Abstract
A response to a recent critique by Cem Bozşahin of the theory of syntactic semantics as it applies to Helen Keller, and some applications of the theory to the philosophy of computer science.
https://ift.tt/2PJVhR7
Κυριακή 16 Δεκεμβρίου 2018
Ovarian metastasis from breast cancer: a comprehensive review
Abstract
Breast is one of the most common primary origins of secondary ovarian cancer. There are some factors that influence the incidence of ovarian metastases (OM), such as histological type of primary cancer. OM from breast cancers are frequently asymptomatic until the masses have grown to certain size, and the metastatic tumors are frequently manifested as bilateral, solid, small ovarian masses. On the other hand, patients with a history of breast cancer have an increased risk of developing primary ovarian cancer (POC) than the general population. To differentiate OM from POC is essential as the optimal treatments and prognosis are distinct. Medical history, clinical manifestation, imaging examinations, serological examinations, and pathology (including immunohistochemical, genomic and transcriptomic approach) are all essential elements to improve the diagnostic accuracy. Breast cancer patients with OM have a poor prognosis; surgical resection with systemic therapy may help prolong the survival.
https://ift.tt/2EomtCM
ABT-737 and erufosine combination against castration-resistant prostate cancer: a promising but cell-type specific response associated with the modulation of anti-apoptotic signaling
A deeper understanding of the molecular basis of castration-resistant prostate cancer (CRPC) paved the way for the rational design and development of targeted therapies, which yielded promising preclinical results. However, translation of these potentially promising agents into clinics has usually failed, partly because of tumor heterogeneity. In this study, anticancer activities of the Bcl-2 inhibitor ABT-737 and the Akt-inhibitor erufosine (ErPC3) alone and in combination were compared between CRPC (PC-3 and DU-145) and healthy (PNT-1A) cell lines. The combination of ABT-737 and ErPC3 showed synergistic antiproliferative, antimigratory, and apoptotic effects in PC-3 cells. In DU-145 cells, ErPC3 showed a resistant profile, with half-maximal inhibitory concentration (IC50) values more than two-fold of PC-3, and combining ErPC3 with ABT-737 yielded no added benefit for all the incubation periods compared with ErPC3 alone. In PNT-1A cells, ABT-737 and ErPC3 alone and in combination reduced cell survival slightly and only at the highest concentrations. Apoptosis analysis showed that ABT-737 induced increased Akt expression and ErPC3 induced increased Mcl-1 expression in DU-145 cells. In conclusion, the ABT-737 and ErPC3 combination seems to be promising against CRPC, with a favorable safety profile in healthy cells. However, CRPC cell-type-specific resistance may be induced by enhancement of antiapoptotic signaling. *Ezgi Avsar Abdik and Ferda Kaleagasioglu contributed equally to the writing of this article. Correspondence to Ezgi Avsar Abdik, PhD, Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, 26 August Campus, Kayisdagi Street, 326A, Ataşehir, Istanbul 34755, Turkey Tel: +90 216 578 0000/+90 216 578 3198; fax: +90 216 578 0490; e-mail: ezgi.avsar@yeditepe.edu.tr Received October 2, 2018 Accepted November 30, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
https://ift.tt/2BnFuSK
https://ift.tt/2BnFuSK
"Nihon Rinsho"[jour]; +49 new citations
49 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:
These pubmed results were generated on 2018/12/17
PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
https://ift.tt/2USZHJd
A New Insight into the Roles of MiRNAs in Metabolic Syndrome
Metabolic syndrome (MetS), which includes several clinical components such as abdominal obesity, insulin resistance (IR), dyslipidemia, microalbuminuria, hypertension, proinflammatory state, and oxidative stress (OS), has become a global epidemic health issue contributing to a high risk of type 2 diabetes mellitus (T2DM). In recent years, microRNAs (miRNAs), used as noninvasive biomarkers for diagnosis and therapy, have aroused global interest in complex processes in health and diseases, including MetS and its components. MiRNAs can exist stably in serum, liver, skeletal muscle (SM), heart muscle, adipose tissue (AT), and βcells, because of their ability to escape the digestion of RNase. Here we first present an overall review on recent findings of the relationship between miRNAs and several main components of MetS, such as IR, obesity, diabetes, lipid metabolism, hypertension, hyperuricemia, and stress, to illustrate the targeting proteins or relevant pathways that are involved in the progress of MetS and also help us find promising novel diagnostic and therapeutic strategies.
https://ift.tt/2QAVF9P
Effect of early physician follow-up on mortality and subsequent hospital admissions after emergency care for heart failure: a retrospective cohort study [Research]
BACKGROUND:
The 1-year mortality rate in patients with heart failure who are discharged from an emergency department is 20%. We sought to determine whether early follow-up after discharge from the emergency department was associated with decreased mortality or subsequent admission to hospital.
METHODS:This retrospective cohort study conducted in Ontario, Canada, included adult patients who were discharged from 1 of 163 emergency departments between April 2007 and March 2014 with a primary diagnosis of heart failure. Using a propensity score–matched landmark analysis, we assessed follow-up in relation to mortality and admissions to hospital for cardiovascular conditions.
RESULTS:Of 34 519 patients, 16 274 (47.1%) obtained follow-up care within 7 days and 28 846 (83.6%) within 30 days. Compared with follow-up between day 8 and 30, patients with follow-up care within 7 days had a lower rate of mortality over 1 year (hazard ratio [HR] 0.92; 95% confidence interval [CI] 0.87–0.97), and a reduced rate of admission to hospital over 90 days (HR 0.87, 95% CI 0.80–0.94) and 1 year (HR 0.92; 95% CI 0.87–0.97); the mortality rate over 90 days in this group trended to a lower rate (HR 0.90, 95% CI 0.10–1.00). Follow-up care within 30 days, compared with patients without 30-day follow-up, was associated with a reduction in 1-year mortality (HR 0.89, 95% CI 0.82–0.97) but not admission to hospital (HR 1.02, 95% CI 0.94–1.10). In this group, there was a trend toward an increase in 90-day admission to hospital (HR 1.14, 95% CI 1.00–1.29).
INTERPRETATION:Follow-up care within 7 days of discharge from the emergency department was associated with lower rates of long-term mortality, as well as subsequent hospital admissions, and a trend to lower short-term mortality rates. Timely access to longitudinal care for patients with heart failure who are discharged from the emergency setting should be prioritized.
https://ift.tt/2QymafU
Systematic review and meta-analysis of prognostic factors for idiopathic inflammatory myopathy-associated interstitial lung disease
Objective
To clarify prognostic factors for idiopathic inflammatory myopathy (IIM)-associated interstitial lung disease (ILD).
DesignSystematic review and meta-analysis using the Grades of Recommendation, Assessment, Development and Evaluation system.
Data sourcesMedline, EMBASE and Science Citation Index Expanded were searched through 9 August 2018.
Eligibility criteria for selecting studiesThe review includes primary studies addressing all-cause mortality of IIM-associated ILD. Potential prognostic factors were any clinical information related to the outcome.
Data extraction and synthesisTwo reviewers extracted relevant data independently and assessed risk of bias using the Quality in Prognostic Studies tool. Meta-analysis was conducted using a random effects model and if inappropriate the results were reported qualitatively. Prognostic factors were determined based on statistically significant results derived from multivariate analysis.
ResultsOf a total of 5892 articles returned, 32 were deemed eligible for analysis and cumulatively, these studies reported 28 potential prognostic factors for all-cause mortality. Each study was subject to certain methodological constraints. The four prognostic factors, which demonstrated statistically significant results on both univariate and multivariate analyses, were as follows: age (MD 5.90, 3.17–8.63/HR 1.06, 1.02–1.10 and 2.31, 1.06–5.06), acute/subacute interstitial pneumonia (A/SIP) (OR 4.85, 2.81–8.37/HR 4.23, 1.69–12.09 and 5.17, 1.94–13.49), percentage of predicted forced vital capacity (%FVC) (OR 0.96, 0.95–0.98/HR 0.96, 0.93–0.99) and anti-Jo-1 antibody (OR 0.35, 0.18–0.71/HR 0.004, 0.00003–0.54) (univariate/multivariate, 95% CI). Other prognostic factors included ground glass opacity/attenuation (GGO/GGA) and extent of radiological abnormality. The quality of the presented evidence was rated as either low or very low.
ConclusionsOlder age, A/SIP, lower value of %FVC, GGO/GGA and extent of radiological abnormality were demonstrated to predict poor prognosis for IIM-associated ILD while a positive test for anti-Jo-1 antibody indicated better prognosis. However, given the weak evidence they should be interpreted with caution.
Trial registration numberCRD42016036999.
https://ift.tt/2CgXXlD
Precision-Exercise-Prescription in patients with lung cancer undergoing surgery: rationale and design of the PEP study trial
Introduction
Lung cancer is a significant burden on societies worldwide, and the most common cause of death in patients with cancer overall. Exercise intervention studies in patients with lung cancer have consistently shown benefits with respect to physical and emotional functioning. However, to date, exercise training has not been consistently implemented into clinical practice given that interventions have been costly and not aligned with clinical care.
Methods/designThe Precision-Exercise-Prescription (PEP) study is a prospective randomised controlled trial comparing the effectiveness and feasibility of a personalised intervention exercise programme among patients with lung cancer undergoing surgery. Two-hundred patients who are diagnosed with stage primary or secondary lung cancer and are eligible to undergo surgical treatment at Huntsman Cancer Institute comprise the target population. Patients are randomised to either the (1) outpatient precision-exercise intervention group or (2) delayed intervention group. The intervention approach uses Motivation and Problem Solving, a hybrid behavioural treatment based on motivational interviewing and practical problem solving. The dosage of the exercise intervention is personalised based on the individual's Activity Measure for Post-Acute-Care outpatient basic mobility score, and incorporates four exercise modes: mobility, callisthenics, aerobic and resistance. Exercise is implemented by physical therapists at study visits from presurgery until 6 months postsurgery. The primary endpoint is the level of physical function assessed by 6 min walk distance at 2 months postsurgery. Secondary outcomes include patient-reported outcomes (eg, quality of life, fatigue and self-efficacy) and other clinical outcomes, including length of stay, complications, readmission, pulmonary function and treatment-related costs up to 6 months postsurgery.
Ethics/disseminationThe PEP study will test the clinical effectiveness and feasibility of a personalised exercise intervention in patients with lung cancer undergoing surgery. Outcomes of this clinical trial will be presented at national and international conferences and symposia and will be published in international, peer-reviewed journals. Ethics approval was obtained at the University of Utah (IRB 00104671).
Trial registration numberhttps://ift.tt/2Cgesya
In-hospital dementia-related deaths following implementation of the national dementia plan: observational study of national death certificates from 1996 to 2016
Objective
To examine changes in places of dementia-related death following implementation of the national dementia plan and other policy initiatives.
DesignObservational study.
SettingJapan between October 1996 and September 2016. Four major changes in health and social care systems were identified: (1) the public long-term care insurance programme (April 2000); (2) community centres as a first access point for older residents (April 2006); (3) medical care system for older people (April 2008) and (4) the national dementia plan (April 2013).
Participants9 60 423 decedents aged 65 years or older whose primary cause of death was Alzheimer's disease, vascular or other types of dementia or senility.
Main outcome measuresPlace of death which was classified into 'hospital', 'intermediate geriatric care facility' (rehabilitation facility aimed at home discharge), 'nursing home' or 'own home'.
ResultsThe annual number of deaths at hospital was consistently increased over time from 1996 to 2016 (age-adjusted OR: 6.01; 95% CI 5.81 to 6.21 versus home deaths). Controlling for individual characteristics, regional supply of hospital and nursing home beds and other changes in health and social care systems, death from dementia following the national dementia plan was likely to occur in hospital (adjusted OR: 1.21; 95% CI 1.18 to 1.24), intermediate geriatric care facility (adjusted OR: 1.53; 95% CI 1.48 to 1.58) or nursing home (adjusted OR: 1.64; 95% CI 1.60 to 1.69) rather than at home.
ConclusionsAs the number of deaths from dementia increased over the decades, in-hospital deaths increased regardless of the national dementia plan. Further strategies should be explored to improve the availability of palliative and end-of-life care at patients' places of residence.
https://ift.tt/2SV6FLV
The personal and social experiences of community-dwelling younger adults after stroke in Australia: a qualitative interview study
Objectives
To examine the personal and social experiences of younger adults after stroke.
DesignQualitative study design involving in-depth semi-structured interviews and rigorous qualitative descriptive analysis informed by social constructionism.
ParticipantsNineteen younger stroke survivors aged 18 to 55 years at the time of their first-ever stroke.
SettingParticipants were recruited from urban and rural settings across Australia. Interviews took place in a clinic room of the Florey Institute of Neuroscience and Mental Health (Melbourne, Australia), over an online conference platform or by telephone.
ResultsFour main themes emerged from the discourses: (1) psycho-emotional experiences after young stroke; (2) losing pre-stroke life construct and relationships; (3) recovering and adapting after young stroke; and (4) invalidated by the old-age, physical concept of stroke. While these themes ran through the narratives of all participants, data analysis also drew out interesting variation between individual experiences.
ConclusionsFor many younger adults, stroke is an unexpected and devastating life event that profoundly diverts their biography and presents complex and continued challenges to fulfilling age-normative roles. While adaptation, resilience and post-traumatic growth are common, this study suggests that more bespoke support is needed for younger adults after stroke. Increasing public awareness of young stroke is also important, as is increased research attention to this problem.
https://ift.tt/2STHpFx
Poststroke depression and risk of stroke recurrence and mortality: protocol of a meta-analysis and systematic review
Introduction
A number of observational studies have indicated that poststroke depression could increase the risk of stroke outcomes. There is a meta-analysis indicating that poststroke depression is a risk factor of all-cause mortality. This paper reports the protocol for a systematic review and meta-analysis to clarify the associations of poststroke depression with stroke recurrence and mortality in order to determine whether poststroke depression is a predictor of stroke outcomes according to data extracted from relevant observational studies.
Methods and analysisMEDLINE, Web of Science databases, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews will be used to conduct the search. Published studies written in English will be included. The risk of bias for the studies included in the systematic review or meta-analysis will be assessed by the Newcastle–Ottawa Quality Assessment Scale. HRs for stroke recurrence and mortality with 95% CIs will be included as primary outcomes. Subgroup analyses and meta-regression will be performed.
Ethics and disseminationEthics approval will not be needed because the data used in this systematic review will be extracted from published studies. The results of the systematic review focusing on whether depression after stroke is a predictor for stroke recurrence and mortality will be disseminated by publication in a peer-reviewed journal.
PROSPERO registration numberCRD42018107944.
https://ift.tt/2CfZmZE
Scoping review of priority setting of research topics for musculoskeletal conditions
Objective
Describe research methods used in priority-setting exercises for musculoskeletal conditions and synthesise the priorities identified.
DesignScoping review.
Setting and populationStudies that elicited the research priorities of patients/consumers, clinicians, researchers, policy-makers and/or funders for any musculoskeletal condition were included.
Methods and analysisWe searched MEDLINE and EMBASE from inception to November 2017 and the James Lind Alliance top 10 priorities, Cochrane Priority Setting Methods Group, and Cochrane Musculoskeletal and Back Groups review priority lists. The reported methods and research topics/questions identified were extracted, and a descriptive synthesis conducted.
ResultsForty-nine articles fulfilled our inclusion criteria. Methodologies and stakeholders varied widely (26 included a mix of clinicians, consumers and others, 16 included only clinicians, 6 included only consumers or patients and in 1 participants were unclear). Only two (4%) reported any explicit inclusion criteria for priorities. We identified 294 broad research priorities from 37 articles and 246 specific research questions from 17 articles, although only four (24%) of the latter listed questions in an actionable format. Research priorities for osteoarthritis were identified most often (n=7), followed by rheumatoid arthritis (n=4), osteoporosis (n=4) and back pain (n=4). Nearly half of both broad and specific research priorities were focused on treatment interventions (n=116 and 111, respectively), while few were economic (n=8, 2.7% broad and n=1, 0.4% specific), implementation (n=6, 2% broad and n=4, 1.6% specific) or health services and systems research (n=15, 5.1% broad and n=9, 3.7% specific) priorities.
ConclusionsWhile many research priority-setting studies in the musculoskeletal field have been performed, methodological limitations and lack of actionable research questions limit their usefulness. Future studies should ensure they conform to good priority-setting practice to ensure that the generated priorities are of maximum value.
PROSPERO registration numberCRD42017059250.
https://ift.tt/2SPTifV
Exploring patient-reported outcomes of home-based cardiac rehabilitation in relation to Scottish, UK and European guidelines: an audit using qualitative methods
Objectives
The Heart Manual (HM) is the UK's leading facilitated home-based cardiac rehabilitation (CR) programme for individuals recovering from myocardial infarction and revascularisation. This audit explored patient-reported outcomes of home-based CR in relation to current Scottish, UK and European guidelines.
SettingPatients across the UK returned their questionnaire after completing the HM programme to the HM Department (NHS Lothian).
ParticipantsQualitative data from 457 questionnaires returned between 2011 and 2018 were included for thematic analysis. Seven themes were identified from the guidelines. This guided initial deductive coding and provided the basis for inductive subthemes to emerge.
ResultsThemes included: (1) health behaviour change and modifiable risk reduction, (2) psychosocial support, (3) education, (4) social support, (5) medical risk management, (6) vocational rehabilitation and (7) long-term strategies and maintenance. Both (1) and (2) were reported as having the greatest impact on patients' daily lives. Subthemes for (1) included: guidance, engagement, awareness, consequences, attitude, no change and motivation. Psychosocial support comprised: stress management, pacing, relaxation, increased self-efficacy, validation, mental health and self-perception. This was followed by (3) and (4). Patients less frequently referred to (5), (6) and (7). Additional themes highlighted the impact of the HM programme and that patients attributed the greatest impact to a combination of all the above themes.
ConclusionsThis audit highlighted the HM as comprehensive and inclusive of key elements proposed by Scottish, UK and EU guidelines. Patients reported this had a profound impact on their daily lives and proved advantageous for CR.
https://ift.tt/2CfZkRw
Early weight gain after stopping smoking: a predictor of overall large weight gain? A single-site retrospective cohort study
Objectives
Most people gain weight on stopping smoking but the extent of weight gain varies greatly. Interventions aimed at all quitters to prevent weight gain on cessation have proven unpopular but targeting people who have gained excess weight immediately after quitting may improve uptake and cost-effectiveness. We examined whether early large postcessation weight gain predicts overall large weight gain.
DesignRetrospective cohort study.
SettingPrimary care setting—smoking cessation centre in Prague, Czech Republic.
ParticipantsOut of 3537 patients treated between 2005 and 2013, 1050 were continuous abstainers (verified by carbon monoxide measurement) at 1-year follow-up and formed the cohort of the current report. 48.7% were women (n=511) with the mean age of 46 (±14.4) years.
MethodsIn this retrospective cohort study, all patients underwent usual tobacco dependence treatment using evidence-based methods. Weight was measured prior to smoking cessation and at each visit after quitting.
ResultsThe mean weight gain in the first month (n=763) was 0.79% (±2.03%), in the second month (n=646) was 1.49% (±2.58%), for the third month (n=566) 2.33% (±3.44%) and 4.1% (±5.31%) after 1-year follow-up (n=1050). The regression coefficient per 1% rise in the first 3 months was +0.13% (95% CI –0.04% to 0.30%). A receiver operating curve analysis showed that patients gaining more than 0.98% of their baseline weight during first 3 months had a sensitivity of 66% and specificity of 44% for gaining 7% or more weight by 12 months. In addition, lower body mass index and an increase in appetite at 3 months after quitting were associated with greater weight gain, while using nicotine replacement therapy was associated with less weight gain at 1-year follow-up.
ConclusionsPeople who stop smoking and gain a larger amount of weight early after quitting are not more likely to gain excessively at 1 year.
https://ift.tt/2SV6FeT
Interventions targeted at health professionals to reduce unnecessary caesarean sections: a qualitative evidence synthesis
Objective
To establish the views and experiences of healthcare professionals in relation to interventions targeted at them to reduce unnecessary caesareans.
DesignQualitative evidence synthesis.
SettingStudies undertaken in high-income, middle-income and low-income settings.
Data sourcesSeven databases (CINAHL, MEDLINE, PsychINFO, Embase, Global Index Medicus, POPLINE and African Journals Online). Studies published between 1985 and June 2017, with no language or geographical restrictions. We hand-searched reference lists and key citations using Google Scholar.
Study selectionQualitative or mixed-method studies reporting health professionals' views.
Data extraction and synthesisTwo authors independently assessed study quality prior to extraction of primary data and authors' interpretations. The data were compared and contrasted, then grouped into summary of findings (SoFs) statements, themes and a line of argument synthesis. All SoFs were Confidence in the Evidence from Reviews of Qualitative research (GRADE-CERQual) assessed.
Results17 papers were included, involving 483 health professionals from 17 countries (nine high-income, six middle-income and two low-income). Fourteen SoFs were identified, resulting in three core themes: philosophy of birth (four SoFs); (2) social and cultural context (five SoFs); and (3) negotiation within system (five SoFs). The resulting line of argument suggests three key mechanisms of effect for change or resistance to change: prior beliefs about birth; willingness or not to engage with change, especially where this entailed potential loss of income or status (including medicolegal barriers); and capacity or not to influence local community and healthcare service norms and values relating to caesarean provision.
ConclusionFor maternity care health professionals, there is a synergistic relationship between their underpinning philosophy of birth, the social and cultural context they are working within and the extent to which they were prepared to negotiate within health system resources to reduce caesarean rates. These findings identify potential mechanisms of effect that could improve the design and efficacy of change programmes to reduce unnecessary caesareans.
PROSPERO registration numberCRD42017059455.
https://ift.tt/2CfZh8i
Correction: Self-rated health among migrants from the former Soviet Union in Germany: a cross-sectional study
Stolpe S, Ouma M, Winkler V, et al. Self-rated health among migrants from the former Soviet Union in Germany: a cross-sectional study. BMJ Open 2018;8:e022947. doi: 10.1136/bmjopen-2018-022947.
This article was previously published with an error in the affiliations.
Affiliation number 3 should be:
Heidelberg Institute of Global Health, Unit Epidemiology and Biostatistics (EpiStat), University Hospital Heidelberg, Heidelberg, Germany.
Affiliation number 4 should be:
Chair for Epidemiology, Ludwig-Maximilians-Universität München at UNIKA-T Augsburg, Augsburg, Germany.
Co-author Andreas Deckert is associated to affiliation number 3.
Co-author Christa Meisinger is associated to affiliations 4 and 6.
https://ift.tt/2SXUf63
Improving the quality of administration of the Surgical Safety Checklist: a mixed methods study in New Zealand hospitals
While the WHO Surgical Safety Checklist (the Checklist) can improve patient outcomes, variable administration can erode benefits. We sought to understand and improve how operating room (OR) staff use the Checklist. Our specific aims were to: determine if OR staff can discriminate between good and poor quality of Checklist administration using a validated audit tool (WHOBARS); to determine reliability and accuracy of WHOBARS self-ratings; determine the influence of demographic variables on ratings and explore OR staff attitudes to Checklist administration.
DesignMixed methods study using WHOBARS ratings of surgical cases by OR staff and two independent observers, thematic analysis of staff interviews.
ParticipantsOR staff in three New Zealand hospitals.
Outcome measuresReliability of WHOBARS for self-audit; staff attitudes to Checklist administration.
ResultsAnalysis of scores (243 participants, 2 observers, 59 cases) supported tool reliability, with 87% of WHOBARS score variance attributable to differences in Checklist administration between cases. Self-ratings were significantly higher than observer ratings, with some differences between professional groups but error variance from all raters was less than 10%. Key interview themes (33 interviewees) were: Team culture and embedding the Checklist, Information transfer and obstacles, Raising concerns and 'A tick-box exercise'. Interviewees felt the Checklist could promote teamwork and a safety culture, particularly enabling speaking up. Senior staff were of key importance in setting the appropriate tone.
ConclusionsThe WHOBARS tool could be useful for self-audit and quality improvement as OR staff can reliably discriminate between good and poor Checklist administration. OR staff self-ratings were lenient compared with external observers suggesting the value of external audit for benchmarking. Small differences between ratings from professional groups underpin the value of including all members of the team in scoring. We identified factors explaining staff perceptions of the Checklist that should inform quality improvement interventions.
https://ift.tt/2Ci2tQY
Unrelated Events Are Linked in Memory When They Happen Close Together
When two events occur within a brief window of time they become linked in memory, such that calling forth memory of one helps retrieve memory for the other event, according to research published in Psychological Science, a journal of the Association for Psychological Science. This happens even when temporal proximity is the only feature that the two events share.
"Our research shows that people are constantly recording information about the order in which events happen, even if those events are unrelated. They can then use the order to help search memory," explains psychological scientist M. Karl Healey of Michigan State University.
Memory scientists have long been interested in determining whether temporal proximity acts as a tether of sorts that connects memories for different events. In most studies, researchers have tried to examine the phenomenon by asking people to memorize lists of words in the lab, but it is unclear how well this lab-based approach translates to memory for real-world events.
"In the fall of 2016, I was obsessing over US election coverage and it occurred to me that many other people probably were, too. This provided the opportunity for a more naturalistic test—we could ask people to remember news stories rather than word lists," Healey explains.
In one online study, Healey and coauthor Mitchell G.Uitvlugt collected and analyzed data following Election Day in 2016. The study participants had 7 minutes to recall as many election-related news stories as they could – for each story, they also drafted a short newspaper-style headline.
Healey and Uitvlugt identified actual news stories that corresponded with the headlines generated by the participants, noting the date that the stories appeared. For their analyses, the researchers did not include stories that were not associated with specific election-related events. This process yielded 7,759 headlines from 855 participants.
The researchers then calculated a lag score that measured the transition, in days, from one headline in a participant's story sequence to the next.
The results showed that participants tended to recall stories in time-based clusters: Short transitions between stories (0 to 10 days) were much more common than would be expected according to chance. Furthermore, long transitions of more than 50 days were less frequent than one would expect by chance. The analyses showed that what participants remembered wasn't due to news events naturally clustering close together in time but rather the clustering of stories together in memory.
This pattern held even after the researchers accounted for similarity between events. And a second online study, in which a separate group of 561 participants recalled news stories from the previous 4 months, showed similar results.
"I was surprised at how well these real-world data agreed with lab data," says Healey. "Although remembering world events you've read about over the course of months seems different than memorizing a list of random words presented over the course of minutes, at a fundamental level it seems both are governed by the same principles."
Uitvlugt and Healey point out that the participants could not have prepared for the memory task, which rules out the possibility that participants used specific strategies when the events occurred to aid subsequent recall. Instead, the findings suggest that our memories are tagged with time-correlated information as we encode them, and that this information can be used when we search memory later on.
"This research tells us something about memory in general. It suggests we all have a tendency to bind events together in memory when they occur near together in time," Healey says.
All data have been made available at the Computational Basis of Cognitive Control Lab website.
https://ift.tt/2QU7jMg
8 reasons we are on the cusp of Peak EMS
A bold prediction that EMS patient transport to the hospital by ambulance is sure to peak, level off and decline as we near 2020
https://ift.tt/2Lpcsa4
The oral selective oestrogen receptor degrader (SERD) AZD9496 is comparable to fulvestrant in antagonising ER and circumventing endocrine resistance
The oral selective oestrogen receptor degrader (SERD) AZD9496 is comparable to fulvestrant in antagonising ER and circumventing endocrine resistance
The oral selective oestrogen receptor degrader (SERD) AZD9496 is comparable to fulvestrant in antagonising ER and circumventing endocrine resistance, Published online: 17 December 2018; doi:10.1038/s41416-018-0354-9
The oral selective oestrogen receptor degrader (SERD) AZD9496 is comparable to fulvestrant in antagonising ER and circumventing endocrine resistancehttps://ift.tt/2Cgdpya
Interferon-alpha promotes immunosuppression through IFNAR1/STAT1 signalling in head and neck squamous cell carcinoma
Interferon-alpha promotes immunosuppression through IFNAR1/STAT1 signalling in head and neck squamous cell carcinoma
Interferon-alpha promotes immunosuppression through IFNAR1/STAT1 signalling in head and neck squamous cell carcinoma, Published online: 17 December 2018; doi:10.1038/s41416-018-0352-y
Interferon-alpha promotes immunosuppression through IFNAR1/STAT1 signalling in head and neck squamous cell carcinomahttps://ift.tt/2CeQS4Q
(Pro)renin receptor promotes colorectal cancer through the Wnt/beta-catenin signalling pathway despite constitutive pathway component mutations
(Pro)renin receptor promotes colorectal cancer through the Wnt/beta-catenin signalling pathway despite constitutive pathway component mutations
(Pro)renin receptor promotes colorectal cancer through the Wnt/beta-catenin signalling pathway despite constitutive pathway component mutations, Published online: 17 December 2018; doi:10.1038/s41416-018-0350-0
(Pro)renin receptor promotes colorectal cancer through the Wnt/beta-catenin signalling pathway despite constitutive pathway component mutationshttps://ift.tt/2STGZzg
Completion Lymph Node Dissection or Radiation Therapy for Sentinel Node Metastasis in Merkel Cell Carcinoma
Abstract
Background
For sentinel lymph node (SLN) metastasis from Merkel cell carcinoma (MCC), the benefit of completion lymph node dissection (CLND) versus radiation therapy (RT) is unclear. This study compares outcomes for patients with SLN metastasis undergoing CLND or RT. We also evaluated positive non-SLNs as a prognostic factor.
Methods
Using a prospective database, we identified MCC patients with SLN metastasis who underwent CLND or RT. At our institution, CLND was recommended for patients with acceptable perioperative risk, while therapeutic RT was offered to those with high perioperative risk. Primary outcomes were MCC-specific survival (MCCSS), disease-free survival (DFS), nodal recurrence-free survival (NRFS), and distant recurrence-free survival (DRFS).
Results
From 2006 to 2017, 163 patients underwent CLND (n = 137) or RT (n = 26). Median follow-up was 1.9 years. CLND had no significant differences for MCCSS (5-year survival 71% vs. 64%, p = 1.0), DFS (52% vs. 61%, p = 0.8), NRFS (76% vs. 91%, p = 0.3), or DRFS (65% vs. 75%, p = 0.3) compared with RT. Patients with positive non-SLNs (n = 44) had significantly worse MCCSS (5-year survival 39% vs. 87%, p < 0.001), DFS (35% vs. 60%, p = 0.005), and DRFS (54% vs. 71%, p = 0.03) compared with negative non-SLNs (n = 93). Multivariate analysis showed positive non-SLNs were independently associated with MCCSS, DFS, and DRFS.
Conclusions
CLND and RT may have similar outcomes for MCC patients with SLN metastasis when treatment aligns with our institutional practices. For patients undergoing CLND, positive non-SLNs is an important prognostic factor associated with poor survival and distant recurrence. This high-risk group should be considered for adjuvant systemic therapy trials.
https://ift.tt/2zVXKCP
OncotypeDX Recurrence Score Does Not Predict Nodal Burden in Clinically Node Negative Breast Cancer Patients
Abstract
Background
OncotypeDX recurrence score (RS)® has been found to predict recurrence and disease-free survival in patients with node negative breast cancer. Whether RS is useful in guiding locoregional therapy decisions is unclear. We sought to evaluate the relationship between RS and lymph node burden.
Methods
Patients with invasive breast cancer who underwent sentinel lymph node dissection from 2010 to 2015 were identified from a prospectively maintained database. Patients were excluded if they were clinically node positive or if they received neoadjuvant chemotherapy. RS was classified as low (< 18), intermediate (18–30), or high (> 30). The association between RS, lymph node burden, and disease recurrence was evaluated. Statistical analyses were performed in R version 3.4.0; p < 0.05 was considered significant.
Results
A positive SLN was found in 168 (15%) of 1121 patients. Completion axillary lymph node dissection was performed in 84 (50%) of SLN-positive patients. The remaining 84 (50%) patients had one to two positive SLNs and did not undergo further axillary surgery. RS was low in 58.5%, intermediate in 32.6%, and high in 8.9%. RS was not associated with a positive SLN, number of positive nodes, maximum node metastasis size, or extranodal extension. The median follow-up was 23 months. High RS was not associated with locoregional recurrence (p = 0.07) but was significantly associated with distant recurrence (p = 0.0015).
Conclusions
OncotypeDX RS is not associated with nodal burden in women with clinically node-negative breast cancer, suggesting that RS is not useful to guide decisions regarding extent of axillary surgery for these patients.
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Single Nucleotide Polymorphisms in Selected Genes in Inflammatory Bowel Disease
Introduction. Inflammatory bowel disease (IBD) is a complicated, multifunctional disorder characterized by chronic, recurring inflammation of the digestive tract. The two main types of IBD are ulcerative colitis (UC) and Crohn's disease (CD). The aim of the study was to determine single nucleotide polymorphism in fragments of the genes CARD15/NOD2 and DLG5 in patients from the Lublin Voivodeship. Patients and Methods. The study was carried out in Lublin (Poland) in 2016. 27 individuals participated in the research. The research group comprised 9 patients with a diagnosis of Crohn's disease and 9 with ulcerative colitis, aged 20 to 48, and 9 healthy volunteers. Results. No SNPs were confirmed for the CARD15/NOD2 gene fragment, but a substitution (T>C) was found in the DLG5 gene in a Crohn's disease patient. Conclusion. Absence of extraintestinal symptoms in patients with Crohn's disease may be associated with the absence of CARD15/NOD2 SNPs. The study suggests that SNPs (T>C substitution) affect the function of the DLG5 protein and thus play a role in the development of IBD, in particular Crohn's disease. The analysis presented is a pilot study due to the small number of samples.
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Clinical Decision-Making in Chronic Spine Pain: Dilemma of Image-Based Diagnosis of Degenerative Spine and Generation Mechanisms for Nociceptive, Radicular, and Referred Pain
Background. Spine-related pain is a complex heterogeneous condition. Excessive reliance on radiological imaging might lead to overdiagnosis of incidental asymptomatic spinal changes and unnecessary surgery. Approaches to the clinical management of spine pain should (1) identify pain generators, types, patterns, and mechanisms; (2) confirm clinical suspension with a diagnostic injection; and (3) ensure that treatment is aimed at controlling pain and improving patient function rather than image-based surgical success. Method. This case series (7 cases) discusses commonly seen clinical presentation of spine pain analytically, with illustrations of possible pain generators, mechanisms, pathways, and pain types. Each case discusses pain types and location (axial nociceptive, referred, and radicular neuropathic), generators (degenerated disc, herniated disc, facet joint, and sacroiliac joint), pathways (sinuvertebral ventral ramus and medial and lateral branches dorsal ramus), and radiculopathy versus radicular pain, elaborating on coccydynia and cervicogenic headaches, epimere versus hypomere muscle embryology, function, innervation, and role in spine-related pain. Results. Multiple pain generators might coexist in the same patient causing mixed pain types and referral patterns with multiple mechanisms and pathways. History review, physical examination, and diagnostic injections are the mainstays of diagnosis. Conclusions. Image-detected spondylosis might be an asymptomatic process. Clinical presentation is related to stenosis or pain. The mechanism of pain is related to compression, inflammation, or microinstability. Spine pain can be nociceptive axial, neuropathic radicular, and/or referred pain. Although image findings are helpful in radicular neuropathic pain from disc herniation, they are unreliable in nociceptive pain, and correlation with clinical and diagnostic injections is mandatory.
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Effect of Potent P2Y12 Inhibitors on Ventricular Arrhythmias and Cardiac Dysfunction in Coronary Artery Disease: A Systematic Review and Meta-Analysis
Background. Previous studies have shown that receptor inhibitors might prevent ventricular arrhythmias and cardiac dysfunction in patients with coronary artery disease. However, few studies have focused on comparison of the efficacy of novel oral potent P2Y12 receptor inhibitors with clopidogrel on these outcomes. Methods and Results. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) that were published in electronic databases of MEDLINE, EMBASE, Cochrane Central Register of Clinical Trials, and ClinicalTrials.gov before June 20, 2018. We compared the effect of prasugrel and ticagrelor with clopidogrel on outcomes of ventricular tachycardia (VT), ventricular fibrillation (VF), heart failure (HF), and cardiogenic shock (CS). Data were combined using both the fixed-effects models and the random-effects models, and the heterogeneity was assessed with the statistic. Nine RCTs (6 with prasugrel and 3 with ticagrelor) with 45,227 patients were included. Patients receiving prasugrel were associated with a lower risk of combined VT and VF (rate ratio [RR]: 0.72, 95% confidence interval [CI]: 95% CI: 0.52-0.99, p=0.043), as well as combined HF and CS (RR: 0.81, 95% CI: 0.70-0.94, p=0.005), compared with clopidogrel. Patients receiving ticagrelor were also associated with a reduced risk of VT and VF (RR: 0.85, 95% CI: 0.72-1.02, p=0.077), although without statistical significance, but not of HF and CS (RR: 0.96, 95% CI: 0.81-1.13, p=0.620). Conclusions. This meta-analysis of RCTs shows that, compared with clopidogrel, novel oral inhibitors, especially prasugrel, might have better effect on improving ventricular rhythm and cardiac function.
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Derivation and Differentiation of Canine Ovarian Mesenchymal Stem Cells
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UV‐B‐activated B16 melanoma cells or HaCaT keratinocytes increase melanogenesis via ANGPTL2 induction, an activity antagonized by Chrysanthemum extract
Abstract
Sunburn causes inflammation, which increases melanin production in skin and causes hyperpigmentation. Angiopoietin‐like protein (ANGPTL) 2 is an inflammatory mediator induced in sun‐exposed skin areas. However, whether ANGPTL2 functions in melanin production remains unclear. To assess this possibility, we overexpressed Angptl2 in the melanoma line B16 and in the keratinocyte line HaCaT. Relative to controls, Angptl2‐expressing B16 cells produced higher melanin levels via tyrosinase induction. Accordingly, Angptl2‐expressing HaCaT cells secreted relatively high levels of both endothelin‐1 (ET‐1) and α‐melanocyte stimulating hormone (α‐MSH). Moreover, treatment with an extract from Chrysanthemum indicum x Erigeron annuus (CE) suppressed ANGPTL2 expression and repressed tyrosinase induction in melanocytes and of α‐MSH and ET‐1 in keratinocytes. Our data suggests that ANGPTL2 expression in keratinocytes and melanin‐producing cells accelerates pigment production and that treatment of skin with a CE extract could prevent melanin accumulation.
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Biomechanical evaluation of a transcondylar screw from the dorsolateral plate support on the stabilization of orthogonal plate configuration in distal humeral fracture
Publication date: Available online 16 December 2018
Source: Injury
Author(s): Akira Hara, Toshiya Kudo, Satoshi Ichihara, Hideaki Iwase, Masashi Nagao, Yuichiro Maruyama, Kazuo Kaneko
Abstract
Introduction
Intra-articular distal humeral fractures involving both columns require double-plate fixation. In orthogonal plate fixation, screws from the medial plate reach the radial column, while screws from the dorsolateral plate run posterior–anterior, not creating interdigitation. The Synthes LCP-DHP system has an orthogonal plate configuration that enables dorsolateral plating with support, as the radial and ulnar columns are linked via interdigitation of the distal screws. We hypothesized that the transcondylar screw from the posterolateral plate, which interdigitates with screws from the medial plate, enables more rigid stabilization of orthogonal plating in distal humeral AO type C fractures.
Methods
A previous study reported the biomechanical properties of orthogonal plate fixation using an AO type 13-C2.3 intra-articular fracture model with a 1-cm supracondylar gap using artificial bones (Kudo et al., Injury, 2016). We performed a biomechanical study of the dorsolateral plate with support, and inserted one 2.7-mm locking screw through the support in the lateral-to-medial direction, creating interdigitation of the distal screws. A 0–200 N axial load was applied separately to the radial and ulnar columns. We calculated the stiffness of both columns, and the anterior displacement of the condylar fragment. We compared the biomechanical properties of orthogonal plating with versus without interdigitation.
Results
There were no significant differences between the two groups in radial or ulnar axial compression. The ulnar column was stiffer than the radial column in both groups. There were no significant differences between groups in the angular displacements of the capitellum or trochlea. The capitellum moved more anteriorly than the trochlea during axial compression in both groups.
Discussion
The radial and ulnar columns were linked via interdigitation of the distal screws by adding one transcondylar screw from the dorsolateral plate, which did not affect radial column stiffness or capitellar anterior movement under axial compression. In the orthogonal configuration, axial compression induced more anterior displacement of the capitellum than the trochlea, which may induce secondary fragment or screw dislocation on the dorsolateral plate or nonunion at the supracondylar level.
Conclusions
The transcondylar screw from the dorsolateral plate did not affect axial compression of the radial column or capitellar anterior displacement.
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Competitive advantage gained from the use of helicopter emergency medical services (HEMS) for trauma patients: evaluation of 1724 patients
Publication date: Available online 16 December 2018
Source: Injury
Author(s): M. Weinlich, P. Martus, M.B. Blau, H. Wyen, F. Walcher, S. Piatek, J.P. Schüttrumpf
Abstract
Objectives
The aim of the study was to analyze helicopter emergency medical service (HEMS) in comparison to EMS, in respect to patient's mortality and morbidity.
Design
From a cohort of traumatized patients (n = 1724) prospectively enrolled in the German trauma registry (DGU-R) at Frankfurt University Hospital from 2009-2013, 1646 could be analyzed for in-hospital mortality and short-term outcome (GOS) at discharge and compared between HEMS and EMS.
Measurements and main results
129 patients (7.8%) died in the hospital. Unadjusted mortality was significantly lower in the HEMS group compared to EMS (p = 0.001). In a multiple logistic regression analysis after adjustment of variables including reanimation and age as the strongest predictors, in-hospital mortality was significantly reduced in HEMS (p = 0.014, OR = 0.21). Further predictors in the multiple logistic regression analysis were GCS > = 8 (p = 0.001), RRsys (p < 0.001), ISS at Head/Neck > = 3 (p = 0.003), and total ISS > = 9 (p < 0.001). Total rescue time and on scene time were associated with mortality (p < 0.001) but not included in the multiple logistic regression model. Without adjustment, short-term outcome (GOS) was significantly improved (p = 0.014). In a linear model, after adjusting for multiple variables including age, ISS Head/Neck > = 3, ISS Extremities > = 3, GCS > = 8, and RRsys as the strongest predictors (p < 0.001), the association remained significant (p = 0.043). Further predictors in the multiple linear regression analysis were total ISS > = 9 (p = 0.002), ISS abdomen (p = 0.001), and ISS Chest (p = 0.011).
Conclusions
A significant improvement for in-hospital survival for HEMS could be demonstrated. Especially in Germany, with a high number of secondary call outs (about 44%) after EMS has already reached the traumatized patient, HEMS must be the first choice for severely injured trauma patients. Dispatch criteria for immediate alarm of HEMS are recommended under practical considerations.
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Lupinus mutabilis Edible Beans Protect against Bacterial Infection in Uroepithelial Cells
Lupinus mutabilis is a South American herb with edible beans, known to reduce serum glucose levels in diabetic patients. Furthermore, L. mutabilis contains phytochemicals known to decrease bacterial load. Based on the increased urinary tract infections experienced among patients with diabetes, we investigated the effect of L. mutabilis on bladder epithelial cells in the protection of E. coli infection during normal and high glucose concentrations. We did not observe any direct antibacterial effect by L. mutabilis extract. Instead we observed an influence on the host cells, with indirect impact on bacteria and their possibility of causing infection. L. mutabilis extract decreased adhesion to bladder epithelial cells of uropathogenic bacteria, including drug-resistant strains. Moreover, uroplakin1a, involved in adhesion, was downregulated while the antimicrobial peptide RNase 7 was upregulated in L. mutabilis treated cells irrespectively of glucose concentration. This supports an early effect fighting bacteria. Additionally, L. mutabilis prevented bacterial biofilm formation, which is used by bacteria to evade the immune system and antibiotics. In summary, L. mutabilis protects against bacterial infection in uroepithelial cells by preventing adhesion through alteration of the cell surface, increasing antimicrobial peptide expression, and reducing biofilm formation. Together, this promotes bacterial clearance, suggesting that L. mutabilis as extract or as a dietary item can contribute to the prevention of urinary tract infections, which is of importance in an era of increasing antibiotic resistance.
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Effects of Plasma Albumin on the Pharmacokinetics of Esomeprazole in ICU Patients
Objectives. To evaluate the effects of plasma albumin on pharmacokinetics of esomeprazole in ICU patients. Methods. This study was performed in 32 consecutive intensive care unit (ICU) patients. They were divided into two groups according to the plasma albumin levels. Nineteen patients with low plasma albumin levels (30 g/L (male/female, 9/4) were assigned to high plasma albumin group (HPAG). All patients were received intravenous (IV) of 40 mg esomeprazole in 5 min. Blood samples were collected via basilic vein at different time points and concentrations of esomeprazole were determined by UPLC-MS/MS. Results. ,, V, CL, and between two groups were significantly difference (P
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Muscle Ciliary Neurotrophic Factor Receptor α Contributes to Motor Neuron STAT3 Activation Following Peripheral Nerve Lesion
Abstract
Expression of the ciliary neurotrophic factor (CNTF) receptor essential ligand binding subunit, CNTF receptor α (CNTFRα), is induced in motor neurons and skeletal muscle following peripheral nerve lesion. We previously found muscle CNTFRα promotes motor neuron axon regeneration post‐lesion. Both nerve lesion and CNTF administration activate motor neuron signal transducer and activator of transcription 3 (STAT3), a transcription factor implicated in axon growth, suggesting CNTF receptors may contribute to the lesion‐induced STAT3 activation. However, many receptor types signal through STAT3, and if CNTF receptors contribute, motor neuron receptors seemed most likely to regulate motor neuron STAT3. To determine the role played by muscle CNTFRα, we used in vivo, muscle‐specific CNTFRα depletion in mice and report here that this selectively impairs the second phase, sustained motor neuron STAT3 activation post‐lesion. Thus, muscle CNTFRα makes an essential contribution to motor neuron STAT3 activation during axon regeneration and may thereby promote axon regeneration through such signaling. We also report CNTFRα quantitative PCR suggesting involvement of many denervated muscle types, as well as muscle damaged at the lesion site. The present data add to the evidence suggesting that enhancing muscle CNTFRα expression may promote motor neuron regeneration in trauma and disease.
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Kaempferia parviflora and Its Methoxyflavones: Chemistry and Biological Activities
Kaempferia parviflora (KP), a health-promoting herb, has been traditionally used for treating a variety of diseases. Pharmacological studies have claimed the various benefits from KP and its main effective methoxyflavones, including cellular metabolism-regulating activity, anticancer activity, vascular relaxation and cardioprotective activity, sexual enhancing activity, neuroprotective activity, antiallergic, anti-inflammatory, and antioxidative activity, antiosteoarthritis activity, antimicroorganism activity, and transdermal permeable activity. These might be associated with increased mitochondrial functions and activated cGMP-NO signaling pathway. However, the underlying molecular mechanisms of KP and its methoxyflavones are still under investigation. The clinical applications of KP and its methoxyflavones may be limited due to their low bioavailability. But promising strategies are on the way. This review will comprehensively discuss the biological activities of KP and its methoxyflavones.
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Hepatoprotective Effect of Eriobotrya japonica Leaf Extract and Its Various Fractions against Carbon Tetra Chloride Induced Hepatotoxicity in Rats
Eriobotrya japonica is traditionally used as an antipyretic, digestive, and diuretic agent. Its flowers possess free radical–scavenging, antioxidative, and hepatoprotective effects. We investigated the hepatoprotective potential of E. japonica leaf extract and its various fractions against hepatotoxicity in rats. Liver injury was stimulated by the oral administration of carbon tetrachloride (CCl4; 2.5 mL/kg b.wt.). Male albino rats (n = 55) were distributed arbitrarily into 11 groups: Group I, normal control group; Group II, CCl4 (positive control group); Group III, CCl4 + silymarin; Groups IV and V, CCl4 + two doses of 250 and 500 mg/kg of the 80% methanolic extract of E. japonica leaves, respectively; Groups VI and VII, CCl4 + 250 mg/kg and 500 mg/kg of the ethyl acetate fraction, respectively; Groups VIII and IX, CCl4 + 250 and 500 mg/kg of the butanol fraction, respectively; and Groups X and XI, CCl4 + 250 and 500 mg/kg of the aqueous fraction of E. Japonica leaves, respectively. CCl4-treated rats that were given 250 or 500 mg/kg of the methanol extract of E. Japonica leaves, or its ethyl acetate, butanol, or aqueous fractions, had significantly lower levels of biochemical parameters such as alanine aminotransferase, aspartate transaminase, alkaline phosphate, total protein, gamma-glutamyl transferase, and bilirubin levels than those of the CCl4 positive group. However, the extract and fractions did not significantly affect lipid profiles. Thus, we conclude that Eriobotrya leaf extract and its fractions have a hepatoprotective effect against CCl4-induced hepatotoxicity in rats.
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Implementing a comprehensive translational oncology platform: from molecular testing to actionability.
| Related Articles |
Implementing a comprehensive translational oncology platform: from molecular testing to actionability.
J Transl Med. 2018 Dec 14;16(1):358
Authors: Mitri ZI, Parmar S, Johnson B, Kolodzie A, Keck JM, Morris M, Guimaraes AR, Beckett BR, Borate U, Lopez CD, Kemmer KA, Alumkal JJ, Beer TM, Corless CL, Mills GB, Gray JW, Bergan RC
Abstract
BACKGROUND: In order to establish the workflows required to implement a real-time process involving multi-omic analysis of patient samples to support precision-guided therapeutic intervention, a tissue acquisition and analysis trial was implemented. This report describes our findings to date, including the frequency with which mutational testing led to precision-guided therapy and outcome for those patients.
METHODS: Eligible patients presenting to Oregon Health and Science University Knight Cancer Institute were enrolled on the study. Patients with biopsy proven metastatic or locally advanced unresectable prostate cancer, breast cancer, pancreatic adenocarcinoma, or refractory acute myelogenous leukemia receiving standard of care therapy were eligible. Metastatic site biopsies were collected and analyzed using the Knight Diagnostic Lab GeneTrails comprehensive solid tumor panel (124 genes). CLIA certified genomic information was made available to the treating physician.
RESULTS: Between 1/26/2017 and 5/30/2018, 38 patients were enrolled, with 28 successfully undergoing biopsy. Of these, 25 samples yielded sufficient tumor for analysis. The median biopsy cellularity and number of cores collected were 70% (15-90%) and 5 (2-20), respectively. No procedure-related complications occurred. GeneTrails analysis revealed that 22 of 25 (88%) tumor samples harbored at least one potentially actionable mutation, and 18 (72%) samples harbored 2 or more potentially actionable mutations. The most common genetic alterations identified involved: DNA damage repair genes, cell cycle regulating genes, PIK3CA/Akt/mTOR pathway, and FGF gene family. To date, CLIA certified genomic results were used by treating physicians for precision-guided therapy in 5 (23%) patients.
CONCLUSION: We report the feasibility of real-time tissue acquisition and analysis to support a successful translational oncology platform. The workflow will provide the foundation to improve access and accrual to biomarker driven precision oncology trials.
PMID: 30551737 [PubMed - in process]
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CD5-Positive Intravascular Large B-Cell Lymphoma in a Patient with Wilson’s Disease: Case Report and Review of the Literature
Intravascular large B-cell lymphoma (IVLBCL) is a rare extra-nodal B-cell lymphoma that proliferates within small/intermediate blood vessels and capillaries while sparing large blood vessels and organ parenchyma. Clinical presentation is highly variable and may include B symptoms, neurological deficits, and/or cutaneous findings. The diagnosis of IVLBCL is difficult due to multiorgan involvement and nonspecific symptoms. We describe the case of a 68-year-old male who presented with progressive weakness, confusion, and falls. He had a past medical history of liver cirrhosis secondary to Wilson's disease. Physical exam and laboratory results revealed a lethargic man with jaundice, hepatic encephalopathy, and abnormal liver/kidney function tests. He expired after a short hospital course in the setting of hepatic and renal failure. Postmortem examination revealed large neoplastic lymphoid cells involving multiple organ blood vessels; however skin and neurologic involvement was absent. The neoplastic cells demonstrated B-cells positive for CD5, rendering a diagnosis of IVLBCL. Our case represents the occurrence of IVLBCL with CD5-positivity in a patient with Wilson's disease, diagnosed at autopsy demonstrating the challenging nature of diagnosing IVLBCL.
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Corrigendum
Philip Seibler, Lena F. Burbulla, Marija Dulovic, Simone Zittel, Johanne Heine, Thomas Schmidt, Franziska Rudolph, Ana Westenberger, Aleksandar Rakovic, Alexander Münchau, Dimitri Krainc, Christine Klein. Iron overload is accompanied by mitochondrial and lysosomal dysfunction in WDR45 mutant cells. Brain 2018; 141: 3052–3064. doi:10.1093/brain/awy230.
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Beyond the headlines: Fetal movement awareness is an important stillbirth prevention strategy
Publication date: Available online 15 December 2018
Source: Women and Birth
Author(s): Vicki Flenady, David Ellwood, Billie Bradford, Michael Coory, Philippa Middleton, Glenn Gardener, Ingela Radestad, Caroline Homer, Miranda Davies-Tuck, Della Forster, Adrienne Gordon, Katie Groom, Caroline Crowther, Sue Walker, Claire Foord, Jane Warland, Margaret Murphy, Joanne Said, Fran Boyle, Keelin O'Donoghue
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Endoplasmic Reticulum Stress Markers and Their Possible Implications in Leprosy’s Pathogenesis
Mycobacterium leprae causes leprosy, a dermatoneurological disease which affects the skin and peripheral nerves. One of several cellular structures affected during M. leprae infection is the endoplasmic reticulum (ER). Infection by microorganisms can result in ER stress and lead to the accumulation of unfolded or poorly folded proteins. To restore homeostasis in the cell, the cell induces a series of signaling cascades known as the unfolded protein response called UPR (unfolded protein response). The present work is aimed at investigating the in situ expression of these markers in cutaneous lesions of clinical forms of leprosy and establish possible correlation expression patterns and types of lesion. A total of 43 samples from leprosy patients were analyzed by immunohistochemistry with monoclonal antibodies against GRP78/BiP, PERK, IRE1α, and ATF6. A statistically significant difference between the indeterminate, tuberculoid, and lepromatous clinical forms was detected, with high expression of GRP78/BiP, PERK, IRE1α, and ATF6 in tuberculoid forms (TT) when compared to lepromatous leprosy (LL) and indeterminate (I) leprosy. These results represent the first evidence of ER stress in samples of skin lesions from leprosy patients. We believe that they will provide better understanding of the complex pathogenesis of the disease and facilitate further characterization of the cascade of molecular events elicited during infection.
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Toll-Like Receptor 4–Myeloid Differentiation Primary Response Gene 88 Pathway Is Involved in the Shikonin Treatment of CIA by Regulating Treg/Th17 Expression
Objective. To investigate the effect of shikonin on (CIA) collagen-induced arthritis and its influence and mechanism on the balance between Th17 cells and Treg cells. Methods. Three doses of shikonin were administered orally to mice before the onset of CIA, and celecoxib was used as positive control drug. The arthritis response was monitored visually by macroscopic scoring and hindpaw swelling. Histology of knee was used to assess the occurrence of cartilage destruction and bone erosion. Serum collagen type II (C II) antibody levels associated with CIA were assessed with ELISAs. RT-PCR and quantitative PCR were employed to determine the mRNA expression of cytokines and TLRs in the surface of DCs in the patella with adjacent synovium and spleen in CIA. The expression of cytokines and transcription factors in the peripheral immune organs was tested by Western blotting. Results. Shikonin treatment suppressed the macroscopic score and incidence of arthritis. Swelling of hind paws, cartilage destruction, and serum anti-C II concentration were delayed with shikonin when compared to controls. Shikonin treatment suppressed the arthritis in a dose-dependent manner. Moreover, the expression of Th17 cytokines (IL-17A) was greatly inhibited both in the synovium and spleen in treated groups compared with those in control groups. The mRNA and protein levels of IL-10 and TGF-β, however, were upregulated after shikonin treatment. The expression of Foxp3 in the synovium and spleen was upregulated, and the expression of ROR-γt in the synovium and spleen was downregulated after shikonin treatment through RT-PCR, quantitative PCR, and Western blotting. The DCs in the spleen of shikonin-treated mice had lower expression of TLR4 and MyD88, and the expression of TLR2 and TLR9 in the spleen was not different between the two groups. Conclusion. Shikonin has anti-inflammatory effects on CIA. Shikonin treatment can inhibit Th17 cytokines expression and induce Treg responses through inhibiting the activation of TLR4/MyD88 pathway.
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Degalactotigonin, a Steroidal Glycoside from Solanum nigrum, Induces Apoptosis and Cell Cycle Arrest via Inhibiting the EGFR Signaling Pathways in Pancreatic Cancer Cells
Degalactotigonin (1) and three other steroidal compounds solasodine (2), O-acetyl solasodine (3), and soladulcoside A (4) were isolated from the methanolic extract of Solanum nigrum, and their chemical structures were elucidated by spectroscopic analyses. The isolated compounds were evaluated for cytotoxic activity against human pancreatic cancer cell lines (PANC1 and MIA-PaCa2) and lung cancer cell lines (A549, NCI-H1975, and NCI-H1299). Only degalactotigonin (1) showed potent cytotoxicity against these cancer cell lines. Compound 1 induced apoptosis in PANC1 and A549 cells. Further study on its mechanism of action in PANC1 cells demonstrated that 1 significantly inhibited EGF-induced proliferation and migration in a concentration-dependent manner. Treatment of PANC1 cells with degalactotigonin induced cell cycle arrest at G0/G1 phase. Compound 1 induced downregulation of cyclin D1 and upregulation of p21 in a time- and concentration-dependent manner and inhibited EGF-induced phosphorylation of EGFR, as well as activation of EGFR downstream signaling molecules such as Akt and ERK.
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Intramedullary Spinal Cord Metastasis from Renal Cell Carcinoma: A Systematic Review of the Literature
Intramedullary spinal cord metastases from renal cell carcinomas (RCCs) are rare and can cause serious diagnostic and therapeutic dilemmas. The related reports are very few. This review was aimed to perform an analysis of all reported cases with intramedullary spinal cord metastases from RCCs. In January 2018, we performed a literature search in PubMed database using a combination of the keywords "intramedullary spinal cord metastasis" and "renal cell carcinoma". In addition, we present the clinical, neuroradiological, and histopathological findings in our patient with an intramedullary metastasis from a RCC. 17 cases were generated in our research. The mean interval from diagnosis of RCC to diagnosis of ISCM was 22 months. The median survival of surgically treated patients was 8.6 months and 8 months in patients who underwent radical surgery. Based on our review, RCCs can invade the medulla of the spinal cord several years after removal of the primary lesion. The prognosis of ISCMs from RCCs was poor. Retrograde passage of tumor cells into the spinal cord from the inferior vena cava via the epidural venous sinuses may have been the pathological mechanism for ISCM in our patient. Radical resection and radiation are effective ways of achieving recovery of neurologic function and improving quality of life. More reports are needed to enable exploration of the mechanisms of metastasis and the optimal forms of therapy.
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Orf virus infection of human keratinocytes and dermal fibroblasts: limited virus detection and interference with intercellular adhesion molecule‐1 up‐regulation
Abstract
Orf virus (Parapoxvirus ovis, ORFV) is a dermatotropic virus causing pustular dermatitis in small ruminants and humans. We analyzed isolated human primary keratinocytes (KC) and dermal fibroblasts (FB) for cell death and virus replication by infection with a patient‐derived ORFV isolate. ORFV infection was associated with rapid induction of cell death in KC allowing for considerable virus removal. Upon infection with ORFV, KC and FB harbored intracytoplasmic ORFV and showed viral protein presence, however missing virus spread indicated an abortive infection. Upon ORFV exposure, KC but not FB secreted the pro‐inflammatory cytokine interleukin (IL)‐6. ORFV infection enhanced the frequency of KC expressing intercellular adhesion molecule (ICAM)‐1 which was independent of IL‐6. Interestingly, ORFV inhibited ICAM‐1 up‐regulation on infected but not on non‐infected KC. Even interferon‐γ, a potent inducer of ICAM‐1, upregulated ICAM‐1 only on non‐infected KC. Transfer of ORFV‐free supernatant from infected to non‐infected KC induced ICAM‐1 on non‐infected KC pointing to the involvement of soluble mediator(s). Similarly as in KC, in FB interference with ICAM‐1 up‐regulation by ORFV infection was also observed. In conclusion, we shed light on epidermal and dermal defense mechanisms to ORFV infection and point to a novel ICAM‐1‐related immune evasion mechanism of ORFV in human skin.
This article is protected by copyright. All rights reserved.
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Lenalidomide and Low Dose Dexamethasone Plus Elotuzumab or Carfilzomib for Relapsed or Refractory Multiple Myeloma: A Comparison of Progression-Free Survival with Reconstructed Individual Participant Data
Background. Refractory and relapsed multiple myeloma (RRMM) remains a clinical challenge. We compared the progression-free survival (PFS) of RRMM patients treated with lenalidomide and low dose dexamethasone plus elotuzumab or carfilzomib (ELD vs. CLD), using reconstructed individual patient data (IPD) based on two published trials reports. Methods. We extracted data of study-level characteristics from original trial reports. We evaluated the comparability between the two treatment groups in terms of baseline status. Digitization of PFS Kaplan-Meier curves, reconstruction of IPD data, and subsequent survival analysis were performed. Distribution of progression and death events over time was visualized as histograms and corresponding kernel density lines, and Kaplan-Meier survival curves were plotted. Hazard ratio (HR) and corresponding 95% confidence interval (95% CI) were calculated. Results. Significant difference in race and disease stage distribution was found (P
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Cutaneous Malignancy due to Arsenicosis in Bangladesh: 12-Year Study in Tertiary Level Hospital
Bangladesh is grappling with the largest mass poisoning of a population in the world due to contamination of drinking water with naturally occurring inorganic arsenic. It is estimated that 75 million people of 59 (out of 64) districts are at risk of drinking contaminated water with arsenic above 50μg/L. Long term exposure to arsenic causes cancers, including skin, lung, and bladder. This is a randomized prospective study to see the prevalence of skin cancer from arsenic affected area of Bangladesh, as well as their variation by geographical area, age, gender, location on the body, and socioeconomic conditions, in outpatient department of plastic surgery unit of Bangabandhu Sheikh Mujib Medical University (BSMMU). A total of 960 patients with skin cancers comprised of 528 males and 432 females were selected for the study from January 2004 to December 2015. In this 12-year study, we found squamous cell carcinoma, basal cell carcinoma, melanoma, and Merkel cell carcinoma to be associated with the ingestion of arsenic contaminated ground water. This is a reflection of a small part of the total national scenario of devastating result of arsenic mediated cancer in terms of skin malignancy. This study will help the future researchers who are contemplating to work on arsenic induced health problem.
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Bioinformatics Analysis of the Molecular Mechanism of Aging on Fracture Healing
Increasing age negatively affects different phases of bone fracture healing. The present study aimed to explore underlying mechanisms related to bone fracture repair in the elderly. GSE17825 public transcriptome data from the Gene Expression Omnibus database were used for analysis. First, raw data were normalized and differentially expressed genes (DEGs) were identified. Next, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses were implemented to evaluate pathways and DEGs. A protein–protein interaction (PPI) network was then constructed. A total of 726, 861, and 432 DEGs were identified between the young and elderly individuals at 1, 3, and 5 days after fracture, respectively. The results of GO, KEGG, and PPI network analyses suggested that the inflammatory response, Wnt signaling pathway, vascularization-associated processes, and synaptic-related functions of the identified DEGs are markedly enriched, which may account for delayed fracture healing in the elderly. These findings provide valuable clues for investigating the effects of aging on fracture healing but should be validated through further experiments.
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In vitro and in vivo evidence of tyrosinase inhibitory activity of a synthesized (Z)‐5‐(3‐hydroxy‐4‐methoxybenzylidene)‐2‐thioxothiazolidin‐4‐one (5‐HMT)
Abstract
Tyrosinase is a key enzyme that catalyzes the initial rate‐limiting steps of melanin synthesis. Due to its critical role in melanogenesis, various attempts were made to find potent tyrosinase inhibitors although many were not safe and effective in vivo. We evaluated tyrosinase inhibitory activity of six compounds. Among them, (Z)‐5‐(3‐hydroxy‐4‐methoxybenzylidene)‐2‐thioxothiazolidin‐4‐one (5‐HMT) had the greatest inhibitory effect and potency as the IC50 value of 5‐HMT was lower than that of kojic acid, widely‐known tyrosinase inhibitor. Based on in silico docking simulation, 5‐HMT had a greater binding affinity than kojic acid with a different binding conformation in the tyrosinase catalytic site. Furthermore, its skin depigmentation effect was confirmed in vivo as 5‐HMT topical treatment significantly reduced UVB‐induced melanogenesis in HRM2 hairless mice. In conclusion, our study demonstrated that 5‐HMT has a greater binding affinity and inhibitory effect on tyrosinase and may be a potential candidate for a therapeutic agent for preventing melanogenesis.
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
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Alimentary Pharmacology &Therapeutics, EarlyView. https://ift.tt/2qECBIJ
