preparing it for SNARE complex assembly.

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Matrix metalloproteinase-7 induces homotypic tumor cell aggregation via proteolytic cleavage of the membrane-bound Kunitz-type inhibitor HAI-1 [Molecular Bases of Disease]

Matrix metalloproteinase-7 (MMP-7) plays important roles in tumor progression and metastasis. Our previous studies have demonstrated that MMP-7 binds to colon cancer cells via cell surface-bound cholesterol sulfate and induces significant cell aggregation by cleaving cell-surface protein(s). These aggregated cells exhibit a dramatically enhanced metastatic potential. However, the molecular mechanism inducing this cell-cell adhesion through the proteolytic action of MMP-7 remained to be clarified. Here, we explored MMP-7 substrates on cell surface; the proteins on cell surface were first biotinylated and a labeled protein fragment specifically released from the cells after MMP-7-treatment was analyzed using LC-MS/MS. We found that hepatocyte growth factor activator inhibitor type 1 (HAI-1), a membrane-bound Kunitz-type serine protease inhibitor, is an MMP-7 substrate. We also found that the cell-bound MMP-7 cleaves HAI-1 mainly between Gly-451 and Leu-452 and thereby releases the extracellular region as soluble HAI-1 (sHAI-1). We further demonstrated that this sHAI-1 can induce cancer cell aggregation and determined that the HAI-1 region corresponding to amino acids 141-249, which does not include the serine protease inhibitor domain, has the cell aggregation-inducing activity. Interestingly, cell surface cholesterol sulfate-independent proteolytic action of MMP-7 is critical for the sHAI-1-mediated induction of cell aggregation, whereas cholesterol sulfate is needed for the MMP-7-catalyzed generation of sHAI-1. Considering that MMP-7-induced cancer cell aggregation is an important mechanism in cancer metastasis, we propose that sHAI-1 is an essential component of MMP-7-induced stimulation of cancer metastasis and may therefore represent a suitable target for antimetastatic therapeutic strategies.

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A mechanistic model to predict effects of cathepsin B and cystatin C on {beta}-amyloid aggregation and degradation [Protein Structure and Folding]

β-Amyloid (Aβ) aggregation is thought to initiate a cascade of neurodegenerative events in Alzheimer's disease (AD). Much effort is underway to develop strategies to reduce Aβ concentration or inhibit aggregation. Cathepsin B (CatB) proteolytically degrades Aβ into nonaggregating fragments, but is potently inhibited by cystatin C (CysC). It has been suggested that decreasing CysC would facilitate Aβ clearance by relieving CatB inhibition. On the other hand, CysC binds Aβ and inhibits Aβ aggregation, suggesting that an intervention that increases CysC would prevent Aβ aggregation. Both approaches have been tested in animal models, yielding contradictory results, possibly because of the opposing influences of CysC on Aβ degradation versus aggregation. Here we sought to develop a model that quantitatively predicts the effects of CysC and CatB on Aβ aggregation. Aβ aggregation kinetics in the absence of CatB or CysC was measured. The rate constant for Aβ degradation by CatB, and the equilibrium constant for binding of CysC to Aβ, were determined. We derived a mathematical model that combines material balances and kinetic rate equations. The model accurately predicted Aβ aggregation kinetics at various CatB and CysC concentrations. We derived approximate expressions for the halftimes of degradation and aggregation, and show that their ratio can be used to estimate, at any given Aβ, CatB or CysC concentration, whether aggregation or degradation will result. Our results may be useful for designing experiments and interpreting results from investigations of manipulation of CysC concentration as an AD therapy.

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The lignan manassantin is a potent and specific inhibitor of mitochondrial complex I and bioenergetic activity in mammals [Metabolism]

Dineolignans manassantin A and B from the plant Saururus cernuus are used in traditional medicine to manage a wide range of ailments such as edema, jaundice, and gonorrhea. Cell-based studies have identified several molecular target candidates of manassantin including NF-kappaB, MAPK, STAT3 and hypoxia-inducible factor 1 alpha (HIF-1alpha). It is unclear whether or how these structurally diverse proteins or pathways mediate any of the medical benefits of manassantin in vivo. Moreover, it has been recently reported that manassantin causes developmental arrest in zebrafish by inhibiting the mitochondrial complex I, but it is unknown whether manassantin inhibits mitochondrial respiration in intact mammalian cells and live animals. Here, we present direct evidence that manassantin potently and specifically inhibits the mitochondrial complex I and bioenergetic activity in mammalian systems. Manassantin had no effect on complex II- or complex IV-mediated respiration. Of note, it decreased NADH-ubiquinone reductase activity but not that of NADH-ferricyanide reductase. Treatment with manassantin reduced cellular ATP levels and concomitantly stimulated AMP-activated protein kinase (AMPK) in vitro and in vivo. As an adaptive response to manassantin-induced bioenergetic deficiency, mammalian cells upregulated aerobic glycolysis, a process mediated by AMPK independent of HIF-1alpha. These results together demonstrate a biologically important activity of manassantin in the control of complex I-mediated respiration and its profound effects on oxygen utilization, energy homeostasis and glucose metabolism in mammalian cells.

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An improved labeling strategy enables automated detection of single-virus fusion and assessment of HIV-1 protease activity in single virions [Methods and Resources]

Enveloped viruses transfer their genomes into host cells by fusing their membrane to that of the cell. To visualize single-virus fusion in living cells, researchers take advantage of HIV-1's proteolytic maturation, which can generate free fluorescent proteins within the viral particle. Co-labeling viruses with a content marker and a fluorescently tagged Vpr (a viral core protein) enables detection of single-virus fusions, but a major limitation of this approach is that not all viral particles incorporate both markers. Here, we designed a labeling strategy based on the bifunctional mCherry-2xCL-YFP-Vpr construct, in which 2xCL denotes a tandem cleavage site for the viral protease. This bi-functional marker was efficiently cleaved during virus maturation, producing free mCherry and the core-associated YFP-Vpr. A nearly perfect colocalization of these two markers in virions and their fixed 1:1 ratio enabled automated detection of singleparticle fusion in both fixed and live cells based upon loss of the mCherry signal. Furthermore, a drop in FRET efficiency between YFP and mCherry due to cleavage of the bi-functional marker, which manifested as a marked shift in the normalized YFP/mCherry fluorescence ratio, reliably predicted viral protease activity in single virions. This feature could discriminate between the particles containing free mCherry, and therefore likely representing mature viruses, and immature particles whose fusion cannot be detected. In summary, our new labeling strategy offers several advantages compared with previous approaches, including increased reliability and throughput of detection of viral fusion. We anticipate that our method will have significant utility for studying viral fusion and maturation.

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D1-Asn-298 in photosystem II is involved in a hydrogen-bond network near the redox-active tyrosine YZ for proton exit during water oxidation [Molecular Biophysics]

In photosynIn photosynthetic water oxidation, two water molecules are converted into one oxygen molecule and four protons at the Mn4CaO5 cluster in photosystem II (PSII) via the S-state cycle. Efficient proton exit from the catalytic site to the lumen is essential for this process. However, the exit pathways of individual protons through the PSII proteins remain to be identified. In this study, we examined the involvement of a hydrogen-bond network near the redox-active tyrosine YZ in proton transfer during the S-state cycle. We focused on spectroscopic analyses of a site-directed variant of D1-Asn-298, a residue involved in a hydrogen-bond network near YZ. We found that the D1-N298A mutant of Synechocystis sp. PCC 6803 exhibits an O2 evolution activity of ~10% of the wildtype. D1-N298A and the wildtype D1 had very similar features of thermoluminescence glow curves and of an FTIR difference spectrum upon YZ oxidation, suggesting that the hydrogen-bonded structure of YZ and electron transfer from the Mn4CaO5 cluster to YZ were little affected by substitution. In the D1- N298A mutant, however, the flash-number dependence of delayed luminescence showed a monotonic increase without oscillation, and FTIR difference spectra of the S-state cycle indicated partial and significant inhibition of the S2→S3 and S3→S0 transitions, respectively. These results suggest that the D1-N298A substitution inhibits the proton transfer processes in the S2→S3 and S3→S0 transitions. This in turn indicates that the hydrogen-bond network near YZ can be functional as a proton transfer pathway during photosynthetic water oxidation.

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Host transcription factor Speckled 110kDa (Sp110), a nuclear body protein, is hijacked by Hepatitis B virus protein X for viral persistence [Cell Biology]

Promyelocytic leukemia nuclear bodies (PMLNB) are sub-nuclear organelles which are the hub of numerous proteins. DNA/RNA viruses often hijack cellular-factors resident in PML-NBs to promote their proliferation in host cells. Hepatitis B virus (HBV), belonging to Hepadnaviridae family, remains undetected in early infection as it does not induce the innate immune response and is known to be the cause of several hepatic diseases leading to cirrhosis and hepatocellular carcinoma. The association of PML-NB proteins and HBV is being addressed in a number of recent studies. Here, we report that PML-NB protein Speckled 110kDa (Sp110), is SUMO1-modified and undergoes a deSUMOylation driven release from the PML-NB in presence of HBV. Intriguingly, Sp110 knock-down significantly reduced viral DNA-load in the culture supernatant by activation of type-I interferon response pathway. Further, we found that Sp110 differentially regulates several direct target genes of HBx, a viral co-factor. Subsequently, we identified Sp110, as a novel interactor of HBx and found this association to be essential for the exit of Sp110 from the PML-NB during HBV infection and HBx recruitment on the promoter of these genes. HBx, in turn, modulates the recruitment of its associated transcription cofactors p300/HDAC1 to these co-regulated genes, thereby altering the host gene expression programme in favor of viral persistence. Thus we report a mechanism by which HBV can evade host immune-response by hijacking PML-NB protein Sp110 and therefore propose it to be a novel target for antiviral therapy.

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Differential regulation of the Rac1 GTPase activating protein (GAP) BCR during oxygen/glucose deprivation in hippocampal and cortical neurons [Neurobiology]

Brain ischemia causes oxygen and glucose deprivation (OGD) in neurons, triggering a cascade of events leading to synaptic accumulation of glutamate. Excessive activation of glutamate receptors causes excitotoxicity and delayed cell death in vulnerable neurons. Following global cerebral ischemia, hippocampal CA1 pyramidal neurons are more vulnerable to injury than their cortical counterparts, but the mechanisms that underlie this difference are unclear. Signalling via Rho-family small GTPases, their upstream Guanine nucleotide Exchange Factors (GEFs) and GTPase Activating Proteins (GAPs) is differentially dysregulated in response to OGD/ischemia in hippocampal and cortical neurons. Increased Rac1 activity caused by OGD/ischemia contributes to neuronal death in hippocampal neurons, via diverse effects on NADPH oxidase activity and dendritic spine morphology. The Rac1 GEF Tiam1 mediates an OGD-induced increase in Rac1 activity in hippocampal neurons, however the identity of an antagonistic GAP remains elusive. Here, we show that the Rac1 GAP BCR associates with NMDA receptors (NMDARs) along with Tiam1, and this protein complex is more abundant in hippocampal compared to cortical neurons. While total BCR is similar in the two neuronal types, BCR is more active in hippocampal compared to cortical neurons. OGD causes an NMDAR- and Ca2+- permeable AMPAR-dependent deactivation of BCR in hippocampal, but not cortical neurons. BCR knock-down occludes OGD-induced Rac1 activation in hippocampal neurons. Furthermore, disrupting the Tiam1-NMDAR interaction with a fragment of Tiam1 blocks OGD-induced Tiam1 activation, but has no effect on the deactivation of BCR. This work identifies BCR as a critical player in Rac1 regulation during OGD in hippocampal neurons.

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MicroRNA-302a suppresses influenza A virus-stimulated interferon regulatory factor-5 expression and cytokine storm induction [Immunology]

During influenza A virus (IAV) infection, cytokine storms play a vital and critical role in clinical outcomes. We have previously reported that microRNA (miR)-302c regulates IAV-induced IFN expression by targeting the 3'-UTR of nuclear factor kappa B (NF-κB)-inducing kinase (NIK). In the current study, we found that miR-302a, another member of miR-302 cluster, controls the IAV-induced cytokine storm. According to results from cell-based and knock-out mouse models, IAV induces a cytokine storm via interferon regulatory factor-5 (IRF-5). We also found that IAV infection upregulates IRF-5 expression and that IRF-5 in turn promotes IAV replication. Furthermore, we observed that IRF-5 is a direct target of miR-302a, which downregulated IRF-5 expression by binding its 3'-UTR. Moreover, IAV increased IRF-5 expression by downregulating miR-302a expression. Interestingly, miR-302a inhibited IAV replication. In IAV-infected patients, miR-302a expression was downregulated, whereas IRF-5 expression was upregulated. Taken together, our work uncovers and defines a signaling pathway implicated in an IAV-induced cytokine storm.

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Upfront charging of overseas visitors using the NHS

When asked what makes them proud to be British, more people cite the NHS than anything else, ahead of British history, sense of humour, and the monarchy.1 Its popularity transcends all ages and...

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Cathepsin B is dispensable for cellular processing of cathepsin B-cleavable antibody-drug conjugates

Antibody-drug conjugates (ADCs) are designed to selectively bind to tumor antigens via the antibody and release their cytotoxic payload upon internalization. Controllable payload release through judicious design of the linker has been an early technological milestone. Here, we examine the effect of the protease-cleavable valine-citrulline (VC(S)) linker on ADC efficacy. The VC(S) linker was designed to be cleaved by cathepsin B, a lysosomal cysteine protease. Surprisingly, suppression of cathepsin B expression via CRISPR-Cas9 gene deletion or shRNA knockdown had no effect on the efficacy of ADCs with VC(S) linkers armed with a monomethyl auristatin E (MMAE) payload. Mass spectrometry studies of payload release suggested that other cysteine cathepsins can cleave the VC(S) linker. Also, ADCs with a non-protease-cleavable enantiomer, the VC(R) isomer, mediated effective cell killing with a cysteine-VC(R)-MMAE catabolite generated by lysosomal catabolism. Based on these observations, we altered the payload to a pyrrolo[2,1-c][1,4]benzodiazepine dimer (PBD) conjugate that requires linker cleavage in order to bind its DNA target. Unlike the VC-MMAE ADCs, the VC(S)-PBD ADC is at least 20-fold more cytotoxic than the VC(R)-PBD ADC. Our findings reveal that the VC(S) linker has multiple paths to produce active catabolites, and that antibody and intracellular targets are more critical to ADC efficacy. These results suggest that protease-cleavable linkers are unlikely to increase the therapeutic index of ADCs and that resistance based on linker processing is improbable.

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PP2A inactivation mediated by PPP2R4 haploinsufficiency promotes cancer development

Protein phosphatase 2A (PP2A) complexes counteract many oncogenic kinase pathways. In cancer cells, PP2A function can be compromised by several mechanisms, including sporadic mutations in its scaffolding A and regulatory B subunits or more frequently through overexpression of cellular PP2A inhibitors. Here we identify a novel genetic mechanism by which PP2A function is recurrently affected in human cancer, involving haploinsufficiency of PPP2R4, a gene encoding the cellular PP2A activator PTPA. Notably, up to 70% of cancer patients showed a heterozygous deletion or missense mutations in PPP2R4. Cancer-associated PTPA mutants exhibited decreased abilities to bind the PP2A-C subunit or activate PP2A and failed to reverse the tumorigenic phenotype induced by PTPA suppression, indicating they function as null alleles. In Ppp2r4 gene-trapped (gt) mice showing residual PTPA expression, total PP2A activity and methylation were reduced, selectively affecting specific PP2A holoenzymes. Both PTPAgt/gt and PTPA+/gt mice showed higher rates of spontaneous tumors, mainly hematologic malignancies and hepatocellular adenomas and carcinomas. These tumors exhibited increased c-Myc phosphorylation and increased Wnt or Hedgehog signaling. We observed a significant reduction in lifespan in PTPA+/gt mice compared to wildtype mice. Additionally, chemical induced skin carcinogenesis was accelerated in PTPA+/gt compared to wildtype mice. Our results provide evidence for PPP2R4 as a haploinsufficient tumor suppressor gene, defining a high-penetrance genetic mechanism for PP2A inhibition in human cancer.

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Correction to: Evaluating the impact of a walking program in a disadvantaged area: using the RE-AIM framework by mixed methods

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Occupational blood exposures in health care workers: incidence, characteristics, and transmission of bloodborne pathogens in South Korea

Health care workers (HCWs) are at high risk for occupational blood exposures (OBEs) and transmission of bloodborne pathogens. This study elucidated the incidence rate and epidemiological characteristics of OBE...

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Prevalence of multimorbidity in Germany: impact of age and educational level in a cross-sectional study on 19,294 adults

Multimorbidity is one of the most important and challenging aspects in public health. Multimorbid people are associated with more hospital admissions, a large number of drug prescriptions and higher risks of m...

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Correction to: A large and persistent outbreak of typhoid fever caused by consuming contaminated water and street-vended beverages: Kampala, Uganda, January – June 2015

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Correction to: Oral health literacy and oral health outcomes in an adult population in Brazil

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Trion-Species-Resolved Quantum Beats in MoSe2

ACS Nano

DOI: 10.1021/acsnano.7b06444

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Phase I study of the combination of crizotinib (as a MET inhibitor) and dasatinib (as a c-SRC inhibitor) in patients with advanced cancer

Summary

Background Both MET and c-SRC are important mediators of cancer progression and there is cross talk between the two molecules. Preclinical studies have demonstrated combination of MET and c-SRC inhibitors is effective in multiple cancer types. Methods We analyzed the safety and efficacy of administering a c-SRC inhibitor (dasatinib) in combination with a MET inhibitor (crizotinib) in a two-arm concurrent phase I study. Arm A consisted of crizotinib fixed at 250 mg twice per day with escalation of dasatinib. Arm B consisted of dasatinib fixed at 140 mg daily with escalation of crizotinib. Endpoints included dose-limiting toxicities (DLTs), recommended phase II dose (RP2D), and response (RECIST 1.1). Results We enrolled 61 patients (arm A: 31, arm B: 30). The most common cancers were sarcoma (21%) and prostate cancer (16%). In Arm A, at dose level 2 (DL2), 40% (2/5) experienced DLTs. In the expanded DL1, 21% (4/19) experienced DLTs (all grade 3). In Arm B, at DL2, 50% (2/4) experienced DLTs. In the expanded DL1, 22% (4/18) experienced DLTs (all grade 3). RP2D was determined to be arm A, DL1 (250 mg crizotinib orally twice per day plus 50 mg dasatinib orally daily). Partial response (N = 1) and stable disease for ≥6 months (N = 3) were seen. Conclusions The combination of crizotinib and dasatinib is safe to administer but tolerability is limited given the high rate of adverse events. Responses and durable stable disease were limited. Further precision therapy approach using this specific combination may be difficult given the toxicity.

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Self-harming has risen dramatically among UK teenage girls

In every 10,000 teenage girls in the UK, more than 37 have self-harmed. The large rise in rates of self-harming may be due to stress or mental health problems

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This Battersea dentist is up for two prestigious awards

Dr Mihir Shah, head dentist at Battersea Park Dental, in Battersea Park Road, is a finalist for both the The Private Dentistry Awards 2017 and The Dentistry Awards 2017. Mr Shah said: "It's an honour to have been put forward for both awards by my patients and my colleagues.

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A Simplified Multipath Component Modeling Approach for High-Speed Train Channel Based on Ray Tracing

High-speed train (HST) communications at millimeter-wave (mmWave) band have received a lot of attention due to their numerous high-data-rate applications enabling smart rail mobility. Accurate and effective channel models are always critical to the HST system design, assessment, and optimization. A distinctive feature of the mmWave HST channel is that it is rapidly time-varying. To depict this feature, a geometry-based multipath model is established for the dominant multipath behavior in delay and Doppler domains. Because of insufficient mmWave HST channel measurement with high mobility, the model is developed by a measurement-validated ray tracing (RT) simulator. Different from conventional models, the temporal evolution of dominant multipath behavior is characterized by its geometry factor that represents the geometrical relationship of the dominant multipath component (MPC) to HST environment. Actually, during each dominant multipath lifetime, its geometry factor is fixed. To statistically model the geometry factor and its lifetime, the dominant MPCs are extracted within each local wide-sense stationary (WSS) region and are tracked over different WSS regions to identify its "birth" and "death" regions. Then, complex attenuation of dominant MPC is jointly modeled by its delay and Doppler shift both which are derived from its geometry factor. Finally, the model implementation is verified by comparison between RT simulated and modeled delay and Doppler spreads.

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A Novel Floating Memristor Emulator with Minimal Components

A new floating emulator for the flux-controlled memristor is introduced in this paper. The proposed emulator circuit is very simple and consists of only two current feedback operational amplifiers (CFOAs), two analog multipliers, three resistors, and two capacitors. The emulator can be configured as an incremental or decremental type memristor by using an additional switch. The mathematical model of the emulator is derived to characterize its behavior. The hysteresis behavior of the emulator is discussed in detail, showing that the pinched hysteresis loops in - plane depend not only on the amplitude-to-frequency ratio of the exciting signal but also on the time constant of the emulator circuit itself. Experimental tests are provided to validate the emulator's workability.

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Cryoablation of Primary Breast Cancer in Patients with Metastatic Disease: Considerations Arising from a Single-Centre Data Analysis

Background. Patients presenting with stage IV breast cancer might benefit by removal of the primary tumor. We report our experience with CT-guided cryoablation of the primary tumor, with the aim of evaluating its role in this subgroup of patients. Patients and Methods. Data of 35 patients with mean age of 58 years with breast cancer at stage IV submitted to CT-guided cryoablation of the primary tumor between 2010 and 2016 were prospectively evaluated. All patients, except three, were preoperatively and postoperatively evaluated with breast MRI to assess the extent of tumor necrosis. Retreatment was performed in case of incomplete ablation. Results. Mean tumor size was 3.02 ± 1.4 cm. Six patients had multicentric disease. Complete tumor necrosis was 85.7% and 100% at 2-month and 6-month follow-up, respectively, as 5 patients with tumors > 3 cm required a redo cryoablation. No patient developed major complications. Minor side effects occurred in 30 patients (82%). All patients were discharged the same day of the procedure. During a mean follow-up of 46 months (range 3–84), 7 patients (20%) experienced local recurrences that were treated with redo cryoablation, and 7 (20%) died for disease progression. Conclusions. Our results suggest that cryoablation of the primary tumor is safe and effective in the treatment of patients presenting with stage IV breast cancer.

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An Approach to Classical Quantum Field Theory Based on the Geometry of Locally Conformally Flat Space-Time

This paper gives an introduction to certain classical physical theories described in the context of locally Minkowskian causal structures (LMCSs). For simplicity of exposition we consider LMCSs which have locally Euclidean topology (i.e., are manifolds) and hence are Möbius structures. We describe natural principal bundle structures associated with Möbius structures. Fermion fields are associated with sections of vector bundles associated with the principal bundles while interaction fields (bosons) are associated with endomorphisms of the space of fermion fields. Classical quantum field theory (the Dirac equation and Maxwell's equations) is obtained by considering representations of the structure group of a principal bundle associated with a given Möbius structure where , while being a subset of , is also isomorphic to . The analysis requires the use of an intertwining operator between the action of on and the adjoint action of on and it is shown that the Feynman slash operator, in the chiral representation for the Dirac gamma matrices, has this intertwining property.

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Multimodal Imaging Analysis in a Case with Congenital Fovea-Involving Retinal Macrovessel and Excellent Visual Acuity

Purpose. Congenital retinal macrovessels (CRM) represent rare aberrant vasculature of the retinal vessels that can supply or drain the macula. In this report, the optical coherence tomography angiography features of a congenital retinal macrovessel are discussed. Methods. The history and examination findings are presented alongside swept-source OCT angiography with corresponding B scan and en face OCT imaging. Patients. The case is a 12-year-old female patient with excellent best-corrected visual acuity in both eyes. Results. Swept-source OCT angiography demonstrated considerable loss of the foveal avascular zone at the levels of the superficial and deep capillary plexus. Discussion. In this case there was no detrimental effect on vision despite anatomical loss of the foveal avascular zone.

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Switch to Aflibercept in the Treatment of Neovascular AMD: Long-Term Results

Purpose. To report the long-term clinical outcomes after switching from intravitreal bevacizumab or ranibizumab to aflibercept therapy in eyes with AMD. Methods. Retrospective analysis of changes in BCVA, SD-OCT image, and frequency of injections after 1, 2, and 3 years of follow-up. Results. 164 eyes were analyzed, 101 eyes switched from bevacizumab (group 1) and 63 from ranibizumab (group 2). One year after the switch, there was an overall nonsignificant mean decrease of 2 ETDRS letters in BCVA. Three years after, there was an overall mean decrease of 7 ETDRS letters, which was statistically significant. A significant improvement in the mean CRT was found at 1, 2, and 3 years. There was a significant decrease in the mean number of injections per year (7.8 to 6.5, ) between the first and third year. Conclusion. Aflibercept can be useful in the management of refractory neovascular AMD, with a good morphological response. However, in the long-term, BCVA stabilization was not achieved.

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Developing a Tile-Based Rendering Method to Improve Rendering Speed of 3D Geospatial Data with HTML5 and WebGL

A dedicated plug-in has been installed to visualize three-dimensional (3D) city modeling spatial data in web-based applications. However, plug-in methods are gradually becoming obsolete, owing to their limited performance with respect to installation errors, unsupported cross-browsers, and security vulnerability. Particularly, in 2015, the NPAPI service was terminated in most existing web browsers except Internet Explorer. To overcome these problems, the HTML5/WebGL (next-generation web standard, confirmed in October 2014) technology emerged. In particular, WebGL is able to display 3D spatial data without plug-ins in browsers. In this study, we attempted to identify the requirements and limitations of displaying 3D city modeling spatial data using HTML5/WebGL, and we propose alternative ways based on the bin-packing algorithm that aggregates individual 3D city modeling data including buildings in tile units. The proposed method reduces the operational complexity and the number and volume of transmissions required for rendering processing to improve the speed of 3D data rendering. The proposed method was validated on real data for evaluating its effectiveness in 3D visualization of city modeling data in web-based applications.

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Deletion Involving the 7q31-32 Band at the CADPS2 Gene Locus in a Patient with Autism Spectrum Disorder and Recurrent Psychotic Syndrome Triggered by Stress

Autism spectrum disorder (ASD) is a neurodevelopmental disorder marked by impairments in social functioning, language, communication, and behavior. Recent genome-wide association studies show some microdeletions on the 7q31-32 region, including the CADPS2 locus in autistic patients. This paper reports the case of a patient with ASD and recurrent psychotic syndrome, in which a deletion on the 7q31-32 band at the CADPS2 gene locus was evidenced, as well as a brief review of the literature on the CADPS2 gene and its association with ASD.

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Experimental Study of Vibrational Acceleration Spread and Comparison Using Three Citrus Canopy Shaker Shaking Tines

The goal of this article is to experimentally study how the vibrational acceleration spreads along the branch shaken by PVC tine, steel tine, and nylon tine for citrus canopy shaking harvesting and to compare the difference. PVC tine and steel tine have potential to be used as shaking rod for citrus canopy shaking harvesting. Nylon tine is a commonly used shaking rod. A tractor-mounted canopy shaker was developed to do the trial. The shaking frequency was set at 2.5 and 5 Hz. Experimental results showed that the vibrational acceleration at the shaking spot is not the highest. Spreading from shaking spot to the stem, it increases evidently. When spreading from stems of the outside subbranch to stems of the nearest inside subbranch, its average decrease percentage is 42%. The overall vibrational acceleration of shaking at 5 Hz is 1.85 times as high as shaking at 2.5 Hz. The overall vibrational acceleration exerted by straight PVC tine and steel tine is 1.77 and 1.97 times as high as that exerted by straight nylon tine, respectively. It is indicated that replacing nylon tine with steel tine or PVC tine helps remove the fruits inside the canopy. Replacing with steel tine is more effective than with PVC tine.

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Increased Oxidative Damage of RNA in Early-Stage Nephropathy in db/db Mice

To evaluate RNA oxidation in the early stage of diabetic nephropathy, we applied an accurate method based on isotope dilution high-performance liquid chromatography-triple quadruple mass spectrometry to analyze the oxidatively generated guanine nucleosides in renal tissue and urine from db/db mice of different ages. We further investigated the relationship between these oxidative stress markers, microalbumin excretion, and histological changes. We found that the levels of 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodGuo) were increased in the urine and renal tissue of db/db mice and db/db mice with early symptoms of diabetic nephropathy suffered from more extensive oxidative damage than lean littermate control db/m mice. Importantly, in contrast to the findings in db/m mice, the 8-oxoGuo levels in the urine and renal tissue of db/db mice were higher than those of 8-oxodGuo at four weeks. These results indicate that RNA oxidation is more apparent than DNA oxidation in the early stage of diabetic nephropathy. RNA oxidation may provide new insight into the pathogenesis of diabetic nephropathy, and urinary 8-oxoGuo may represent a novel, noninvasive, and easily detected biomarker of diabetic kidney diseases if further study could clarify its source and confirm these results in a large population study.

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Bifurcations and Dynamics of the Rb-E2F Pathway Involving miR449

We focused on the gene regulative network involving Rb-E2F pathway and microRNAs (miR449) and studied the influence of time delay on the dynamical behaviors of Rb-E2F pathway by using Hopf bifurcation theory. It is shown that under certain assumptions the steady state of the delay model is asymptotically stable for all delay values; there is a critical value under another set of conditions; the steady state is stable when the time delay is less than the critical value, while the steady state is changed to be unstable when the time delay is greater than the critical value. Thus, Hopf bifurcation appears at the steady state when the delay passes through the critical value. Numerical simulations were presented to illustrate the theoretical results.

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Selective and Irreversible Induction of Necroptotic Cell Death in Lung Tumorspheres by Short-Term Exposure to Verapamil in Combination with Sorafenib

The presence of highly resistant cancer cells and the toxicity to normal cells are key factors that limit chemotherapy. Here, we used two models of highly resistant lung cancer cells: (1) adherent cells growing under prolonged periods of serum starvation (PPSS) and (2) cells growing as floating tumorspheres (FTs) to evaluate the effect of Verapamil (VP) in combination with Sorafenib (SF). Compared to cells growing under routine culture conditions (RCCs), PPPS cells or FTs were highly sensitive to short-term exposure (24 h) to VP 100 μM + SF 5 μM (VP100 + SF5). Recovery experiments exposing cells to VP100 + SF5 for 24 h followed by incubation in drug-free media for 48 h demonstrated that while PPSS as well as FT cells were unable to recover, cancer cells and the noncancerous cell line Beas-2B growing under RCCs were less sensitive and were also able to recover significantly. VP100 + SF5 induced significant changes in the expression of protein associated with apoptosis, autophagy, and to a lesser extent necroptosis. Coincubation experiments with z-VAD-FMK, necrostatin 1, or chloroquine showed evidence that necroptosis played a central role. Our data demonstrates that highly resistant cancer cells can be selectively eliminated by VP + SF and that necroptosis plays a central role.

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Metals in Fishes from Yongshu Island, Southern South China Sea: Human Health Risk Assessment

In order to assess the bioaccumulation of metals associated with gender, tissues, and their potential ecological risk, four species of fish were collected from the Yongshu Island in the Southern South China Sea. Metals and stable Pb isotopes in their tissues (muscle, gill, liver, intestine, and ovary) were determined. The concentrations of metals (mg/kg, dry weight) in these species were ND–21.60 (Cd), 1.21–4.87 (Cr), 0.42–22.4 (Cu), 1.01–51.8 (Mn), 0.30–3.28 (Ni), 6.04–1.29 × 103 (Zn), 14.89–1.40 × 103 (Fe), and 0.22–3.36 (Pb). In general, the liver and intestine absorbed more metals than the other tissues. Metals accumulation can be influenced by gender and feeding behavior and in fact, female fish and dietary exposure are more prone to accumulate metals. In addition, Pb isotopic ratios indicated that all species had significant biological fractionation, which may not make them good tracers for source identification. The metal concentrations of most samples were lower than the national standard values of the FAO (USA), which suggested that human consumption of these species may not cause health risks. However, since the surrounding areas are developing rapidly, the potential environmental risk of metals will intensify and should receive more attention.

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Acute Strenuous Exercise Induces an Imbalance on Histone H4 Acetylation/Histone Deacetylase 2 and Increases the Proinflammatory Profile of PBMC of Obese Individuals

This study evaluated the response of global histone H4 acetylation (H4ac), histone deacetylase 2 (HDAC2) activity, as well as the production of proinflammatory cytokines and monocyte phenotypes of lean and obese males after exercise. Ten lean and ten obese sedentary men were submitted to one session of strenuous exercise, and peripheral blood mononuclear cells (PBMC) were stimulated in vitro with lipopolysaccharide (LPS). Global H4ac levels, HDAC2 activity in PBMC, and IL-6, IL-8, and TNF-α production were analyzed. Monocyte phenotype was determined in accordance with the expression of CD14 and CD16. At rest, obese individuals presented higher frequency of proinflammatory CD14+CD16+ monocytes. LPS induced a significant augment in global H4ac and in the production of IL-6, IL-8, and TNF-α mainly in obese individuals. After exercise, the increased production of IL-8 and TNF-α and peripheral frequency of CD14+CD16+ were observed in both groups. In addition, exercise also induced a significant hyperacetylation of histone H4 and decreased HDAC2 activity in both nonstimulated and LPS-stimulated PBMC of obese individuals. Our data indicate that the obesity impacts on H4ac levels and that strenuous exercise leads to an enhanced chronic low-grade inflammation profile in obesity via an imbalance on H4ac/HDAC2.

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Effect of Glycine, Pyruvate, and Resveratrol on the Regeneration Process of Postischemic Intestinal Mucosa

Background. Intestinal ischemia is often caused by a malperfusion of the upper mesenteric artery. Since the intestinal mucosa is one of the most rapidly proliferating organs in human body, this tissue can partly regenerate itself after the onset of ischemia and reperfusion (I/R). Therefore, we investigated whether glycine, sodium pyruvate, and resveratrol can either support or potentially harm regeneration when applied therapeutically after reperfusion injury. Methods. I/R of the small intestine was initiated by occluding and reopening the upper mesenteric artery in rats. After 60 min of ischemia and 300 min of reperfusion, glycine, sodium pyruvate, or resveratrol was administered intravenously. Small intestine regeneration was analyzed regarding tissue damage, activity of saccharase, and Ki-67 positive cells. Additionally, systemic parameters and metabolic ones were obtained at selected periods. Results. Resveratrol failed in improving the outcome after I/R, while glycine showed a partial beneficial effect. Sodium pyruvate ameliorated metabolic acidosis, diminished histopathologic tissue injury, and increased cell proliferation in the small intestine. Conclusion. While glycine could improve in part regeneration but not proliferation, sodium pyruvate seems to be a possible therapeutic agent to facilitate proliferation and to support mucosal regeneration after I/R injury to the small intestine.

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An Approach to Classical Quantum Field Theory Based on the Geometry of Locally Conformally Flat Space-Time

This paper gives an introduction to certain classical physical theories described in the context of locally Minkowskian causal structures (LMCSs). For simplicity of exposition we consider LMCSs which have locally Euclidean topology (i.e., are manifolds) and hence are Möbius structures. We describe natural principal bundle structures associated with Möbius structures. Fermion fields are associated with sections of vector bundles associated with the principal bundles while interaction fields (bosons) are associated with endomorphisms of the space of fermion fields. Classical quantum field theory (the Dirac equation and Maxwell's equations) is obtained by considering representations of the structure group of a principal bundle associated with a given Möbius structure where , while being a subset of , is also isomorphic to . The analysis requires the use of an intertwining operator between the action of on and the adjoint action of on and it is shown that the Feynman slash operator, in the chiral representation for the Dirac gamma matrices, has this intertwining property.

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Self-harming has risen dramatically among UK teenage girls

In every 10,000 teenage girls in the UK, more than 37 have self-harmed. The large rise in rates of self-harming may be due to stress or mental health problems

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Aster yomena extract ameliorates pro-inflammatory immune response by suppressing NF-κB activation in RAW 264.7 cells

Aster yomena, an edible vegetable, is a perennial herb found in Korea, China, Japan, and Siberia. It is used as folk medicine to treat cough, bronchial asthma, and insect bites. A. yomena was recently shown to have antioxidant and anti-asthmatic activities. Studies have not yet evaluated the anti-inflammatory effects of the various solvent fractions of A. yomena. We investigated the anti-inflammatory activity of various solvent fractions (hexane, dichloromethane, ethyl acetate, and butanol) from ethanol extract of A.

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