Synedrella nodiflora is used by traditional healers in Ghana for the management of epilepsy and pain. The hydro-ethanolic extract of the whole plant has demonstrated antinociceptive ef...
http://ift.tt/2shgXIs
Δευτέρα 26 Ιουνίου 2017
Analgesic effects of a hydro-ethanolic whole plant extract of Synedrella nodiflora (L.) Gaertn in paclitaxel-induced neuropathic pain in rats
A training manual for event history data management using Health and Demographic Surveillance System data
The objective of this research note is to introduce a training manual for event history data management. The manual provides a first comprehensive guide to longitudinal Health and Demographic Surveillance Syst...
http://ift.tt/2sLOVIH
Total knee arthroplasty with corrective osteotomy for knee osteoarthritis associated with malunion after tibial plateau fracture: a case report
When surgeons perform total knee arthroplasty in patients with knee osteoarthritis due to malunion following fractures around the knee joint, corrective osteotomy is recommended for severe deformities. Most su...
http://ift.tt/2sh0rrL
Quality in intensive care units: proposal of an assessment instrument
There is an increasing need for standardized instruments for quality assessment that are able to reflect the actual conditions of the intensive care practices, especially in low and middle-income countries. Th...
http://ift.tt/2sLGrRN
Comparing regional models of congenital bleeding disorders: preliminary steps in the Italian context
Among these diseases, congenital bleeding disorders (CBD) represent a significant societal burden in terms of high morbidity costs and health outcomes. In Italy, the organization and provision of health care i...
http://ift.tt/2sh0rbf
The neural bases of ictal tachycardia in temporal lobe seizures
Temporal lobe epilepsy (TLE) can lead to intense changes in cardiac autonomic functions during both interictal and ictal periods (Lotufo et al., 2012; Eggleston et al., 2014). Tachycardia, defined as a decrease in the ECG R-R intervals (RR) (increase in heart rate), is the most common cardiac change occurring during epileptic seizures (Opherk and Hirsch, 2002; O'Regan and Brown, 2005; Toth et al., 2010) whereas bradycardia occurs in only 2% of them (Moseley et al., 2010). Tachycardia was proposed as a biomarker providing a somatic indicator of temporal lobe (TL) seizure onset (Osorio, 2014; Schiecke et al., 2014; Osorio and Manly, 2014; Jeppesen et al., 2015; Osorio and Manly, 2015; Behbahani et al., 2016; Van de Vel et al., 2016), opening the way to automatized and noninvasive seizure detection and treatment delivery prior to, or at the onset of, a TL seizure.
http://ift.tt/2sgWTWv
Reversal of long term potentiation-like plasticity in primary motor cortex in patients with progressive supranuclear palsy
Progressive Supranuclear Palsy (PSP) is a neurodegenerative disorder due to the deposition of tau-protein aggregates in several brain regions leading to parkinsonism, oculomotor abnormalities, early postural instability and falls. To date, the pathophysiological mechanisms of PSP are still poorly understood (Colosimo et al., 2014; Wenning et al., 2013).
http://ift.tt/2sLXaEg
Diagnostic utility of distal nerve conduction studies and sural near-nerve needle recording in polyneuropathy
Nerve conduction studies (NCS) are a very useful tool in diagnosing polyneuropathy (PNP) both with respect to confirming the PNP and classifying it as primarily demyelinating or axonal (Donofrio and Albers, 1990; Tankisi et al., 2005). Since most PNPs follow a length dependent pattern, the sensory nerves of the feet are usually affected in the early stages (Oh et al., 2001; Park et al., 2003; Singleton et al., 2008; Singleton, 2005). The sural nerve is the most frequently examined nerve in the electrodiagnosis of PNP (Burke et al., 1974).
http://ift.tt/2sgNlel
What Is the Effect of Strength Training on Pain and Sleep in Patients With Fibromyalgia?.
Objective: The study aimed to investigate the effect of an 8-wk structured strength training program on pain and sleep quality in patients with fibromyalgia. Design: Fifty-two patients with fibromyalgia were evaluated; 31 submitted to strength training and 21 comprised the control group. The instruments used were the Fibromyalgia Impact Questionnaire and The Pittsburgh Sleep Quality Index. The questionnaires were applied before the first training session, at 12 sessions, and after 24 sessions. Descriptive statistics (mean, SD, and frequency) and inferential tests were used. Results: After 8 wks of intervention, significant differences were found between groups in subjective quality of sleep (P = 0.03), sleep disturbance (P = 0.02), daytime dysfunction (P = 0.04), and total sleep score (P
http://ift.tt/2sLLSAh
http://ift.tt/2sLLSAh
Effects of Transcranial Direct Current Stimulation Plus Physical Therapy on Gait in Patients With Parkinson Disease: A Randomized Controlled Trial.
Objective: The aim of the study was to study the combined effects of transcranial direct current stimulation (tDCS) and physical therapy on the walking ability of patients with Parkinson disease (PD). Study Design: The study used an experimental, double-blinded, randomized controlled trial. Results: After intervention, group 1 (only tDCS) demonstrated a significant increase in gait speed by 0.13 to 0.14 m/sec (17.8%-19.2%) and an increase in step length by 5.9 to 6.1 cm (14.0%-14.5%), whereas group 2 (tDCS and physical therapy) revealed a significant increase in gait speed by 0.10 to 0.13 m/sec (14.9%-19.4%) and step length by 4.5 to 5.4 cm (10.6%-12.8%) and group 3 (sham tDCS and physical therapy) showed a significant increase in gait speed by 0.09 to 0.14 m/sec (13.0%-20.3%) and step length by 3.0 to 5.4 cm (6.8%-12.3%). All these results lasted for at least 8 wks after intervention. Upon comparing the parameters of gait among the three groups at every follow-up visit, no significant difference was observed. Conclusions: Anodal tDCS or physical therapy could be used alone or together as a combination treatment to improve the walking speed of patients with Parkinson disease. The effects lasted for approximately 8 wks. The combination treatment was not superior to the use of tDCS or physical therapy alone. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.
http://ift.tt/2shcHZs
http://ift.tt/2shcHZs
Increased number of beam angles is associated with higher cardiac dose in adjuvant fixed gantry intensity-modulated radiation therapy of left-sided breast cancer
In the treatment of breast cancer, fixed gantry intensity-modulated radiotherapy (FG-IMRT) can be delivered via standard tangents or multiple gantry angles, which alters the dose distribution for nearby organs at risk. We analyzed the relationship between angle number and mean heart dose (MHD) in adjuvant FG-IMRT treatment of left-sided breast cancer as is currently practiced in the community.
http://ift.tt/2sgxCf2
Cavernous nerve injury by radiotherapy may potentiate erectile dysfunction in rats
Radiation-induced erectile-dysfunction (RiED) is one of the most common side effects of radiotherapy (RT) and significantly reduces the quality of life (QoL) of cancer patients. Approximately 50% of prostate cancer patients develop RiED within 3–5 years after completion of RT. A series of vascular, muscular, and neurogenic injuries after prostate RT lead to RiED, however, the precise role of RT-induced neurogenic injury in RiED has not been fully established. The cavernous nerves (CN) are post-ganglionic parasympathetic nerves located beside the prostate gland that assists in the penile erection.
http://ift.tt/2sLpdnE
Comparative Outcomes after Definitive Chemoradiotherapy using Proton Beam Therapy versus Intensity-Modulated Radiation Therapy for Esophageal Cancer: A Retrospective Single-Institutional Analysis
To compare clinical outcomes between proton beam therapy (PBT) and intensity-modulated radiation therapy (IMRT) in patients with esophageal cancer (EC) treated with definitive chemoradiotherapy (CRT).
http://ift.tt/2sgF7CX
Clinical outcomes of several IMRT techniques for patients with head and neck cancer: A propensity score weighted analysis
Helical Tomotherapy (HT) and Volumetric-modulated Arc Therapy RapidArc (RapidArc) are two different IMRT techniques used to treat patients with head and neck cancer. In this study, we have prospectively compared their efficacy and toxicity. After inverse probability of treatment weighting (IPTW), loco-regional control and cancer specific survival rates at 18 months were significantly better in the Tomotherapy® group. No significant difference was shown on progression-free or overall survival.
http://ift.tt/2sLwZO9
Implementing Radiation Dose-Volume Liver Response in Biomechanical Deformable Image Registration
Deformable image registration (DIR) of the liver after radiotherapy is challenging due to the complex radiation dose-dependent volume response of normal hepatic tissue. A modified biomechanical modeling method for hepatic tissue including independent dose-driven deformation forces was developed and implemented on a series of patients, then compared with a previously developed biomechanical DIR algorithm. This proposed DIR technique resulted in improved target registration and deformed segment volume accuracy.
http://ift.tt/2sgygJD
PSMA PET-CT for Prostate Cancer: Distribution of Disease and Implications for Radiotherapy Planning
Prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is a novel diagnostic test for the detection of prostate cancer (PC), offering high sensitivity and specificity. However, the detailed pattern of occult disease distribution and its potential impact on radiotherapy (RT) planning has not been investigated.
http://ift.tt/2sLN3PY
The influence of health insurance policy on radiation oncology physician SBRT/SABR use practices: a North American survey
European data suggest that 8 fraction stereotactic body radiotherapy (SBRT) regimens may be similar in efficacy with less toxicity than ≤5 fraction SBRT for central lung lesions. However, under current Centers for Medicare & Medicaid Services guidelines, SBRT in the United States (US) is only reimbursed for ≤5 fractions, whereas there are no such restrictions for reimbursement in Canada. We hypothesize that US-specific SBRT reimbursement policies influence utilization of ≥5 fraction SBRT in US academic centers when compared to comparable Canadian centers.
http://ift.tt/2sgQKK0
Host recognition by lactic acid bacterial phages
Abstract
Bacteriophage infection of lactic acid bacteria (LAB) is one of the most significant causes of inconsistencies in the manufacture of fermented foods, affecting production schedules and organoleptic properties of the final product. Consequently, LAB phages, and particularly those infecting Lactococcus lactis, have been the focus of intensive research efforts. During the past decade, multidisciplinary scientific approaches have uncovered molecular details on the exquisite process of how a lactococcal phage recognises and binds to its host. Such approaches have incorporated genomic/molecular analyses and their partnership with phage structural analysis and host cell wall biochemical studies are discussed in this review, which will also provide our views on future directions of this research field.http://ift.tt/2tQyKbw
Unexpected complexity in the lactate racemization system of lactic acid bacteria
Abstract
Analysis of lactate racemase (Lar) in lactic acid bacteria (LAB) has been a scientific challenge for many years, as indicated by the numerous contradictory reports on this activity. Recently, genetic and biochemical studies of the Lar system of Lactobacillus plantarum have unveiled the complexity of this particular enzymatic system. Lar activity is associated with LarA and its nickel-containing cofactor, synthesized from nicotinic acid adenine dinucleotide by the three biosynthetic enzymes: LarB, LarC, and LarE. In addition to these core Lar enzymes, a nickel transporter (Lar(MN)QO), a lactic acid channel (LarD) and a transcriptional regulator (LarR) which promotes expression of the lar genes in the presence of excess L-lactate are also part of the Lar system of Lb. plantarum and of many other LAB. These proteins promote racemization of external L-lactate, in addition to carrying out intracellular racemization. This additional outcome suggests that racemization of L-lactate is not only required for cell wall biosynthesis, as reported before, but may have additional roles in lactate production and utilization in LAB. Finally, bioinformatics analyses indicate that some Lar homologs probably catalyze reactions other than lactate racemization.http://ift.tt/2thkbAu
An amazing cause of false pet positivity: Diagnosed after a lung cancer surgery
Abstract
Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) has an effective role in both diagnosis and management of patients with lung cancer. There are many reasons could cause false positivity on PET/CT.A 60-year-old man was admitted a mass on thorax CT and diagnosed as squamous cell carcinoma. Lobectomy with lymph node dissection was performed after evaluation of distant metastases. There were pathological lymph nodes detected on PET/CT at six month following period. Endobronchial ultrasonography guided transbronchial needle aspiration was performed for differantial diagnosis. The pathologic diagnosis was granuloma which developed in response to suture material. We interpreted this granulomatous reaction as gossypiboma which developed against long-left or forgotten suture material. In conclusion, based on this case, gossypiboma (or granulomatous inflammation in response to foreign bodies) should be also considered in differential diagnosis of intrathoracic lymph nodes with PET positivity in a previously operated patient.
http://ift.tt/2ubwivs
Nonfatal and fatal intoxications with pure caffeine – report of three different cases
Abstract
Caffeine is not usually perceived as a drug by most people because it is found in many foods and drinks, including caffeinated energy drinks, as well as in over the counter analgesics and cold preparations. Recently in Poland it has become increasingly common to take pure caffeine, bought through online stores, as a psychoanaleptic. This creates a much higher risk of severe and even fatal poisoning in comparison with the risk associated with the abuse of food products and non-prescription medicines containing low doses of caffeine. This paper presents three different cases of poisoning that occurred when pure caffeine was taken as psychostimulant; in cases 1 and 2 poisoning was the result of a single overdose, while in the case 3 poisoning resulted from a cumulative overdose. In the case 1 there was a severe intoxication (persistent vomiting, hypotension, tremor), and the concentration of caffeine in the blood was found to be 80.16 μg/mL. The patient was treated using hemodialysis, which caused a rapid decrease in blood levels of caffeine and relief of the clinical symptoms of poisoning. Cases 2 and 3 were fatal poisonings, and recorded levels of caffeine in post mortem blood samples were 140.64 μg/mL and 613.0 μg/mL. In case 2 the patient died 10 min after admission to hospital as a result of sudden cardiac arrest, which was preceded by an attack of convulsions, and in case 3 death occurred in home and was also sudden in nature. Taking pure caffeine as a stimulant is associated with a high risk of overdose and the development of serious and even fatal poisoning, and those using pure caffeine are generally completely unaware of these risks. In such cases, death is usually sudden due to functional mechanisms.
http://ift.tt/2tQaFBv
Current Controversies on Wernicke’s Area and its Role in Language
Abstract
Purpose of Review
The aim of the study is to assess historical anatomical and functional definitions of Wernicke's area in light of modern lesion and neuroimaging data.
Recent Findings
"Wernicke's area" has become an anatomical label usually applied to the left posterior superior temporal gyrus and adjacent supramarginal gyrus. Recent evidence shows that this region is not critical for speech perception or for word comprehension. Rather, it supports retrieval of phonological forms (mental representations of phoneme sequences), which are used for speech output and short-term memory tasks. Focal damage to this region produces phonemic paraphasia without impairing word comprehension, i.e., conduction aphasia. Neuroimaging studies in recent decades provide evidence for a widely distributed temporal, parietal, and frontal network supporting language comprehension, which does not include the anatomically defined Wernicke area.
Summary
The term Wernicke's area, if used at all, should not be used to refer to a zone critical for speech comprehension.
http://ift.tt/2sLgWzQ
Clinical and pathological factors related to brain relapse–free survival in breast cancer patients
I want to congratulate Li and colleagues for their article [1] in which they did a comprehensive analysis in 108 consecutive patients with breast cancer brain metastases to define clinicopathologic factors associated with early onset of brain metastasis and survival outcomes after development of them. Of these patients, 16% were metastatic (stage IV disease) at initial diagnosis.
http://ift.tt/2sVOfib
High tumor budding count is associated with adverse clinicopathologic features and poor prognosis in breast carcinoma
This study is to address the significance of tumor budding (TB) in breast carcinoma. Totally 244 estrogen receptor-positive (ER+)/HER2-negative (HER2-) and 131 triple-negative breast carcinoma (TNBC) diagnosed from 2004 to 2014 were analyzed. TB (cluster of up to 5 tumor cells at the invasive front) was evaluated using five 200x high power field (HPF) at the hotspot. The highest TB (H-TB) in 1 HPF and average TB (A-TB) in 5 HPFs were correlated with lymph node and distant metastasis, lymphovascular invasion (LVI), local recurrence, overall survival (OS), disease-free survival (DFS).
http://ift.tt/2sbMVuj
Inflammatory cell infiltrates in advanced metastatic uveal melanoma
Current treatments for metastatic uveal melanoma (mUM) are limited and rarely prolong patient survival. Immunotherapy trials for mUM are few, and to-date have demonstrated only marginal success. High densities of tumour-associated-macrophages (TAMs) and infiltrating T-lymphocytes (TILs) in primary UM are associated with poor prognosis. Little is known about the immune microenvironment of mUM. Our aim was to examine the presence and distribution of TAMs and TILs in mUM within the liver. Whole tissue-sections of liver mUM (n=35) were examined by immunohistochemistry.
http://ift.tt/2sVDGvH
Clinical and pathological factors related to brain relapse–free survival in breast cancer patients—reply
We thank Dr. Altundag for his interest in our manuscript [1] and for taking the time to express his concerns, thus giving us the opportunity to further elucidate some of our observations in relation to those aforementioned concerns.
http://ift.tt/2sbHawG
Adults with Autism Make More Consistent Choices
People with autism spectrum conditions (ASC) often show a reduced sensitivity to contextual information in perceptual tasks, but new research suggests that this reduced sensitivity may actually lead to more consistent choices in high-level decision-making tasks.
The findings, published in Psychological Science, a journal of the Association for Psychological Science, indicate that individuals with ASC are less susceptible to the effects of decoy options when evaluating and choosing the "best" product among several options relative to individuals without ASC.
"People with autism are indeed more consistent in their choices than the neurotypical population. From an economic perspective, this suggests that people with autism are more rational and less likely to be influenced by the way choices are presented," says psychology researcher George Farmer of the University of Cambridge.
While numerous studies have compared the performance of individuals with ASC and neurotypical individuals on a variety of low-level perceptual tasks, Farmer and University of Cambridge co-authors William J. Skylark and Simon Baron-Cohen noticed that relatively little research had examined their performance in the realm of decision making.
"People with autism are thought to focus more on detail and less on the bigger picture – this is often found in more perceptual studies, for instance by showing that people with autism are less susceptible to some visual illusions," explains Farmer. "We wanted to know if this tendency would apply to higher-level decision-making tasks."
The researchers recruited 90 adults with ASC and 212 neurotypical adults to participate in an online decision-making study. The researchers used 10 product pairs and the products in each pair differed on two dimensions. Importantly, the pairs were always presented as part of a trio that included a third decoy item.
Participants saw each pair twice — in one case, the accompanying decoy was designed to target product A; in the other case, it was designed to target product B. The participants indicated the "best" option out of the three presented.
For example, participants might be asked to choose one of three USB drives that varied according to their capacity and their lifespan. Product A has a capacity of 32 GB and a lifespan of 20 months, while Product B has less capacity (16 GB) but a longer lifespan (36 months). The decoy, with a capacity of 28 GB and lifespan of 16 months, is objectively worse than A and should therefore be ignored.
Participants also completed measures assessing aspects of cognitive ability and a measure that assessed traits typically associated with ASC.
With purely rational economic decision making, the decoy items would be irrelevant and participants would make the same choice both times that products A and B were shown. If the decoys were effective, however, participants would switch their selection when the decoy changed, favoring the product targeted by the decoy in each trio. In the example above, people would be more likely to choose Product A with the decoy present than they would if there were simply comparing Product A and B.
The data revealed that, compared with neurotypical participants, participants with ASC made more consistent choices and made fewer switches in their selections.
In a second experiment, the researchers recruited participants from the general population, administering the same task with only those who scored in the bottom and top deciles of a validated measure of traits typically associated with autism. Their results showed an attenuated pattern similar to that seen in the first experiment: Participants who scored high on autistic traits were more likely to make consistent choices compared with low-scoring participants.
Together, the findings indicate that individuals with ASC are less likely to show a cognitive bias that often affects their neurotypical peers.
"[C]hoice consistency is regarded as normative in conventional economic theory, so reduced context sensitivity would provide a new demonstration that autism is not in all respects a 'disability'," the researchers write in their paper.
"These findings suggest that people with autism might be less susceptible to having their choices biased by the way information is presented to them—for instance, via marketing tricks when choosing between consumer products," Farmer adds.
The results also indicate that the reduced sensitivity to context that is associated with ASC may extend well beyond low-level cognitive processes, shedding new light on the nature of "autistic cognition," the researchers argue:
"Altered preferences in a choice task involving verbally described consumer products would suggest the need for a broader characterization and integrated theorizing across levels and domains of processing," they conclude.
The design and analysis plans for the autism-spectrum-conditions study were preregistered at the Open Science Framework, and all data and materials for both studies have been made publicly available at the Open Science Framework. The data and materials are also publicly available via Apollo, the University of Cambridge institutional repository. The complete Open Practices Disclosure for this article is available online. This article has received badges for Open Data, Open Materials, and Preregistration.
This research was funded by the Wellcome Trust (Grant RG76641) and the Isaac Newton Trust (Grant RG70368).
http://ift.tt/2tf7WUS
Prognostic prediction by liver tissue proteomic profiling in patients with colorectal liver metastases; rule of thumb
Future Oncology Ahead of Print.
http://ift.tt/2sLh5mN
Letter in reply: Prognostic prediction by liver tissue proteomic profiling in patients with colorectal liver metastases
Future Oncology Ahead of Print.
http://ift.tt/2sgBHQw
Robotic-assisted radical cystectomy versus open radical cystectomy for management of bladder cancer: review of literature and randomized trials
Future Oncology Ahead of Print.
http://ift.tt/2sL2xUo
Highlights of the San Antonio Breast Cancer Symposium 2016
Future Oncology Ahead of Print.
http://ift.tt/2sgiKgR
Emergency Department Escalation in Theory and Practice: A Mixed-Methods Study Using a Model of Organizational Resilience
Escalation policies are used by emergency departments (EDs) when responding to an increase in demand (eg, a sudden inflow of patients) or a reduction in capacity (eg, a lack of beds to admit patients). The policies aim to maintain the ability to deliver patient care, without compromising safety, by modifying "normal" processes. The study objective is to examine escalation policies in theory and practice.
http://ift.tt/2tdJPFD
Capacity? Informed Consent; Informed Discharge? Uncertainty!
SEE RELATED ARTICLE, P. ■■■.
http://ift.tt/2ubDjMN
What Is the Efficacy of Droperidol for the Management of Acute Psychosis-Induced Agitation?
The search strategy identified 14 total studies, of which 6 (n=733 total patients) met the inclusion criteria. Three studies were conducted in an emergency setting, whereas the other 3 were performed in an inpatient psychiatric or other medical setting. Three studies compared droperidol with haloperidol, one study compared droperidol with olanzapine, one study compared droperidol with midazolam, and one study compared droperidol with placebo.
http://ift.tt/2tdDLNk
What Elements of the History, Examination, Laboratory Testing, or Point-of-Care Ultrasonography Are Most Useful in the Diagnosis of Acute Appendicitis in Children?
The search strategy yielded a total of 2,921 references, of which 21 trials were included, totaling 8,605 patients. In studies in which suspected acute appendicitis was an inclusion criterion, the weighted prevalence was 42.8% compared with 13.4% in studies of undifferentiated abdominal pain. None of the identified history, physical examination, or laboratory findings had sufficient positive or negative likelihood ratios to rule in or rule out acute appendicitis in patients with suspected acute appendicitis (Table).
http://ift.tt/2ublY6T
Does Antipyresis Improve Mortality in Critically Ill Septic Patients?
The authors included 8 randomized controlled trials for analysis, 4 of which assessed 28-day mortality and 4 of which assessed inhospital mortality (Table). In total, the review included 1,531 patients, 1,507 of whom were included for analysis of the primary outcome. Pooled data analysis found similar 28-day or inhospital mortality rates between patients receiving and not receiving antipyretics (RR 0.93; 95% CI 0.79 to 1.09). Analyses of secondary outcomes demonstrated that patients receiving antipyretics experienced lower 14-day mortality (RR 0.68; 95% CI 0.49 to 0.92) and postintervention body temperature (mean difference –0.38°C [–68°F]; 95% CI –0.63 [–1.13°F] to –0.13°C [–0.23°F]).
http://ift.tt/2tdZvbL
Cardiac Events and the Maximum Diameter of Coronary Artery Aneurysms in Kawasaki Disease
To clarify the occurrence of cardiac events based on the maximal diameter of the maximal coronary artery aneurysm (CAA) in Kawasaki disease (KD).
http://ift.tt/2tf8ie7
Nonalcoholic Fatty Liver Disease in Italian Children with Down Syndrome: Prevalence and Correlation with Obesity-Related Features
To assess the prevalence of overweight/obesity in a cohort of Italian children with Down syndrome (DS) and to investigate the correlation of both obesity and DS with nonalcoholic fatty liver disease (NAFLD).
http://ift.tt/2rVN6G1
A Newborn with No Bones: Neonatal Hypophosphatasia with Respiratory Distress
A male infant was born as the first child of nonconsanguinous parents. Antenatal ultrasound had identified polyhydramnios, mesomelic fetal limb shortening, and a small fetal thoracic cavity concerning for a skeletal dysplasia with hypoplastic lungs. Amniocentesis at 21 weeks of gestation showed no FGFR3 mutation to indicate thanatophoric dysplasia or achondroplasia. At term emergency cesarean delivery was undertaken for fetal bradycardia, and the child developed severe respiratory distress requiring intubation and ventilation at 3 minutes of life.
http://ift.tt/2rWhCQ1
Rehospitalization Through Childhood and Adolescence: Association with Neonatal Morbidities in Infants of Very Low Birth Weight
To evaluate the impact of major neonatal morbidities on the risks for rehospitalization in children and adolescents born of very low birth weight.
http://ift.tt/2tfaBxU
Cardiac Morphology and Function in Preterm Growth Restricted Infants: Relevance for Clinical Sequelae
To assess cardiac morphology and function in preterm infants with fetal growth restriction (FGR) compared with an appropriate for gestational age cohort, and to ascertain clinical correlation with neonatal sequelae.
http://ift.tt/2teW2dx
Patched Skin Bilirubin Assay to Monitor Neonates Born Extremely Preterm Undergoing Phototherapy
To verify the reliability and safety of transcutaneous bilirubin (TcB) measurements in patched skin areas in neonates born extremely preterm under phototherapy.
http://ift.tt/2rWjmZJ
Skeletal Muscle Channelopathies: Rare Disorders with Common Pediatric Symptoms
To ascertain the presenting symptoms of children with skeletal muscle channelopathies to promote early diagnosis and treatment.
http://ift.tt/2tf5lKp
Profiling of antibiotic resistance of bacterial species recovered from routine clinical isolates in Ethiopia
With the alarming rise in antibiotic resistance in African countries, the need for a surveillance system in the region has become pressing. The rapid expansion of data networks makes it possible to set up heal...
http://ift.tt/2sbCzKW
Toxicity and Outcomes in Patients with and without Esophageal Stents in Locally Advanced Esophagus Cancer
Utilization of esophageal stents to relieve dysphagia is increasing in patients with locally advanced esophagus cancer while impacts on toxicity and outcomes are unclear. We retrospectively analyzed our cohort of curatively treated esophageal cancer patients and analyzed toxicities and outcomes comparing stent vs. no-stent patients. We found that patients who received stents had more acute esophageal toxicity, were less likely to undergo esophagectomy, and had worse overall survival than no-stent patients.
http://ift.tt/2rWl1yw
Decreased survival after combining thoracic irradiation and an anti-PD-1 antibody is correlated with increased T cell infiltration into cardiac and lung tissues
Combining immunotherapy and irradiation has the potential to greatly increase survival in cancer patients, but the effects of this combination on surrounding tissues has not been studied. We treated mice with either antibody or anti-PD-1 antibody, with or without thoracic irradiation, monitored survival, then analyzed immune cell infiltration into cardiac and lung tissues. Animals treated with both anti-PD-1 and thoracic irradiation had significantly decreased survival, and significantly increased infiltration of thoracic organs by CD3+ cells.
http://ift.tt/2ubRC4a
Health-related Quality of Life and Costs Associated With Eosinophilic Esophagitis: A Systematic Review
Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease characterized by esophageal inflammation and dysfunction. Little is known about the humanistic and economic burden of the disease on patients, their caregivers and the healthcare system. A systematic review was conducted to evaluate the existing literature on the disease burden of EoE for patients and their caregivers.
http://ift.tt/2tfcN8l
Conceptions of pregnancy health and motivations for healthful behavior change among women in American Samoa
Publication date: Available online 26 June 2017
Source:Women and Birth
Author(s): Erica L. Kocher, Jeanette M. Sternberg Lamb, Stephen T. McGarvey, Mata'uitafa Faiai, Bethel T. Muasau-Howard, Nicola L. Hawley
BackgroundAmerican Samoan women are particularly at risk of obesity-related non-communicable disease (NCD), requiring efficacious interventions to protect their health and that of their infants. Prior studies have identified pregnancy as an ideal time for behavior change interventions related to NCD.AimThis study aimed to understand American Samoan women's conceptions of health during pregnancy, their motivations for pregnancy behavior change, and the role of their family in both enabling and preventing these changes.MethodsEighteen women (2–19 weeks post-partum) completed semi-structured interviews that explored their experiences of pregnancy-related behavior change and social support. A thematic analysis identified prominent themes. A stages of change framework was used to describe the sample's readiness for behavior change.FindingsParticipants expressed a Westernized conception of health during pregnancy that focused on eating a balanced diet and exercising regularly; behaviors that would usually be stigmatized outside of pregnancy. Many were in the contemplative/pre-contemplative stages of change, although some reported initiating healthful behaviors in pregnancy. Participants overwhelmingly described external motivations for adopting healthy behaviors, most notably the perceived benefit to their baby. During pregnancy, women reported protective treatment from their families as a result of communal ownership over the baby that is potentially limiting for women's agency over their health.ConclusionsThis study confirmed pregnancy as an opportune moment for health behavior intervention, especially within the context of Samoan culture. Future efforts should capitalize on external motivations for behavior change but also encourage the development of internal motivators to sustain changes initiated in pregnancy post-partum.
http://ift.tt/2rW31UZ
Guided bone regeneration at zirconia and titanium dental implants: a pilot histological investigation
Abstract
Aim
To test whether guided bone regeneration (GBR) of peri-implant defects at zirconia (ZrO2) implants differs from GBR at titanium (Ti) implants regarding the bone integration of the implant and of the grafting material.
Materials and methods
Maxillary premolars and molars were extracted in seven dogs. After 5 months, four semi-saddle bone defects were created in each maxilla. Implant placement and simultaneous GBR were performed using the following randomly assigned modalities: (1) ZrO2 implant + deproteinized bovine bone mineral (DBBM) granules + a collagen membrane (CM), (2) ZrO2 implant + DBBM with 10% collagen matrix + CM, (3) ZrO2 implant + DBBM block + CM, and (4) Ti implant + DBBM granules + CM. After 3 months, one central histological section of each site was prepared. Histomorphometrical assessments were performed evaluating the augmented area (AA) within the former bone defect (primary outcome), the area of new bone (NB), bone substitute (BS), and non-mineralized tissue (NMT) within AA in mm2. In addition, the distance between the most coronal bone-to-implant contact and the margin of the former bone defect (fBIC-DEF), and the bone-to-implant contact fraction (BIC) were measured in mm.
Results
AA measured 8.6 ± 4.0 mm2 for ZrO2 implant + DBBM granules, 4.7 ± 1.6 mm2 for ZrO2 implant + DBBM-collagen, 5.1 ± 1.9 mm2 for ZrO2 implant + DBBM block, and 7.6 ± 2.8 mm2 for Ti implant + DBBM granules. There were no statistically significant differences between the treatment modalities (P > 0.05). NB reached 2.0 ± 1.7 mm2 for ZrO2 implant + DBBM granules, 0.9 ± 0.9 mm2 for ZrO2 implant + DBBM-collagen, 2.1 ± 0.9 mm2 for ZrO2 implant + DBBM block, and 0.8 ± 0.6 mm2 for Ti implant + DBBM granules. fBIC-DEF amounted to 2.1 ± 1.7 mm2 for ZrO2 implant + DBBM granules, to 2.7 ± 1.1 mm2 for ZrO2 implant + DBBM-collagen, to 2.9 ± 1.2 mm2 for ZrO2 implant + DBBM block, and to 3.4 ± 0.4 mm2 for Ti implant + DBBM granules. BIC measured 70 ± 19% for ZrO2 implant + DBBM granules, 69 ± 22% for ZrO2 implant + DBBM-collagen, 77 ± 30% for ZrO2 implant + DBBM block, and 66 ± 27% for Ti implant + DBBM granules.
Conclusions
The findings of the present pilot study suggest that zirconia and titanium implants grafted with DBBM granules and covered with a collagen membrane do not perform differently regarding the augmented ridge contour, the NB formation, and the implant osseointegration.
http://ift.tt/2ubhbSQ
Anti-CGRP Monoclonal Antibodies: the Next Era of Migraine Prevention?
Opinion statement
Migraine is a very disabling disorder with severe impact on patients' lives and substantive costs to society in terms of healthcare costs and lost productivity. Prevention is a key component of migraine therapy, and while numerous preventive options exist, each is burdened by either troublesome side effects or insufficient efficacy. All migraine preventives currently in clinical use were licensed for other purposes and, by chance, have efficacy against migraine. As our understanding of migraine has evolved, calcitonin gene-related peptide (CGRP) has moved to the forefront as a neuropeptide central to migraine pathophysiology. Six small molecule CGRP receptor antagonists were shown to be effective for acute treatment of migraine; two were stopped for hepatotoxicity or one for formulation concern issues and one is now in phase III. Monoclonal antibodies against CGRP or the CGRP receptor have a longer duration of action and have been investigated for migraine prevention. Four are in development and three have completed phase II and one phase III trials; every reported study has been positive. Furthermore, no safety issues have arisen to date, including hepatic or cardiovascular effects, and initial tolerability appears to be excellent. Monoclonal antibodies antagonizing the CGRP pathway represent a novel approach to prevention: a mechanism-specific migraine-targeted therapy. While we must await the results of all the phase III trials, cautious excitement seems warranted as we enter a new era of better tolerated, well-understood, bespoke migraine treatment for this common and disabling neurological disorder.
http://ift.tt/2tdVODh
Development of Focal Segmental Glomerulosclerosis Patient-Reported Outcome Measures: Symptom Diary and Symptom Impact Questionnaire
Focal segmental glomerulosclerosis (FSGS) is a kidney disease that affects patients' functioning and well-being. This study aimed to develop patient-reported outcome questionnaires to measure patient experiences related to FSGS.
http://ift.tt/2ubitx7
Family Aggregation and Heritability of ESRD in Taiwan: A Population-Based Study
Aggregation of end-stage renal disease (ESRD) has been observed in families of European origin, as well as those of African origin. However, it is not well documented if this disease aggregates in Asian families. Furthermore, the contribution of genetic factors and shared environmental factors to family aggregation remains unclear.
http://ift.tt/2tdTBHY
Community Pharmacist Training-and-Communication Network and Drug-Related Problems in Patients With CKD: A Multicenter, Cluster-Randomized, Controlled Trial
Appropriate training for community pharmacists may improve the quality of medication use. Few studies have reported the impact of such programs on medication management for patients with chronic kidney disease (CKD).
http://ift.tt/2ubooSF
Dialysis Payment Model Reform: Managing Conflicts Between Profits and Patient Goals of Care Decision Making
Dialysis patients represent <1% of all patients served by the US Centers for Medicare & Medicaid Services (CMS), but their treatments account for 7% of all CMS expenditures.1 In 2014, total Medicare spending for beneficiaries with end-stage renal disease (ESRD) was nearly $33 billion. Care of dialysis patients near the end of life is particularly expensive, with median Medicare per-patient costs of $20,731 over the last 30 days of life.1 Dialysis patients are hospitalized on average nearly twice per year and spend about 11 days in the hospital per year.
http://ift.tt/2te6Fgp
Development of gluten-free bread formulations containing whole chia flour with acceptable sensory properties
Abstract
Increasing the variety of better-tasting and healthier gluten-free products is important for consumers with gluten-related disorders. This work aimed to develop a gluten-free bread formulation containing whole chia flour with acceptable sensory properties. A mixture design for three ingredients and response surface methodology were used to identify the proportions of potato starch, rice flour and whole chia flour to achieve the best physical properties and result in sensory-accepted products. The physical properties and visual appearance showed that whole chia flour alone is not suitable for bread production. Nevertheless, it is possible to add up to 14% whole chia flour to a rice flour-based gluten-free bread formulation while negligibly diminishing the loaf volume, crumb firmness and crumb moisture. The best formulations were prepared from rice flour blends with 5, 10, and 14% whole chia flour, which received overall acceptability scores of 8.7, 8.1 and 7.9 on a 10-cm scale, respectively, similar to those of their white gluten-free bread and wheat bread counterparts. Incorporating 5%–14% whole chia flour in the formulation increased the levels of ash, lipid, protein and dietary fiber compared to those of the white gluten-free bread.
A mixture design for three ingredients and response surface methodology were used to defining the whole chia flour (WCF) proportions in a good-quality gluten-free bread formulation. The formulations containing 5%–14% WCF received overall acceptability scores similar to those of a white gluten-free and wheat bread counterparts. Incorporating 5%–14% WCF in the formulation increased the levels of ash, lipid, protein and dietary fiber compared to those of the white gluten-free bread.
http://ift.tt/2ubopGd
Cytochrome P450 enzyme RosC catalyzes a multistep oxidation reaction to form the non-active compound 20-carboxyrosamicin
Abstract
The cytochrome P450 enzyme RosC catalyzes a two-step, hydroxylation and alcohol oxidation, oxidation reaction to form the C-20 formyl group in the biosynthesis of a 16-membered macrolide antibiotic rosamicin produced by Micromonospora rosaria IFO13697. RosC is presumed to be involved in the formation of 20-carboxyrosamicin because it has been isolated from the culture broth of M. rosaria. Here, we confirmed that RosC has catalytic activity, with E. coli expressing RosC converting rosamicin into 20-carboxyrosamicin. Therefore, it was revealed that RosC is a multifunctional P450 that catalyzes a three-step oxidation reaction that leads to the formation of the hydroxyl group, formyl group and carboxyl group at C-20 on the macrolactone ring in the rosamicin biosynthetic pathway. Moreover, the cytochrome P450 enzyme TylI, which is involved in formation of the formyl group of a 16-membered macrolide antibiotic tylosin produced by Streptomyces fradiae ATCC 19609, also converted rosamicin into 20-carboxyrosamicin.http://ift.tt/2qWWCfN
Finding a facile way for the bacterial DNA transformation by biosynthesized gold nanoparticles
Abstract
The major problem encountered during genetic manipulation of bacteria is the inability to get transformed because of their natural non-competency. In this study, to overcome this problem, a cost-effective method was developed by combining the properties of gold nanoparticles (GNPs) and the Yoshida effect. Various parameters, including GNP:plasmid ratio, pH and time, were optimized for stability of the GNP–plasmid conjugate. With non-competent Gram-negative cells, the efficiency ranged between 0.1 and 0.45 × 104 transformants μg−1, while the range was (0.02–0.2) × 104 transformants μg−1 with Gram-positive bacteria. GNPs can serve efficiently as a vehicle for better transformation in bacteria.http://ift.tt/2sgVCii
Adaptive radiation of Pseudomonas fluorescens SBW25 in experimental microcosms provides an understanding of the evolutionary ecology and molecular biology of A-L interface biofilm formation
Abstract
Combined experimental evolutionary and molecular biology approaches have been used to investigate the adaptive radiation of Pseudomonas fluorescens SBW25 in static microcosms leading to the colonisation of the air–liquid interface by biofilm-forming mutants such as the Wrinkly Spreader (WS). In these microcosms, the ecosystem engineering of the early wild-type colonists establishes the niche space for subsequent WS evolution and colonisation. Random WS mutations occurring in the developing population that deregulate diguanylate cyclases and c-di-GMP homeostasis result in cellulose-based biofilms at the air–liquid interface. These structures allow Wrinkly Spreaders to intercept O2 diffusing into the liquid column and limit the growth of competitors lower down. As the biofilm matures, competition increasingly occurs between WS lineages, and niche divergence within the biofilm may support further diversification before system failure when the structure finally sinks. A combination of pleiotropic and epistasis effects, as well as secondary mutations, may explain variations in WS phenotype and fitness. Understanding how mutations subvert regulatory networks to express intrinsic genome potential and key innovations providing a selective advantage in novel environments is key to understanding the versatility of bacteria, and how selection and ecological opportunity can rapidly lead to substantive changes in phenotype and in community structure and function.http://ift.tt/2sgEtoP
Editorial: There is light at the end of the tunnel—‘Spotlight on…’
Graphical Abstract Figure.
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http://ift.tt/2sL7Frw
Parinaud syndrome: Any clinicoradiological correlation?
Introduction
The significance of MRI findings of patients with Parinaud syndrome (PS) with respect to clinical characteristics is poorly defined. Over the past decades, all patients with PS undergo magnetic resonance imaging which allows a better identification of the lesion localization. We compared the neuro-ophthalmological findings of patients with PS caused by intrinsic (intra-axial) vs extrinsic (pineal gland tumor) brainstem lesions.
Methods
Medical records of patients with PS evaluated between 2000 and 2016 were retrospectively reviewed.
Results
Twenty-six patients with PS were included. Eight patients had pineal gland tumors and hydrocephalus. Two patients had hydrocephalus due to aqueduct stenosis and fourth ventricle tumor. Sixteen patients suffered from an intrinsic brainstem lesion and seven associated with hydrocephalus.
The neuro-ophthalmological findings did not differ between patients with extrinsic and intrinsic brainstem lesions. No correlation was found between the grade of hydrocephalus and number of clinical findings except for more findings in low-grade hydrocephalus in intrinsic (40%) vs extrinsic (0%) lesions (P=.003). Patients with moderate brainstem lesions and hydrocephalus had more clinical findings (65%) than patients with the same grade of brainstem involvement without hydrocephalus (29%) (P=.03). The resolution rate of ophthalmological findings was comparable in all groups of patients.
Conclusions
Our results did not show differences in neuro-ophthalmological findings between intra- and extra-axial lesions causing PS. However, the presence of hydrocephalus was an important factor influencing clinical findings. The prognosis of PS was less favorable than generally reported.
http://ift.tt/2sbmQMb
Association between Parkinson's disease and diabetes: Data from NEDICES study
Background
Despite growing evidence showing an association between Parkinson's disease (PD) and diabetes, epidemiological studies have shown conflicting results.
Aims of the study
To evaluate the association between PD and diabetes and the impact of diabetes duration in this association in an elderly (≥65 years) Spanish population.
Methods
Data for this cross-sectional population-based analysis were obtained from NEDICES study. Subjects were identified from census list. Diagnosis of PD was confirmed by neurological examination. Diabetes was defined by self-report, being on antidiabetic medication or diagnosis on medical records. Logistic regression analysis adjusted by potential confounders was performed to estimate the association between both conditions and also after dividing patients into short-duration (<10 years) and long-duration (≥10 years) diabetes.
Results
A total of 4998 subjects were included (79 PD and 4919 controls). Univariate analysis did not show any association between prevalence of PD and diabetes (OR 1.89, 95% CI 0.90-3.98, P=.09), although subgroup analysis showed a positive association in those with long-duration diabetes (3.27, 95% CI 1.21-8.85, P=.02).
Conclusions
Diabetes duration might be an important factor in the association between PD and diabetes, and the risk might be limited to those with longer disease duration.
http://ift.tt/2sVrIlC
Complete DNA Sequence of IncM1 Plasmid Bearing the Novel qnrE1 PMQR Variant and blaCTX-M-8 from Klebsiella pneumoniae ST147 [PublishAheadOfPrint]
The recent article by Albornoz et al. (1), reported a member of a new family of plasmid-mediated quinolone resistance genes, named qnrE1, originating from the chromosome of Enterobacter spp....
http://ift.tt/2sbswG0
Nifurtimox is ineffective against drug-resistant mycobacteria [PublishAheadOfPrint]
Multi- and extensively drug-resistant tuberculosis (XDR-TB) and diseases caused by the naturally drug-resistant nontuberculous mycobacteria (NTM) are emerging health threats....
http://ift.tt/2sVhh1f
Preclinical characterization of the inhaled small molecule respiratory syncytial virus L-protein polymerase inhibitor, PC786 [PublishAheadOfPrint]
Although respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infection in infants and young children, attempts to develop an effective therapy have so far proved unsuccessful. Herein we report the preclinical profiles of PC786, a potent non-nucleoside RSV L-protein polymerase inhibitor, designed for inhalation treatment of RSV infection. PC786 demonstrated a potent and selective anti-viral activity against laboratory adapted or clinical isolates of RSVA (IC50: <0.09 - 0.71 nM) and RSVB (IC50: 1.3 - 50.6 nM), which were determined by inhibition of cytopathic effects in HEp-2 cells without causing detectable cytotoxicity. The underlying inhibition of virus replication was confirmed by PCR analysis. The effects of PC786 were largely unaffected by the multiplicity of infection (MOI) and were retained in the face of established RSV replication in a time-of-addition study. Persistent anti-RSV effects of PC786 were also demonstrated in human bronchial epithelial cells. In vivo intranasal once daily dosing with PC786 was able to reduce the virus load to undetectable levels in lung homogenates from RSV infected mice and cotton rats. Treatment with escalating concentrations identified a dominant mutation in the L protein (Y1631H) in vitro. In addition, PC786 potently inhibited RSV RNA-dependent RNA polymerase (RdRp) activity in a cell-free enzyme assay and mini-genome assay in HEp-2 cells (IC50: 2.1 and 0.5 nM, respectively). Thus, PC786 was shown to be a potent anti-RSV agent via inhibition of RdRp activity, making topical treatment with this compound a novel potential therapy for the treatment of human RSV infections.
http://ift.tt/2sbii8D
Characterization of the Activities of Dinuclear Thiolato-Bridged Arene Ruthenium Complexes against Toxoplasma gondii [PublishAheadOfPrint]
The in vitro effects of 18 dinuclear-thiolato bridged arene ruthenium complexes, (1 mono-, 4 di- and 13-tri-thiolato compounds), originally designed as anti-cancer agents, were studied in the apicomplexan parasite Toxoplasma gondii grown in human foreskin fibroblast host cells (HFF). Some tri-thiolato compounds exhibited anti-parasitic efficacy at 250 nM and below. Among those, complex 1 and complex 2 inhibited T. gondii proliferation with IC50 values of 34 and 62 nM, respectively, and they did not affect HFF at dosages of 200 μM or above, resulting in selectivity indices of > 23' 000. The IC50 values of complex 9 were 1.2 nM for T. gondii and above 5 μM for HFF. TEM detected ultrastructural alterations in the matrix of the parasite mitochondria at the early stages of treatment, followed by more pronounced destruction of tachyzoites. However, all three compounds applied at 250 nM for 15 days were not parasiticidal. By affinity chromatography using complex 9 coupled to epoxy-activated sepharose followed by mass spectrometry, T. gondii translation elongation factor-1 alpha and two ribosomal proteins, RPS18, and RPL27 were identified as potential binding proteins. In conclusion, organometallic ruthenium complexes exhibit promising activities against Toxoplasma, and potential mechanisms of action of these compounds as well as their prospective applications for the treatment of toxoplasmosis are discussed.
http://ift.tt/2sVsQpx
Relationship between the Minimum Inhibitory Concentration of Carbapenems and the Clinical Outcome of Patients with Acinetobacter Bacteremia: A Multicenter Study [PublishAheadOfPrint]
The Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) offer different recommendations for carbapenem minimal inhibitory concentration (MIC) susceptibility breakpoints for Acinetobacter spp. In addition, the clinical efficacy of the intermediate category remains uncertain. This study was designed to determine the optimal predictive breakpoints based on survival of patients with Acinetobacter bacteremia treated with a carbapenem. We analyzed the thirty-day mortality rates of 224 adults who received initial carbapenem monotherapy for treatment of Acinetobacter bacteremia at 4 medical centers over a 5-year period according to the carbapenem MICs of the initial isolates. The thirty-day mortality was about 2-fold greater in patients whose isolates had carbapenem MICs ≥8 mg/L than those with ≤4 mg/L. The differences were significant by bivariate analysis (53.1% [60/113] vs. 25.2% [28/111]; P < 0.001) and on survival analysis by the log-rank test (P < 0.001). Classification and regression tree analysis revealed a split between MICs of 4 and 8 mg/L and predicted the same difference in mortality, P < 0.001. Carbapenem treatment for Acinetobacter bacteremia caused by isolates with carbapenem MICs ≥8 mg/L was an independent predictor of 30-day mortality (odds ratio, 4.218; 95% confidence interval, 2.213--8.039; P < 0.001). This study revealed that patients with Acinetobacter bacteremia treated with a carbapenem had a more favorable outcome when the carbapenem MICs of their isolates were ≤4 mg/L compared to those isolates with MIC ≥8 mg/L.
http://ift.tt/2sbtxhm
Meropenem-Vaborbactam Tested against Contemporary Gram-Negative Isolates Collected Worldwide During 2014, Including Carbapenem-Resistant, KPC-Producing, Multidrug-Resistant, and Extensively Drug-Resistant Enterobacteriaceae [PublishAheadOfPrint]
We evaluated the activity of meropenem-vaborbactam against contemporary non-fastidious gram-negative clinical isolates, including resistant phenotypes and carbapenemase genotypes of Enterobacteriaceae. Meropenem-vaborbactam (inhibitor at 8 μg/ml) and comparators were susceptibility tested using reference broth microdilution methods against 14,304 gram-negative clinical isolates collected worldwide during 2014. Carbapenemase encoding genes were screened by PCR/sequencing. Meropenem-vaborbactam (MIC50/90, ≤0.015/0.06 μg/ml) inhibited 99.1 and 99.3% of the 10,426 Enterobacteriaceae isolates tested at ≤1 and ≤2 μg/ml, respectively. Meropenem inhibited 97.3 and 97.7% of these isolates at the same concentrations. Against Enterobacteriaceae displaying carbapenem resistance (CRE) (n=265), multidrug (MDR) (n=1,210) or extensively drug (XDR) (n=161) resistant phenotypes, meropenem-vaborbactam displayed MIC50/90 values at 0.5/32, 0.03/1 and 0.5/32 μg/ml, respectively, whereas meropenem activity was 16/>32, 0.06/32 and 0.5/32 μg/ml, respectively. Among all geographic regions, the highest meropenem-vaborbactam activity was observed for CRE and MDR isolates from the U.S. (MIC50/90, 0.03/1 and 0.03/0.12 μg/ml, respectively). Meropenem-vaborbactam was very active against 135 KPC-producers, and all isolates were inhibited by ≤8 μg/ml (133 isolates at ≤2 μg/ml). This combination had limited activity against isolates producing metallo-β-lactamases (including 25 NDM-1- and 16 VIM-producers) and/or oxacillinases (27 OXA-48/-163) that were detected mainly in Asia-Pacific and some European countries. The activity of meropenem-vaborbactam was similar to that of meropenem alone against Pseudomonas aeruginosa, Acinetobacter spp. and Stenotrophomonas maltophilia. Meropenem-vaborbactam was active against contemporary Enterobacteriaceae collected worldwide, and this combination demonstrated enhanced activity when compared to meropenem and most comparator agents against CRE and KPC-producers that are often MDR.
http://ift.tt/2sVf5Hf
Potent inhibition of HIV-1 replication in resting CD4 T cells by resveratrol and pterostilbene [PublishAheadOfPrint]
HIV-1 infection of resting CD4 T cells plays a crucial and numerically dominant role during virus transmission at mucosal sites and during subsequent acute replication and T cell depletion. Resveratrol and pterostilbene are plant stilbenoids associated with several health promoting benefits. Resveratrol has been shown to inhibit replication of several viruses, including herpes simplex 1 and 2, papillomaviruses, SARS virus and influenza virus. Alone, resveratrol does not inhibit HIV-1 infection of activated T cells, but it does synergize with nucleoside reverse transcriptase inhibitors in these cells to inhibit reverse transcription. Here, we demonstrate that resveratrol and pterostilbene completely block HIV-1 infection at low micromolar dose in resting CD4 T cells, primarily at the reverse transcription step. The anti-HIV effect was fully reversed by exogenous deoxynucleosides and Vpx, a simian immunodeficiency virus protein that increases dNTP levels. These findings are consistent with the reported ability of resveratrol to inhibit ribonucleotide reductase and to lower dNTP levels in cells. This study supports the potential use of resveratrol, pterostilbene or related compounds as adjuvants in anti-HIV pre-exposure prophylaxis (PrEP) formulations.
http://ift.tt/2sb0lXA
The Candidate Antimalarial Drug MMV665909 Causes Oxygen-Dependent mRNA Mistranslation and Synergises with Quinoline-Derived Antimalarials [PublishAheadOfPrint]
To cope with growing resistance to current antimalarials, new drugs with novel modes of action are urgently needed. Molecules targeting protein synthesis appear to be promising candidates. We identified a compound (MMV665909) from the MMV Malaria Box of candidate antimalarials that could produce synergistic growth inhibition with the aminoglycoside antibiotic paromomycin, suggesting a possible action of the compound in mRNA mistranslation. This mechanism of action was substantiated with the yeast cell model using available reporters of mistranslation and other genetic tools. Mistranslation induced by MMV665909 was oxygen-dependent, suggesting a role for reactive oxygen species (ROS). Overexpression of Rli1 (a ROS-sensitive, conserved FeS protein essential in mRNA translation) rescued inhibition by MMV665909, consistent with the drug's action on translation fidelity being mediated through Rli1. The MMV drug also synergised with major quinoline-derived antimalarials which can perturb amino acid availability or promote ROS stress: chloroquine, amodiaquine and primaquine. The data collectively suggest translation-fidelity as a novel target of antimalarial action and support MMV665909 as a promising drug candidate.
http://ift.tt/2sVnFFP
Outbreak of CTX-M-15-producing enterotoxigenic Escherichia coli O159:H20 in the Republic of Korea, 2016 [PublishAheadOfPrint]
We investigated an outbreak of enterotoxigenic Escherichia coli (ETEC) O159:H20 associated with the consumption of a tossed noodle dish in a high school in 2016. Thirty-three ETEC strains isolated from both clinical and food samples were genetically indistinguishable. The outbreak strains were resistant to third-generation cephalosporins and harbored a blaCTX-M-15 gene on a 97-kb self-transferable IncK plasmid. This is the first outbreak caused by CTX-M-15-producing ETEC strains.
http://ift.tt/2sbslu2
Characterization of a Francisella tularensis-Caenorhabditis elegans pathosystem for the evaluation of therapeutic compounds [PublishAheadOfPrint]
Francisella tularensis is a highly infectious Gram-negative intracellular pathogen that causes tularemia. Because of its potential as a bioterrorism agent, there is a need for new therapeutic agents. We therefore developed a whole animal Caenorhabditis elegans-F. tularensis pathosystem for high throughput screening to identify and characterize potential therapeutic compounds. We found that the C. elegans p38 MAP kinase cascade is involved in the immune response to F. tularensis and we developed a robust F. tularensis-mediated C. elegans killing assay with a Z'-factor consistently >0.5, which was then utilized to screen a library of FDA approved compounds that included 1,760 small molecules. In addition to clinically used antibiotics, 5 FDA-approved drugs were also identified as potential hits, including the anti-inflammatory drug diflunisal that showed anti-F. tularensis activity in vitro. Moreover, the NSAID diflunisal, at 4X MIC, blocked the replication of a F. tularensis live vaccine strain (LVS) in primary human macrophages and non-phagocytic cells. Diflunisal was non-toxic to human erythrocytes and HepG2 human liver cells at concentrations ≥32-μg/ml. Finally, diflunisal exhibited synergetic activity with the antibiotic ciprofloxacin in both a checkerboard assay and a macrophage infection assay. In conclusion, the liquid C. elegans — F. tularensis LVS assay described here allows screening for anti-F. tularensis compounds and suggests that diflunisal could potentially be repurposed for the management of tularemia.
http://ift.tt/2ubD44o
Targeting homoserine dehydrogenase from Paracoccidioides Genus against systemic fungal infections [PublishAheadOfPrint]
This work evaluated new potential inhibitors of the enzyme homoserine dehydrogenase (HSD) from Paracoccidioides brasiliensis, one of the etiological agent of paracoccidioidomycosis. The tertiary structure of the protein bonded to the analogue NAD and L-homoserine was modeled by homology. The best output model was subjected to gradient minimization, redocking and molecular dynamics. Virtual screening simulations with 187,841 purchasable molecules from the Zinc database were performed. After the screenings, 14 molecules were selected and analyzed by ADMETox criteria, resulting in four compounds for in vitro assays. The molecules HS1 and HS2 were promising, exhibiting MICs of 64 and 32 μg.mL-1 respectively for the Pb18 isolate of P. brasilensis, 64 μg.mL-1 for two isolates of P. lutzii and also synergy with itraconazole. The application of these molecules in human pathogenic fungi confirmed that the HSD enzyme may be used as a target for the development of drugs with specific action against paracoccidioidomycosis; moreover these compounds may serve as leads in the design of new antifungals.
http://ift.tt/2tdBQbG
Synthetic cyclic peptomers as type III secretion system inhibitors [PublishAheadOfPrint]
Antibiotic resistant bacteria are an emerging threat to global public health. New classes of antibiotics and tools for antimicrobial discovery are urgently needed. The type III secretion system (T3SS), which is required by dozens of Gram-negative bacteria for virulence but largely absent from non-pathogenic bacteria, is a promising virulence blocker target. The ability of mammalian cells to recognize the presence of a functional T3SS and trigger NFB activation provides a rapid and sensitive method to identify chemical inhibitors of T3SS activity. In this study, we generated a HEK293 stable cell line expressing Green Fluorescence Protein (GFP) driven by a promoter containing NFB enhancer elements to serve as a readout of T3SS function. We have identified a family of synthetic cyclic peptide-peptoid hybrid molecules (peptomers) that exhibited dose-dependent inhibition of T3SS effector secretion in Yersinia pseudotuberculosis and Pseudomonas aeruginosa without affecting bacterial growth or motility. Among these inhibitors, EpD-3' N, EpD-1,2N, EpD-1,3' N, EpD-1,2,3' N, and EpD-1,2,4' N exhibited a strong inhibitory effect on translocation of the Yersinia YopM effector protein into mammalian cells (>40% translocation inhibition at 7.5 μM) and showed no toxicity to mammalian cells at 240 μM. In addition, EpD-3' N and EpD-1,2,4' N reduced rounding of HeLa cells caused by the activity of effector proteins from Yersinia that target the actin cytoskeleton. In summary, we have discovered a family of novel cyclic peptomers that inhibit the injectisome T3SS but not the flagellar T3SS.
http://ift.tt/2ub9nAt
Prophylactic Treatment with VT-1161 Protects Immunosuppressed Mice from Rhizopus arrhizus var. arrhizus Infection [PublishAheadOfPrint]
We compared prophylactic or continuous therapy of the investigational drug VT-1161 to posaconazole in treating murine mucormycosis due to Rhizopus arrhizus var. arrhizus. In the prophylaxis studies, only VT-1161 resulted in improved survival and lowered tissue fungal burden of immunosuppressed infected mice. In the continuous therapy, VT-1161 outperformed posaconazole in prolonging mice survival time despite their comparable effect in lowering tissue fungal burden. These results support the further development of VT-1161 against mucormycosis.
http://ift.tt/2tdM8bV
THE NON-ANTIBIOTIC MACROLIDE EM703 IMPROVES SURVIVAL IN A MODEL OF QUINOLONE-TREATED PSEUDOMONAS AERUGINOSA AIRWAY INFECTION [PublishAheadOfPrint]
Macrolide antibiotics are used as anti-inflammatory agents, e.g. for prevention of exacerbations in COPD and cystic fibrosis. Several studies have shown improved outcomes after addition of macrolides to beta-lactam antibiotics when treating severe community-acquired pneumonia. However, a beneficial effect of macrolides when treating Gram-negative bacterial airway infections, e.g. those caused by Pseudomonas aeruginosa, remains to be shown. Macrolide antibiotics have significant side effects, in particular motility-stimulating activity of the gastrointestinal tract and promotion of bacterial resistance. In this study, EM703, a modified macrolide lacking antibiotic and motility-stimulating activities, but with retained anti-inflammatory properties, was used as an adjunct treatment of experimental P. aeruginosa lung infection in combination with a conventional antibiotic. Airway infection in BALB/cJRj mice was induced by nasal instillation of P. aeruginosa. This was followed by treatment with the quinolone levofloxacin in the absence or presence of EM703. Survival, inflammatory responses, and cellular influx to the airways were monitored. Both pretreatment and simultaneous administration of EM703 dramatically improved survival in levofloxacin-treated mice with P. aeruginosa airway infection. In addition, EM703 reduced the levels of proinflammatory cytokines, increased the number of leukocytes in bronchoalveolar fluid, and reduced the number of neutrophils present in the lung tissue. In summary, the findings of this study show that the immunomodulatory properties of the modified macrolide EM703 can be important when treating Gram-negative pneumonia, as exemplified by P. aeruginosa infection in this study.
http://ift.tt/2ubfy7A
Perceived facial changes of Class II Division 1 patients with convex profiles after functional orthopedic treatment followed by fixed orthodontic appliances
The aim of this research was to investigate the perceived facial changes in Class II Division 1 patients with convex profiles after functional orthopedic treatment followed by fixed orthodontic appliances.
http://ift.tt/2sLoOBt
Lateral open bite and crossbite correction in a Class III patient with missing maxillary first premolars
Posterior and Class III elastics were used to correct lateral open bite and anterior crossbite in a 29-year-old man. His occlusion, smile esthetics, and soft tissue profile were significantly improved after 25 months of active orthodontic treatment combined with 4 anterior restorations.
http://ift.tt/2sLbPQp
Gingival crevicular fluid bone turnover biomarkers: How postmenopausal women respond to orthodontic activation
Bone turnover associated with orthodontic tooth movement is evidenced by increased bone turnover markers in gingival crevicular fluid (GCF). Postmenopausal women have an increased concentration of serum bone turnover markers. The filtrate of this serum makes up GCF, but little is known of the bone turnover around teeth in this cohort. The objective of this investigation was to compare the GCF bone turnover markers in premenopausal vs postmenopausal women receiving orthodontic treatment at baseline and at orthodontic activation.
http://ift.tt/2sLgAt1
Authors' response
Thank you for the compliment on our article, "Change in the vertical dimension of Class II Division 1 patients after use of cervical or high-pull headgear," in the November 2016 issue of the AJO-DO.1 We are happy to provide more details and clarification to our article.
http://ift.tt/2sLyewT
No tricks, please
It's time again for your annual national convention, and this year you've decided to take the entire family. The venue is perfect: dependably mild weather, world–renowned restaurants, and plenty for the kids to do. And the program holds enough interesting lectures to keep you enthralled for the 3-day duration of the meeting. Your wife offers to make the hotel reservations to ensure that she will be fulfilled by this brief getaway. She verifies the meeting dates and proceeds to register you and your family for the stay.
http://ift.tt/2sgnS4u
Compliance with removable orthodontic appliances and adjuncts: A systematic review and meta-analysis
The primary aims of this systematic review were to assess objective levels of wear of removable orthodontic appliances and components vs both stipulated and self-reported levels. We also aimed to consider patient experiences and the effectiveness of interventions geared at enhancing compliance.
http://ift.tt/2sL9CUZ
Correlation between buccolingual tooth inclination and alveolar bone thickness in subjects with Class III dentofacial deformities
The purposes of this study were to identify buccolingual inclinations and alveolar bone thickness in patients with Class III dentofacial deformities and to compare these measurements with those from subjects with normal occlusions to verify, based on the correlation between these 2 variables, whether the natural process of bone remodeling provides uniformity of bone thickness or whether it varies around the roots due to tooth inclination.
http://ift.tt/2sLwlAl
Robert Shaye, 1937-2017
Robert Shaye was a man with many interests, and he enjoyed a long and successful academic career. He was born in 1937. He attended high school in New Haven, Connecticut, and college at the University of Connecticut. Afterward, he obtained his doctorate of dental surgery from New York University College of Dentistry. He then completed a certificate of orthodontics from the University of Zurich School of Dentistry in Switzerland. He also completed a certificate in orthodontics from the University of Alabama School of Dentistry.
http://ift.tt/2sgfNNp
Mesiodistal dental movement toward remodeled edentulous alveolar ridge: Digital model assessment
The aims of this study were to compare the changes in posterior dental inclination and angulation, and the posterior tooth crown sizes and alveolar ridge thicknesses consequent to the orthodontic procedures of closing and opening of mandibular first molar edentulous spaces.
http://ift.tt/2sLprLa
Harms and adverse events in clinical research
Harm is "the totality of possible adverse consequences of an intervention or therapy."1 An adverse event is any unfavorable or harmful occurrence in a patient, temporarily related to a medical intervention, but without any judgment about causality.1 Although many biological and mechanical risk factors have been associated with external apical root resorption (EARR), a causal relationship has not yet been established.2 Thus, EARR is an adverse event occurring in orthodontic patients, and its research is a harm-related issue.
http://ift.tt/2sgnUt9
Authors' response
We thank Dr Waxler for his comments and question on our article.1 In the published article, we referred only to the extraction of 4 first premolars—not 4 premolars broadly. That means that the 10% rate reflects only the extraction of 4 first premolars and does not include the extraction of second premolars, combinations of extraction of first and second premolars in opposing arches, unilateral premolar extractions, single incisor extractions, and so on. The inclusion of 4 first premolar extraction rates was for historical comparison only, to mirror the Proffit work from 1994.
http://ift.tt/2sL6YhX
Authors' response
We are pleased that our article has stimulated comments because they are an opportunity for further discussion on this challenging orthodontic subject: root resorption.
http://ift.tt/2sgnQto
Effect of cervical or high-pull headgear on the vertical dimensions of Class II Division 1 patients
We read the article entitled "Change in the vertical dimension of Class II Division 1 patients after use of cervical or high-pull headgear" by Zervas et al in the November 2016 issue with great interest.1 The authors are appreciated for their sincere effort. Having said that, as avid readers of your Journal, we want to raise a few questions that might be beneficial to other readers.
http://ift.tt/2sKVZoE
Authors' response
We thank Drs Brezniak and Wasserstein for their interest in our study. Root resorption is a naturally occurring phenomenon,1 and even teeth that haven't been subjected to orthodontic forces may show some root resorption.2-4 There is, unfortunately, no method that can predict which patients are at risk of severe orthodontically induced inflammatory root resorption, and individual predisposition is a major etiologic factor. Patient-related factors and individual predisposition cannot be changed; however, clinicians can use caution and modify treatment procedures for certain patients.
http://ift.tt/2sgE6um
Miniscrew-assisted customized lingual appliances for predictable treatment of skeletal Class II malocclusion with severe deep overbite and overjet
This report describes the use of miniscrew-assisted customized lingual fixed appliances in a patient with severe skeletal Class II malocclusion. The patient was a 12-year-old Chinese girl with the chief complaint of protrusive lips and anterior teeth. Her diagnosis included a skeletal Class II relationship with maxillary protrusion, a backward-rotated mandible, a full Angle Class II molar relationship, and severe deep overjet and overbite. Four premolars were extracted, and miniscrew anchorage was placed in the maxillary posterior lingual segment to provide maximum anchorage and to achieve vertical control of the intruding molars.
http://ift.tt/2ubtfTX
Anatomic comparison of veins of Labbé between autopsy, digital subtraction angiography and computed tomographic venography
The drainage portion of the vein of Labbé varies, and it is difficult to predict whether the operation is likely to damage this vein. The aim of this study was to correlate the microanatomy of the vein of Labb...
http://ift.tt/2tgwhtB
A vessel length-based method to compute coronary fractional flow reserve from optical coherence tomography images
Hemodynamic simulation for quantifying fractional flow reserve (FFR) is often performed in a patient-specific geometry of coronary arteries reconstructed from the images from various imaging modalities. Becaus...
http://ift.tt/2tQ0Xz2
Lead field theory provides a powerful tool for designing microelectrode array impedance measurements for biological cell detection and observation
Our aim is to introduce a method to enhance the design process of microelectrode array (MEA) based electric bioimpedance measurement systems for improved detection and viability assessment of living cells and ...
http://ift.tt/2tgzoSs
Glycerol-3-phosphate acyltransferase 1 promotes tumor cell migration and poor survival in ovarian carcinoma
Glycerophosphodiesterase EDI3 (GPCPD1; GDE5; GDPD6) has been suggested to promote cell migration, adhesion and spreading, but its mechanisms of action remain uncertain. In this study, we targeted the glycerol-3-phosphate acyltransferase GPAM along with choline kinase-α (CHKA), the enzymes that catabolize the products of EDI3 to determine which downstream pathway is relevant for migration. Our results clearly showed that GPAM influenced cell migration via the signaling lipid lysophosphatidic acid (LPA), linking it with GPAM to cell migration. Analysis of GPAM expression in different cancer types revealed a significant association between high GPAM expression and reduced overall survival in ovarian cancer. Silencing GPAM in ovarian cancer cells decreased cell migration and reduced the growth of tumor xenografts. In contrast to these observations, manipulating CHKA did not influence cell migration in the same set of cell lines. Overall, our findings show how GPAM influences intracellular LPA levels to promote cell migration and tumor growth.
http://ift.tt/2teYzEr
SPIN90 depletion and Microtubule Acetylation Mediate Stromal Fibroblast Activation in Breast Cancer Progression
Biomechanical remodeling of stroma by cancer-associated fibroblasts (CAF) in early stages of cancer is critical for cancer progression, and mechanical cues such as extracellular matrix stiffness control cell differentiation and malignant progression. However, the mechanism by which CAF activation occurs in low stiffness stroma in early stages of cancer is unclear. Here we investigated the molecular mechanism underlying CAF regulation by SPIN90 and microtubule acetylation under conditions of mechanically soft matrices corresponding to normal stromal rigidity. SPIN90 was downregulated in breast cancer stroma but not tumor, and this low stromal expression correlated with decreased survival in breast cancer patients. Spin90 deficiency facilitated recruitment of mDia2 and APC complex to microtubules, resulting in increased microtubule acetylation. This increased acetylation promoted nuclear localization of YAP, which upregulated expression of myofibroblast marker genes on soft matrices. Spin90 depletion enhanced tumor progression, and blockade of microtubule acetylation in CAF significantly inhibited tumor growth in mice. Together our data demonstrate that loss of SPIN90-mediated microtubule acetylation is a key step in CAF activation in low stiffness stroma. Moreover, correlation among these factors in human breast cancer tissue supports the clinical relevance of SPIN90 and microtubule acetylation in tumor development.
http://ift.tt/2teYxfN
Hypoxia-induced downregulation of DUSP-2 phosphatase drives colon cancer stemness
Cancer stem-like cells (CSC) evolve to overcome the pressures of reduced oxygen, nutrients or chemically induced cell death, but the mechanisms driving this evolution are incompletely understood. Here we report that hypoxia-mediated downregulation of the dual specificity phosphatase 2 (DUSP2) is critical for the accumulation of CSC in colorectal cancer. Reduced expression of DUSP2 led to overproduction of cyclooxygenase-2 (COX-2)-derived prostaglandin E2, which promoted cancer stemness via the EP2/EP4 signaling pathways. Genetic and pharmacological inhibition of PGE2 biosynthesis or signal transduction ameliorated loss-of-DUSP2-induced tumor growth and cancer stemness. Genome-wide profile analysis revealed that genes regulated by DUSP2 were similar to those controlled by histone deacetylase. Indeed, treatment with novel histone deacetylase inhibitors abolished hypoxia-induced DUSP2 downregulation, COX-2 overexpression, cancer stemness, tumor growth, and drug resistance. Our findings illuminate mechanisms of cancer stemness and suggest new cancer therapy regimens.
http://ift.tt/2rVzJWs
Identification of interacting stromal axes in triple-negative breast cancer
Triple-negative breast cancer (TNBC) is a molecularly heterogeneous cancer that is difficult to treat. Despite the role it may play in tumor progression and response to therapy, microenvironmental (stromal) heterogeneity in TNBC has not been well characterized. To address this challenge, we investigated the transcriptome of tumor-associated stroma isolated from TNBC (n=57). We identified four stromal axes enriched for T cells (T), B cells (B), epithelial markers (E), or desmoplasia (D). Our analysis method (STROMA4) assigns a score along each stromal axis for each patient, and then combined the axis scores to subtype patients. Analysis of these subtypes revealed that prognostic capacity of the B, T and E scores was governed by the D score. When compared to a previously published TNBC subtyping scheme, the STROMA4 method better captured tumor heterogeneity and predicted patient benefit from therapy with increased sensitivity. This approach produces a simple ontology that captures TNBC heterogeneity and informs how tumor-associated properties interact to affect prognosis.
http://ift.tt/2teGB55
Posttranscriptional upregulation of IDH1 by HuR establishes a powerful survival phenotype in pancreatic cancer cells
Cancer aggressiveness may result from the selective pressure of a harsh nutrient-deprived microenvironment. Here we illustrate how such conditions promote chemotherapy resistance in pancreatic ductal adenocarcinoma (PDA). Glucose or glutamine withdrawal resulted in a 5-10-fold protective effect with chemotherapy treatment. PDA xenografts were less sensitive to gemcitabine in hypoglycemic mice compared to hyperglycemic mice. Consistent with this observation, patients receiving adjuvant gemcitabine (n=107) with elevated serum glucose levels (HgbA1C>6.5%) exhibited improved survival. We identified enhanced antioxidant defense as a driver of chemoresistance in this setting. ROS levels were doubled in vitro by either nutrient withdrawal or gemcitabine treatment, but depriving PDA cells of nutrients before gemcitabine treatment attenuated this effect. Mechanistic investigations based on RNAi or CRISPR approaches implicated the RNA binding protein HuR in preserving survival under nutrient withdrawal, with or without gemcitabine. Notably, RNA deep sequencing and functional analyses in HuR-deficient PDA cell lines identified isocitrate dehydrogenase 1 (IDH1) as the sole antioxidant enzyme under HuR regulation. HuR-deficient PDA cells lacked the ability to engraft successfully in immunocompromised mice, but IDH1 overexpression in these cells was sufficient to fully restore chemoresistance under low nutrient conditions. Overall, our findings highlight the HuR-IDH1 regulatory axis as a critical, actionable therapeutic target in pancreatic cancer. <br /> <p>
http://ift.tt/2rW1xd3
WEE1 kinase inhibitor AZD1775 has pre-clinical efficacy in LKB1-deficient non-small cell lung cancer
G1/S checkpoint loss contributes to carcinogenesis and increases reliance upon the G2/M checkpoint for adaptation to stress and DNA repair, making G2/M checkpoint inhibition a target for novel therapeutic development. AZD1775, an inhibitor against the critical G2/M checkpoint protein WEE1, is currently in clinical trials across a number of tumor types. AZD1775 and DNA-damaging agents have displayed favorable activity in several pre-clinical tumor models, often in the molecular context of TP53 loss. Whether AZD1775 efficacy is modulated by other molecular contexts remains poorly understood. The tumor suppressor serine/threonine kinase 11 (LKB1/STK11) is one of the most frequently mutated genes in non-small cell lung cancer (NSCLC) and is commonly co-mutated with oncogenic KRAS mutations. We investigated the pre-clinical effects of AZD1775 in the context of KRAS/LKB1 in NSCLC. Using NSCLC cell lines, we found that AZD1775 alone and in combination with DNA-damaging agents (e.g., cisplatin and radiation) decreased tumor cell viability in LKB1-deficient NSCLC cells. In vitro, LKB1 deficiency enhanced DNA damage and apoptosis in response to AZD1775 exposure compared with wildtype LKB1 cells. In a genetically engineered mouse model of mutant Kras with concomitant loss of Lkb1, combined AZD1775 and cisplatin extended overall survival compared to cisplatin alone. Our data suggest that lack of phosphorylation of LKB1 by ATM was involved in AZD1775-mediated cytotoxicity. Collectively, these findings provide a clinical application for AZD1775 with DNA-damaging agents in KRAS/LKB1 NSCLC.
http://ift.tt/2tez4mN
GLI1 blockade potentiates the antitumor activity of PI3K antagonists in lung squamous cell carcinoma
Lung squamous cell carcinoma (SCC), strongly associated with smoking, is treated primarily with traditional cytotoxic chemotherapy due to a lack of FDA-approved targeted agents available. Here we identify the Hedgehog pathway transcription factor GLI1 as a critical driver of lung SCC. Analysis of human lung cancer datasets showed that GLI1 mRNA was highly expressed in human lung SCC and portended a poor prognosis. Inhibition of GLI1 in human lung SCC cell lines suppressed tumor cell clonogenicity and proliferation in culture and in vivo. Addition of SHH ligand, SMO antagonists, or other Hedgehog pathway agonists did not affect GLI1 expression in lung SCC cells. However, GLI1 expression was modulated by either inhibition or activation of the PI3K and MAPK pathways. Furthermore, in vivo growth of SCC harboring amplifications of the PI3K gene PIK3CA was attenuated by antagonizing GLI1 and PI3K. Thus, a combinatorial therapeutic strategy that targets the PI3K-mTOR pathway and GLI1 may lead to effective outcomes for PI3K pathway-dependent cancers, in contrast to recent results of human trials with single-agent PI3K antagonists.
http://ift.tt/2rW8ATp
MAPK signaling and inflammation link melanoma phenotype switching to induction of CD73 during immunotherapy
Evolution of tumor cell phenotypes promotes heterogeneity and therapy resistance. Here we found that induction of CD73, the enzyme that generates immunosuppressive adenosine, is linked to melanoma phenotype switching. Activating MAPK mutations and growth factors drove CD73 expression, which marked both nascent and full activation of a mesenchymal-like melanoma cell state program. Proinflammatory cytokines like TNF-alpha cooperated with MAPK signaling through the c-Jun/AP-1 transcription factor complex to activate CD73 transcription by binding to an intronic enhancer. In a mouse model of T cell immunotherapy, CD73 was induced in relapse melanomas, which acquired a mesenchymal-like phenotype. We also detected CD73 upregulation in melanoma patients progressing under adoptive T cell transfer or immune checkpoint blockade, arguing for an adaptive resistance mechanism. Our work substantiates CD73 as target to combine with current immunotherapies, but its dynamic regulation suggests limited value of CD73 pre-treatment expression as a biomarker to stratify melanoma patients.
http://ift.tt/2teYj8E
Unpaired extracellular cysteine mutations of CSF3R mediate gain or loss of function
Exclusive of membrane-proximal mutations seen commonly in chronic neutrophilic leukemia (e.g. T618I), functionally defective mutations in the extracellular domain of the granulocyte colony-stimulating factor receptor (CSF3R) have been reported only in severe congenital and idiopathic neutropenia patients. Here we describe the first activating mutation in the fibronectin like type III domain of the extracellular region of CSF3R (W341C) in a leukemia patient. This mutation transformed cells via cysteine-mediated intermolecular disulfide bonds, leading to receptor dimerization. Interestingly, a CSF3R cytoplasmic truncation mutation (W791X) found on the same allele as the extracellular mutation and the expansion of the compound mutation was associated with increased leukocytosis and disease progression of the patient. Notably, the primary patient sample and cells transformed by W341C and W341C/W791X exhibited sensitivity to JAK inhibitors. We further showed that disruption of original cysteine pairs in the CSF3R extracellular domain resulted in either gain- or loss-of-function changes, part of which was attributable to cysteine-mediated dimer formation. This, therefore, represents the first characterization of unpaired cysteines that mediate both gain and loss of function phenotypes. Overall, our results show the structural and functional importance of conserved extracellular cysteine pairs in CSF3R and suggest the necessity for broader screening of CSF3R extracellular domain in leukemia patients.
http://ift.tt/2rW4vhI
Targeting adenosine in BRAF-mutant melanoma reduces tumor growth and metastasis
Increasing evidence exists for the role of immunosuppressive adenosine in promoting tumor growth and spread in a number of cancer types, resulting in poor clinical outcomes. In this study, we assessed whether the CD73-adenosinergic pathway is active in melanoma patients and whether adenosine restricts the efficacy of clinically approved targeted therapies for commonly mutated BRAFV600E melanoma. In AJCC Stage III melanoma patients, CD73 expression (the enzyme that generates adenosine) correlated significantly with patients presenting nodal metastatic melanoma, suggesting that targeting this pathway may be effective in advanced stage disease. In addition, dabrafenib and trametinib treatment of CD73+ BRAFV600E-mutated melanomas caused profound CD73 downregulation in tumor cells. Inhibition of BRAF and MEK in combination with the A2A adenosine receptor (A2AR) provided significant protection against tumor initiation and metastasis formation in mice. Our results suggest that targeting adenosine may enhance therapeutic responses for melanoma patients receiving targeted or immune-based therapies.
http://ift.tt/2teO9Fb
Immune Escape in Breast Cancer During In Situ to Invasive Carcinoma Transition [Research Articles]
To investigate immune escape during breast tumor progression, we analyzed the composition of leukocytes in normal breast tissues, ductal carcinoma in situ (DCIS), and invasive ductal carcinomas (IDC). We found significant tissue and tumor subtype-specific differences in multiple cell types including T cells and neutrophils. Gene expression profiling of CD45+CD3+ T cells demonstrated a decrease in CD8+ signatures in IDCs. Immunofluorescence analysis showed fewer activated GZMB+CD8+ T cells in IDC than in DCIS, including in matched DCIS recurrent IDC. TCR clonotype diversity was significantly higher in DCIS than in IDCs. Immune checkpoint protein TIGIT expressing T cells were more frequent in DCIS whereas high PD-L1 expression and amplification of CD274 (encoding PD-L1) was only detected in triple negative IDCs. Co-amplification of 17q12 chemokine cluster with ERBB2 subdivided HER2+ breast tumors into immunologically and clinically distinct subtypes. Our results show co-evolution of cancer cells and the immune microenvironment during tumor progression.
http://ift.tt/2sbfhos
Relationship between hospital ward design and healthcare associated infection rates: what does the evidence really tell us? Comment on Stiller et al. 2016
The systematic review published by Stiller et al. in Antimicrobial Resistance & Infection Control in November 2016 concludes that single-patient bedrooms confer a significant benefit for protecting patients fr...
http://ift.tt/2tePETF
No nosocomial transmission under standard hygiene precautions in short term contact patients in case of an unexpected ESBL or Q&A E. coli positive patient: a one-year prospective cohort study within three regional hospitals
Many Highly Resistant Gram Negative Rod (HR-GNR) positive patients are found unexpectedly in clinical cultures, besides patients who are screened and isolated based on risk factors. As unexpected HR-GNR positi...
http://ift.tt/2rW6X7S
Non-prescribed antimicrobial use and associated factors among customers in drug retail outlet in Central Zone of Tigray, northern Ethiopia: a cross-sectional study
Non-prescribed antimicrobial use and their resistance are among the main public health problems, worldwide. In Ethiopia, particularly in the northern part, the magnitude of non-prescribed antimicrobial use and...
http://ift.tt/2tf0o4t
Phenotypic and genomic survey on organic acid utilization profile of Pseudomonas mendocina strain S5.2, a vineyard soil isolate
Root exudates are chemical compounds that are released from living plant roots and provide significant energy, carbon, nitrogen and phosphorus sources for microbes inhabiting the rhizosphere. The exudates shap...
http://ift.tt/2ubshr4
Development of a new method based on unmodified gold nanoparticles and peptide nucleic acids for detecting bovine viral diarrhea virus-RNA
A simple colorimetric assay is presented for detecting bovine viral diarrhea virus (BVDV)-RNA based on aggregation of gold nanoparticles (AuNPs) in the presence of charge-neutral peptide nucleic acids (PNA). F...
http://ift.tt/2tdrtEH
Nutritional value, chemical composition and antioxidant activity of three Tuber species from China
Nutritional value, chemical composition and antioxidant activity of the traditional edible truffles Tuber latisporum, T. subglobosum and T. pseudohimalayense, from China were evaluated. Powder formulations of the...
http://ift.tt/2uaMkpl
Preventing subclinical necrotic enteritis through Lactobacillus johnsonii BS15 by ameliorating lipid metabolism and intestinal microflora in broiler chickens
Increasing studies have focused on the beneficial effects of Lactobacillus johnsonii in certain diseases. Here, we studied the prevention ability of a probiotic strain, L. johnsonii BS15 on subclinical necrotic e...
http://ift.tt/2tdvxVr
Isolation and characterization of Burkholderia fungorum Gan-35 with the outstanding ammonia nitrogen-degrading ability from the tailings of rare-earth-element mines in southern Jiangxi, China
The exploitation of rare-earth-element (REE) mines has resulted in severe ammonia nitrogen pollution and induced hazards to environments and human health. Screening microorganisms with the ammonia nitrogen-deg...
http://ift.tt/2ubcQyV
Risk factors, person, place and time characteristics associated with Hepatitis E Virus outbreak in Napak District, Uganda
Hepatitis E is self-limiting, but can cause death in most at risk groups like pregnant women and those with preexisting acute liver disease. In developing countries it presents as epidemic, in 2014 Hepatitis E...
http://ift.tt/2sb6iUo
The role of Enterococcus spp. and multidrug-resistant bacteria causing pyogenic liver abscesses
Pyogenic liver abscesses (PLA) remain a significant clinical problem. Unfortunately, little is known about current bacterial susceptibility profiles and the incidence of multidrug resistant organisms (MDROs) c...
http://ift.tt/2sVeuFz
SOFIA®RSV: prospective laboratory evaluation and implementation of a rapid diagnostic test in a pediatric emergency ward
Respiratory syncytial virus (RSV) is responsible for severe respiratory infections and higher costs in medical care. The two aims of this work were to assess the performances of SOFIA®RSV tests in "real-life-labo...
http://ift.tt/2sb9m2V
Switchable Acoustic and Optical Resolution Photoacoustic Microscopy for In Vivo Small-animal Blood Vasculature Imaging
http://ift.tt/2teBG4u
3 products to improve firefighter, EMS provider safety
At the Fire-Rescue Med 2017 Conference, I saw three EMS products that really caught my attention. Enough so that I took the time to speak at length with each of the vendor representatives. When I look at new fire and EMS equipment, I have three evaluation criteria: 1. Will it make the job safer for the firefighter or medic" 2. Will it make the firefighter or medic more effective" 3. Will it make the ...
http://ift.tt/2rTFLa7
Induction of Hypoxia in Living Frog and Zebrafish Embryos
http://ift.tt/2sJKDS9
Full text publication rates of research abstracts presented at the European Society of Endodontology (ESE) Congresses in the last 20 years
Abstract
Aim
To evaluate the full-text publication rates of scientific research abstracts presented at the European Society of Endodontology (ESE) Congresses held between 1993 and 2013 (a total of 11 occasions) and to determine factors associated with the manuscripts.
Methodology
An electronic database search was conducted from January 2015 to December 2016 to identify full text English written publications of the research abstracts presented at the last 11 ESE Biennial Congresses from 1993 to 2013. For each occasion, research abstract information were retrieved from the International Endodontic Journal (IEJ) through the official website of the ESE and the following parameters for each abstract presentation were recorded: Year of presentation, first author's affiliation, geographic origin, and type of study. Following full-text article identification, additional information was recorded such as: Year and journal of publication, elapsed time until full publication and number of authors per presentation and publication.
Results
A total of 1165 research abstracts were presented, of which 401 (34.4%) were finally published as full-length articles. Overall 235 articles (58.6%) were published either in the International Endodontic Journal (IEJ, 35.7%) or Journal of Endodontics (JOE, 22.9%). The mean time between abstract presentation and full-text publication was 18.95 months. Munich (2001) had the highest publication rate (44%) whereas Lisbon (2013) had the highest number of published articles (77). Turkey was the country with the highest number of published abstracts (56). However, the Netherlands was the country with the highest number of publications related to the number of presentations (21/26) (80.7%). Differences in authorship between presentation and full publication were found in 179 (44.6%) articles.
Conclusions
A substantial number of research abstracts presented at ESE congresses were not published in peer reviewed journals. Authors prefer to publish their research papers in international journals with high impact factor.
This article is protected by copyright. All rights reserved.
http://ift.tt/2sJqGe2
Histamine H 4 receptor signalling in tongue cancer and its potential role in oral carcinogenesis - a short report
Abstract
Purpose
Recent reports indicate that histamine and its novel, high-affinity histamine H4 receptor (H4R) play a role in carcinogenesis, and thus H4R signalling has become a focus of increasing interest in the pathogenesis of many cancers. The roles of H4R in oral epithelial dysplasia (OED) and oral tongue squamous cell carcinoma (OTSCC) are unknown. The purpose of this study was to assess H4R expression in OTSCC patients and in OTSCC-derived cell lines.
Methods
Biopsies taken from OED, OTSCC and healthy oral mucosa were studied by immunostaining. Primary human oral keratinocytes (HOKs) and two OTSCC-derived cell lines (HSC-3 and SCC-25) were used for the in vitro studies. Quantitative real-time PCR was used to measure oncogene expression in the stimulated HOKs.
Results
We found that H4R-immunoreactivity was significantly reduced in the OED and OTSCC samples, especially in the samples with higher histopathological grades and noticeably increased mast cell counts. The presence of H4R in HSC-3 cells had clearly waned, in contrast to the HOKs. Gene expression data indicated that histamine-relevant inflammatory and environmental elements may participate in the regulation of oncogenes.
Conclusions
Our results suggest an association between H4R and oral carcinogenesis. Furthermore, our findings raise a potential implication of histamine-mediated factors in the regulation of oncogenes, possibly via mast cells, as crucial components of the tumor microenvironment. The identification of new elements that govern oral cancer development is highly relevant for the development of novel therapeutic approaches in OTSCC.
http://ift.tt/2rU9vUh
Progesterone suppresses the invasion and migration of breast cancer cells irrespective of their progesterone receptor status - a short report
Abstract
Purpose
Pre-operative progesterone treatment of breast cancer has been shown to confer survival benefits to patients independent of their progesterone receptor (PR) status. The underlying mechanism and the question whether such an effect can also be observed in PR negative breast cancer cells remain to be resolved.
Methods
We performed proteome profiling of PR-positive and PR-negative breast cancer cells in response to progesterone using a phospho-kinase array platform. Western blotting was used to validate the results. Cell-based phenotypic assays were conducted using PR-positive and PR-negative breast cancer cells to assess the effect of progesterone.
Results
We found that progesterone induces de-phosphorylation of 12 out of 43 kinases tested, which are mostly involved in cellular invasion and migration regulation. Consistent with this observation, we found through cell-based phenotypic assays that progesterone inhibits the invasion and migration of breast cancer cells independent of their PR status.
Conclusion
Our results indicate that progesterone can inhibit breast cancer cell invasion and migration mediated by the de-phosphorylation of kinases. This inhibition appears to be independent of the PR status of the breast cancer cells. In a broader context, our study may provide a basis for an association between progesterone treatment and recurrence reduction in breast cancer patients, thereby providing a lead for modelling a randomized in vitro study.
http://ift.tt/2tcube2
Evaluation of human cytomegalovirus antigen expression in invasive breast carcinoma in a population of Iranian patients
Abstract
Background
The role of human cytomegalovirus (HCMV) in the development of breast carcinoma is questionable. The aim of this study was to evaluate the expression of the immediate early antigen (IE) of HCMV in breast carcinoma and its association with some clinicopathologic factors in a population of Iranian patients.
Methods
Formalin-fixed and paraffin-embedded tissue blocks from the pathology laboratories of the Azahra and Shahid Beheshti hospitals, Isfahan, Iran, from 2013 to 2016, were used in the study. We used immunohistochemistry and real-time PCR to detect the IE-antigen of HCMV in breast carcinoma, normal tissue adjacent to carcinoma, and normal tissue from mammoplasty specimens.
Results
A total of 96 samples were evaluated: 70 invasive breast carcinoma of different histologic subtypes and 26 mammoplasty normal breast tissues. All the samples were negative for IE-antigen expression. No relationship was seen between breast cancer and HCMV in this study.
Conclusions
The results of this study failed to show any relationship between HCMV and the development of breast carcinoma.
http://ift.tt/2teFv9Z
Synchronous bilateral tonsil carcinoma: case presentation and review of the literature
Abstract
Background
The incidence of synchronous bilateral tonsil carcinoma seems to be underreported. For adequate oncologic treatment, it is mandatory to remove all primaries to prevent recurrence or metachronic disease. The purpose of this manuscript is to provide a comprehensive review on this topic and to emphasize the need of bilateral tonsillectomy in cases of cancer of unknown primary (CUP) as well as in the case of a unilateral tonsillar carcinoma.
Material and methods
A systematic review of the literature was performed for "bilateral tonsillar neoplasm", "synchronous cancer of the oropharynx" and "cancer of unknown primary in head and neck".
Results
We present a clinical case with bilateral tonsillar carcinoma in initially suggested cancer of unknown primary. Clinically, both tonsillar sites were unsuspicious, but in PET/CT an ipsilateral enhancement of the tonsil area was detected. The pathological work up of bilateral tonsillectomy specimens revealed bilateral squamous cell carcinoma with HPV-type 16 positivity. The review of the literature revealed 29 cases of bilateral tonsil cancer.
Conclusion
The handling of tonsillar tissue in the frame of panendoscopy in the case of CUP is still controversial. We recommend a bilateral tonsillectomy as a routine procedure for cancer of unknown primary as well as unilateral tonsillar carcinoma. Herewith the detrimental consequences of occult metachronous contralateral tonsillar carcinoma can be prevented.
http://ift.tt/2tO0LjS
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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Alimentary Pharmacology &Therapeutics, EarlyView. https://ift.tt/2qECBIJ
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
