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Clinical Research
Educating early childhood care and education providers to improve knowledge and attitudes about reporting child maltreatment: A randomized controlled trial
May 25, 2017   PloS One
Mathews B, Yang C, Lehman EB, Mincemoyer C, Verdiglione N, Levi BH
Educating early childhood care and education providers to improve knowledge and attitudes about reporting child maltreatment: A randomized controlled trial
May 25, 2017
PloS One
Early childhood care and education providers (CCPs) work with over 7 million young children. These children are vulnerable to physical, sexual and emotional abuse, and neglect. However, CCPs make less than 1% of all reports of suspected child abuse and neglect that are made to child protective services. CCPs are therefore an untapped resource in the public health response to child maltreatment. However, their knowledge and attitudes about duties to report child maltreatment are poorly understood. Moreover, no rigorous research has tested whether their knowledge and attitudes about reporting child maltreatment can be improved. These gaps in knowledge are important because knowledge of the duty and positive attitudes towards it produce more effective reporting, and little evidence exists about how to enhance cognitive and affective attributes. Using the CONSORT approach, we report a single-blind test-retest randomized controlled trial evaluating iLook Out for Child Abuse, a customized online educational intervention for CCPs to increase knowledge and attitudes towards the reporting duty. 762 participants were randomized with results analyzed for 741 participants (372 in the intervention group; 369 in the control). Knowledge of the reporting duty increased in the intervention group from 13.54 to 16.19 out of 21 (2.65 increase, 95% CI: (2.37, 2.93); large effect size 0.95, p < 0.001); the control group remained stable, moving from 13.54 to 13.59 (0.05 increase, 95% CI: (-0.12, 0.22); negligible effect size 0.03, p = 0.684). Attitudes were enhanced on all 13 items for the intervention group, remaining stable in the control, with significant differences between groups on all items (p < 0.05). Gains were largely sustained at four month follow-up. Findings support education for CCPs and other professions. Future research should also explore effects of education on reporting behavior. US National Institutes of Health NCT02225301.
An update on lupus animal models
May 24, 2017   Current Opinion In Rheumatology
Li W, Titov AA, Morel L
An update on lupus animal models
May 24, 2017
Current Opinion In Rheumatology
The complexity and heterogeneity of the clinical presentation in systemic lupus of erythematosus (SLE), combined to the inherent limitations of clinical research, have made it difficult to investigate the cause of this disease directly in patients. Various mouse models have been developed to dissect the cellular and genetic mechanisms of SLE, as well as to identify therapeutic targets and to screen treatments. The purpose of this review is to summarize the major spontaneous and induced mouse models of SLE and to provide an update on the major advances they have contributed to the field. Mouse models of SLE have continued to contribute to understand the cellular, signaling and metabolic mechanisms contributing to the disease and how targeting these pathways can provide therapeutic targets. Whenever possible, we discuss the advantage of using one model over the others to test a specific hypothesis. Spontaneous and induced models of lupus models are useful tools for the study of the cause of the disease, identify therapeutic targets and screen treatments in preclinical studies. Each model shares specific subsets of attributes with the disease observed in humans, which provides investigators a tool to tailor to their specific needs.
Evaluation of somatostatin and nucleolin receptors for therapeutic delivery in non-small cell lung cancer stem cells applying the somatostatin-analog DOTATATE and the nucleolin-targeting aptamer AS1411
May 25, 2017   PloS One
Holmboe S, Hansen PL, Thisgaard H, Block I, Müller C, Langkjær N, Høilund-Carlsen PF, Olsen BB, Mollenhauer J
Evaluation of somatostatin and nucleolin receptors for therapeutic delivery in non-small cell lung cancer stem cells applying the somatostatin-analog DOTATATE and the nucleolin-targeting aptamer AS1411
May 25, 2017
PloS One
Cancer stem cells represent the putative tumor-driving subpopulation thought to account for drug resistance, relapse, and metastatic spread of epithelial and other cancer types. Accordingly, cell surface markers for therapeutic delivery to cancer stem cells are subject of intense research. Somatostatin receptor 2 and nucleolin are known to be overexpressed by various cancer types, which have elicited comprehensive efforts to explore their therapeutic utilization. Here, we evaluated somatostatin receptor 2 targeting and nucleolin targeting for therapeutic delivery to cancer stem cells from lung cancer. Nucleolin is expressed highly but not selectively, while somatostatin receptor 2 is expressed selectively but not highly by cancer cells. The non-small cell lung cancer cell lines A549 and H1299, displayed average levels of both surface molecules as judged based on analysis of a larger cell line panel. H1299 compared to A549 cells showed significantly elevated sphere-forming capacity, indicating higher cancer stem cell content, thus qualifying as suitable test system. Nucleolin-targeting 57Co-DOTA-AS1411 aptamer showed efficient internalization by cancer cells and, remarkably, at even higher efficiency by cancer stem cells. In contrast, somatostatin receptor 2 expression levels were not sufficiently high in H1299 cells to confer efficient uptake by either non-cancer stem cells or cancer stem cells. The data provides indication that the nucleolin-targeting AS1411 aptamer might be used for therapeutic delivery to non-small cell lung cancer stem cells.
Stably engineered nanobubbles and ultrasound - An effective platform for enhanced macromolecular delivery to representative cells of the retina
May 25, 2017   PloS One
Thakur SS, Ward MS, Popat A, Flemming NB, Parat MO, Barnett NL, Parekh HS
Stably engineered nanobubbles and ultrasound - An effective platform for enhanced macromolecular delivery to representative cells of the retina
May 25, 2017
PloS One
Herein we showcase the potential of ultrasound-responsive nanobubbles in enhancing macromolecular permeation through layers of the retina, ultimately leading to significant and direct intracellular delivery; this being effectively demonstrated across three relevant and distinct retinal cell lines. Stably engineered nanobubbles of a highly homogenous and echogenic nature were fully characterised using dynamic light scattering, B-scan ultrasound and transmission electron microscopy (TEM). The nanobubbles appeared as spherical liposome-like structures under TEM, accompanied by an opaque luminal core and darkened corona around their periphery, with both features indicative of efficient gas entrapment and adsorption, respectively. A nanobubble +/- ultrasound sweeping study was conducted next, which determined the maximum tolerated dose for each cell line. Detection of underlying cellular stress was verified using the biomarker heat shock protein 70, measured before and after treatment with optimised ultrasound. Next, with safety to nanobubbles and optimised ultrasound demonstrated, each human or mouse-derived cell population was incubated with biotinylated rabbit-IgG in the presence and absence of ultrasound +/- nanobubbles. Intracellular delivery of antibody in each cell type was then quantified using Cy3-streptavidin. Nanobubbles and optimised ultrasound were found to be negligibly toxic across all cell lines tested. Macromolecular internalisation was achieved to significant, yet varying degrees in all three cell lines. The results of this study pave the way towards better understanding mechanisms underlying cellular responsiveness to ultrasound-triggered drug delivery in future ex vivo and in vivo models of the posterior eye.
Conditional removal of the canonical TGF-β1 signaling delays condylar cartilage degeneration induced by a partial discectomy in mice
May 25, 2017   PloS One
Fang J, Xiao L, Chen R, Zhao Z
Conditional removal of the canonical TGF-β1 signaling delays condylar cartilage degeneration induced by a partial discectomy in mice
May 25, 2017
PloS One
Recent emerging data indicate that the increase in the expression and activity of the transforming growth factor beta 1 (Tgf-β1) signaling may have detrimental effect to mature articular cartilage of knee joints. However, there is no information about whether or not this is the case in condylar cartilages. The objective of this study is to investigate the protein expression and activity of Tgf-β1 signaling in degenerative condylar cartilages. We also investigate biological effects of the conditional deletion of transforming growth factor receptor type II (Tgfbr2) in condylar cartilage of adult mice after a partial discectomy. Two mouse models of osteoarthritis (OA) were used to examine protein expressions of Tgf-β1 and p-Smad2/3 in condylar cartilages at early degenerative stages. In addition, cartilage specific Tgfbr2-deficient adult mice were subjected to a partial discectomy. The morphological condition of condylar cartilages was evaluated in mice at 4 and 12 weeks after the surgery. We found that protein levels of Tgf-β1 and p-Smad2/3 were increased in the degenerative condylar cartilage of the mouse models. The conditional removal of Tgfbr2 in mature condylar cartilage significantly delayed the progressive progression of the cartilage degeneration induced by a partial discectomy. We conclude that the increase in the expression and activity of Tgf-β1 signaling may have detrimental effect to mature condylar cartilages. Therefore, inhibition of Tgf-β1 signaling may be able to protect condylar cartilages from being degraded in mature temporomandibular joints.
Novel mutations in COL4A3, COL4A4, and COL4A5 in Chinese patients with Alport Syndrome
May 25, 2017   PloS One
Liu JH, Wei XX, Li A, Cui YX, Xia XY,   . . . . . .   , Wu QY, Li WW, Asan , Liu ZH, Li XJ
Novel mutations in COL4A3, COL4A4, and COL4A5 in Chinese patients with Alport Syndrome
May 25, 2017
PloS One
Alport syndrome (AS) is a clinically and genetically heterogeneous, progressive nephropathy caused by mutations in COL4A3, COL4A4, and COL4A5, which encode type IV collagen. The large sizes of these genes and the absence of mutation hot spots have complicated mutational analysis by routine polymerase chain reaction (PCR)-based approaches. Here, in order to design a rapid and effective method for the genetic diagnosis of AS, we developed a strategy by utilizing targeted capture associated with next-generation sequencing (NGS) to analyze COL4A3, COL4A4, and COL4A5 simultaneously in 20 AS patients. All the coding exons and flanking sequences of COL4A3, COL4A4, and COL4A5 from the probands were captured followed by HiSeq 2500 sequencing. Candidate mutations were validated by classic Sanger sequencing and quantitative (q)PCR. Sixteen patients (16/20, 75%) showed X-linked inheritance, and four patients (4/20, 20%) showed autosomal recessive inheritance. None of the individuals had autosomal-dominant AS. Fifteen novel mutations, 6 known mutations, and 2 novel fragment deletions were detected by targeted capture and NGS. Of these novel mutations, 12, 3, and 2 mutations were detected in COL4A5, COL4A4, and COL4A3, respectively. A comparison of the clinical manifestations caused by different types of mutations in COL4A5 suggested that nonsense mutations and glycine substitution by an acidic amino acid are more severe than the other missense mutations. Pathogenic mutations were detected in 20 patients. These novel mutations can expand the genotypic spectrum of AS. Our results demonstrated that targeted capture and NGS technology are effective in the genetic diagnosis of AS.
Effects of pulmonary rehabilitation on exacerbation number and severity in people with COPD: An historical cohort study using electronic health records
May 20, 2017   Chest
Moore E, Newson R, Joshi M, Palmer T, Rothnie KJ, Singh S, Majeed A, Soljak M, Quint JK
Effects of pulmonary rehabilitation on exacerbation number and severity in people with COPD: An historical cohort study using electronic health records
May 20, 2017
Chest
In previous systematic reviews, predominantly of randomised controlled trials, pulmonary rehabilitation (PR) has been shown to reduce hospital admissions for acute exacerbations of COPD (AECOPD). However, findings have been less consistent for cohort studies. We aimed to compare rates of hospitalized and general practice (GP) treated AECOPD before and after PR. Using anonymised data from the Clinical Practice Research Datalink and Hospital Episode Statistics, hospital admissions and GP visits for AECOPD were compared one year before and after PR in patients referred for PR. Exacerbation rates were also compared between individuals eligible and referred for PR with those eligible and not referred. 69,089 (64%) of the COPD patients in the cohort were eligible for PR. Of these, only 6,436 (9.3%) were recorded as having been referred for rehabilitation. 62, 019 (89.8%) were not referred and 634 (0.98%) declined referral. When combining GP and hospital exacerbations, people who were eligible and were referred for PR had a slightly higher but not statistically significant exacerbation rate (2.83 exacerbations/patient-year 95% CI: 2.66, 3.00) than those who were eligible but not referred (2.17 exacerbations/patient-year 95% CI: 2.11, 2.24). This study found that less than 10% of patients who were eligible for PR were actually referred. Patients who were eligible and referred for (but not necessarily completed) PR did not have fewer GP visits and hospitalizations for AECOPD in the year after PR compared to those not referred or compared to the year before PR. Copyright © 2017. Published by Elsevier Inc.
Differential expression of islet glutaredoxin 1 and 5 with high reactive oxygen species production in a mouse model of diabesity
May 25, 2017   PloS One
Petry SF, Sharifpanah F, Sauer H, Linn T
Differential expression of islet glutaredoxin 1 and 5 with high reactive oxygen species production in a mouse model of diabesity
May 25, 2017
PloS One
The onset and progression of diabetes mellitus type 2 is highly contingent on the amount of functional beta-cell mass. An underlying cause of beta-cell decay in diabetes is oxidative stress, which markedly affects the insulin producing pancreatic cells due to their poor antioxidant defence capacity. Consequently, disturbances of cellular redox signaling have been implicated to play a major role in beta-cell loss in diabetes mellitus type 2. There is evidence suggesting that the glutaredoxin (Grx) system exerts a protective role for pancreatic islets, but the exact mechanisms have not yet been elucidated. In this study, a mouse model for diabetes mellitus type 2 was used to gain further insight into the significance of Grx for the islets of Langerhans in the diabetic metabolism. We have observed distinct differences in the expression levels of Grx in pancreatic islets between obese, diabetic db mice and lean, non-diabetic controls. This finding is the first report about a decrease of Grx expression levels in pancreatic islets of diabetic mice which was accompanied by declining insulin secretion, increase of reactive oxygen species (ROS) production level, and cell cycle alterations. These data demonstrate the essential role of the Grx system for the beta-cell during metabolic stress which may provide a new target for diabetes mellitus type 2 treatment.
Tea and coffee consumption in relation to DNA methylation in four European cohorts
May 23, 2017   Human Molecular Genetics
Ek WE, Tobi EW, Ahsan M, Lampa E, Ponzi E,   . . . . . .   , Vineis P, Lind L, Flanagan JM, Johansson Å, Epigenome-Wide Association study Consortium
Tea and coffee consumption in relation to DNA methylation in four European cohorts
May 23, 2017
Human Molecular Genetics
Lifestyle factors, such as food choices and exposure to chemicals, can alter DNA methylation and lead to changes in gene activity. Two such exposures with pharmacologically active components are coffee and tea consumption. Both coffee and tea has been suggested to play an important role in modulating disease-risk in humans by suppressing tumour progression, decreasing inflammation and influencing estrogen metabolism. These mechanisms may be mediated by changes in DNA methylation.To investigate if DNA methylation in blood is associated with coffee and tea consumption we performed a genome-wide DNA methylation study for coffee and tea consumption in four European cohorts (N = 3,096). DNA methylation was measured from whole blood at 421,695 CpG sites distributed throughout the genome and analysed in men and women both separately and together in each cohort. Meta-analyses of the results and additional regional-level analyses were performed.After adjusting for multiple testing, the meta-analysis revealed that two individual CpG-sites, mapping to DNAJC16 and TTC17, were differentially methylated in relation to tea consumption in women. No individual sites were associated in men or in the sex-combined analysis for tea or coffee. The regional analysis revealed that 28 regions were differentially methylated in relation to tea consumption in women. These regions contained genes known to interact with estradiol metabolism and cancer. No significant regions were found in the sex-combined and male-only analysis for either tea or coffee consumption. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Effect of early measles vaccine on pneumococcal colonization: A randomized trial from Guinea-Bissau
May 25, 2017   PloS One
Hansen NS, Byberg S, Hervig Jacobsen L, Bjerregaard-Andersen M, Jensen AKG, Martins C, Aaby P, Skov Jensen J, Stabell Benn C, Whittle H
Effect of early measles vaccine on pneumococcal colonization: A randomized trial from Guinea-Bissau
May 25, 2017
PloS One
Measles vaccine (MV) may have non-specific beneficial effects for child health and particularly seems to prevent respiratory infections. Streptococcus pneumoniae is the leading cause of bacterial pneumonia among children worldwide, and nasopharyngeal colonization precedes infection. We investigated whether providing early MV at 18 weeks of age reduced pneumococcal colonization and/or density up to 9 months of age. The study was conducted in 2013-2014 in Guinea-Bissau. Pneumococcal vaccine was not part of the vaccination program. Infants aged 18 weeks were block-randomized 2:1 to early or no early MV; at age 9 months, all children were offered MV as per current policy. Nasopharyngeal swabs were taken at baseline, age 6.5 months, and age 9 months. Pneumococcal density was determined by q-PCR. Prevalence ratios of pneumococcal colonization and recent antibiotic treatment (yes/no) by age 6.5 months (PR6.5) and age 9 months (PR9) were estimated using Poisson regression with robust variance estimates while the pneumococcal geometric mean ratio (GMR6.5 and GMR9) was obtained using OLS regression. Analyses included 512 children; 346 early MV-children and 166 controls. At enrolment, the pneumococcal colonization prevalence was 80% (411/512). Comparing early MV-children with controls, the PR6.5 was 1.02 (95%CI = 0.94-1.10), and the PR9 was 1.04 (0.96-1.12). The GMR6.5 was 1.02 (0.55-1.89), and the GMR9 was 0.69 (0.39-1.21). Early MV-children tended to be less frequently treated with antibiotics prior to follow up (PR6.5 0.60 (0.34-1.05) and PR9 0.87 (0.50-1.53)). Antibiotic treatment was associated with considerably lower colonization rates, PR6.5 0.85 (0.71-1.01) and PR9 0.66 (0.52-0.84), as well as lower pneumococcal density, GMR6.5 0.32 (0.12-0.86) and GMR9 0.52 (0.18-1.52). Early MV at age 18 weeks had no measurable effect on pneumococcal colonization prevalence or density. Higher consumption of antibiotics among controls may have blurred an effect of early MV. clinicaltrials.gov NCT01486355.
Serum microRNA signatures as "liquid biopsies" for interrogating hepatotoxic mechanisms and liver pathogenesis in human
May 25, 2017   PloS One
Krauskopf J, de Kok TM, Schomaker SJ, Gosink M, Burt DA, Chandler P, Warner RL, Johnson KJ, Caiment F, Kleinjans JC, Aubrecht J
Serum microRNA signatures as "liquid biopsies" for interrogating hepatotoxic mechanisms and liver pathogenesis in human
May 25, 2017
PloS One
MicroRNAs (miRNAs) released into the peripheral circulation upon cellular injury have shown a promise as a new class of tissue-specific biomarkers. We were first to demonstrate that next-generation sequencing analysis of serum from human subjects with acetaminophen-induced liver injury revealed a specific signature of circulating miRNAs. We consequently hypothesized that different types of hepatic liver impairments might feature distinct signatures of circulating miRNAs and that this approach might be useful as minimally invasive diagnostic "liquid biopsies" enabling the interrogation of underlying molecular mechanisms of injury in distant tissues. Therefore we examined serum circulating miRNAs in a total of 72 serum samples from a group of 53 subjects that included patients with accidental acetaminophen overdose, hepatitis B infection, liver cirrhosis and type 2 diabetes as well as gender- and age-matched healthy subjects with no evidence of liver disease. The miRNA signatures were identified using next-generation sequencing that provided analysis for the whole miRNome, including miRNA isoforms. Compared to the healthy subjects, a total of 179 miRNAs showed altered serum levels across the diseased subjects. Although many subjects have elevated alanine aminotransferase suggesting liver impairments, we identified distinct miRNA signatures for different impairments with minimum overlap. Furthermore, the bioinformatics analysis of miRNA signatures revealed relevant molecular pathways associated with the mechanisms of toxicity and or pathogenesis of disease. Interestingly, the high proportion of miRNA isoforms present in the respective signatures indicated a new level of complexity in cellular response to stress or disease. Our study demonstrates for the first time that signatures of circulating miRNAs show specificity for liver injury phenotypes and, once validated, might become useful for diagnosis of organ pathologies as "liquid biopsies".
Investigating the causal effect of smoking on hay fever and asthma: a Mendelian randomization meta-analysis in the CARTA consortium
May 23, 2017   Scientific Reports
Skaaby T, Taylor AE, Jacobsen RK, Paternoster L, Thuesen BH,   . . . . . .   , Romundstad PR, Skorpen F, Kaprio J, R Munafò M, Linneberg A
Investigating the causal effect of smoking on hay fever and asthma: a Mendelian randomization meta-analysis in the CARTA consortium
May 23, 2017
Scientific Reports
Observational studies on smoking and risk of hay fever and asthma have shown inconsistent results. However, observational studies may be biased by confounding and reverse causation. Mendelian randomization uses genetic variants as markers of exposures to examine causal effects. We examined the causal effect of smoking on hay fever and asthma by using the smoking-associated single nucleotide polymorphism (SNP) rs16969968/rs1051730. We included 231,020 participants from 22 population-based studies. Observational analyses showed that current vs never smokers had lower risk of hay fever (odds ratio (OR) = 0·68, 95% confidence interval (CI): 0·61, 0·76; P 
The atherogenic index of plasma and the risk of mortality in incident dialysis patients: Results from a nationwide prospective cohort in Korea
May 26, 2017   PloS One
Lee MJ, Park JT, Han SH, Kim YL, Kim YS, Yang CW, Kim NH, Kang SW, Kim HJ, Yoo TH
The atherogenic index of plasma and the risk of mortality in incident dialysis patients: Results from a nationwide prospective cohort in Korea
May 26, 2017
PloS One
The atherogenic index of plasma (AIP), which is the logarithmic ratio of triglyceride (TG) to high-density lipoprotein cholesterol (HDL-C), had a linear relationship with clinical outcomes in the general population. However, the association of each lipid profile, TG and HDL-C, with survival was not straightforward in dialysis patients. This non-linear association led us to further investigate the prognostic impact of the AIP in these patients. From a nationwide prospective cohort, 1,174 incident dialysis patients were included. Patients were categorized into quintiles according to the AIP. An independent association of the AIP with all-cause and cardiovascular mortality was determined. During a mean follow-up duration of 33.2 months, 170 patients (14.5%) died, and cardiovascular death was observed in 55 patients (4.7%). Multivariate Cox analyses revealed that the lowest (quintile 1, hazard ratio [HR] = 1.76, 95% confidence interval [CI] = 1.02-3.03) and the highest (quintile 5, HR = 2.15, 95% CI = 1.26-3.65) AIP groups were significantly associated with higher all-cause mortality compared to patients in quintile 3 (reference group). In terms of cardiovascular mortality, only the highest AIP group (quintile 5, HR = 2.59, 95% CI = 1.06-6.34) was significantly associated with increased risk of mortality. Sensitivity analyses showed that a U-shaped association between the AIP and all-cause mortality remained significant in non-diabetic and underweight to normal body mass index patients. Both the highest and the lowest AIP groups were independently associated with all-cause mortality, showing a U-shaped association. It suggested further studies are needed to identify targets and subgroups that can benefit from intervention of the AIP in incident dialysis patients.
No relevant association of kinematic gait parameters with Health-related Quality of Life in Parkinson's disease
May 22, 2017   PloS One
Bettecken K, Bernhard F, Sartor J, Hobert MA, Hofmann M, Gladow T, van Uem JMT, Liepelt-Scarfone I, Maetzler W
No relevant association of kinematic gait parameters with Health-related Quality of Life in Parkinson's disease
May 22, 2017
PloS One
Health-related Quality of Life (HrQoL) is probably the most important outcome parameter for the evaluation and management of chronic diseases. As this parameter is subjective and prone to bias, there is an urgent need to identify objective surrogate markers. Gait velocity has been shown to be associated with HrQoL in numerous chronic diseases, such as Parkinson's disease (PD). With the development and wide availability of simple-to-use wearable sensors and sophisticated gait algorithms, kinematic gait parameters may soon be implemented in clinical routine management. However, the association of such kinematic gait parameters with HrQoL in PD has not been assessed to date. Kinematic gait parameters from a 20-meter walk from 43 PD patients were extracted using a validated wearable sensor system. They were compared with the Visual Analogue Scale of the Euro-Qol-5D (EQ-5D VAS) by performing a multiple regression analysis, with the International Classification of Functioning, Disability and Health (ICF) model as a framework. Use of assistive gait equipment, but no kinematic gait parameter, was significantly associated with HrQoL. The widely accepted concept of a positive association between gait velocity and HrQoL may, at least in PD, be driven by relatively independent parameters, such as assistive gait equipment.
Intensive Monitoring of Urine Output is Associated with Increased Detection of Acute Kidney Injury and Improved Outcomes
May 21, 2017   Chest
Jin K, Murugan R, Sileanu FE, Foldes E, Priyanka P, Clermont G, Kellum JA
Intensive Monitoring of Urine Output is Associated with Increased Detection of Acute Kidney Injury and Improved Outcomes
May 21, 2017
Chest
Urine output (UO) is a vital sign for critical ill patients but standards for monitoring and reporting vary widely between ICUs. Careful monitoring of UO could lead to earlier recognition of acute kidney injury (AKI) and better fluid management. We sought to determine if intensity of UO monitoring is associated with outcomes in patients with and without AKI. Retrospective cohort study including 15,724 adults admitted to ICUs from 2000-2008. Intensive UO monitoring was defined as hourly recordings and no gaps >3 hours for the first 48 hours after ICU admission. 4,049 (26%) patients underwent intensive monitoring for UO and we found significantly higher rates of AKI (OR 1.22 p
A randomised control trial of atorvastatin in bronchiectasis patients infected with Pseudomonas aeruginosa- a proof of concept study
May 30, 2017   Chest
Bedi P, Chalmers JD, Graham C, Clarke A, Donaldson S, Doherty C, Govan JR, Davidson DJ, Rossi AG, Hill AT
A randomised control trial of atorvastatin in bronchiectasis patients infected with Pseudomonas aeruginosa- a proof of concept study
May 30, 2017
Chest
There are no randomised control trials of statin therapy in patients with severe bronchiectasis, chronically infected with Pseudomonas aeruginosa. 32 patients chronically infected with P. aeruginosa were recruited in this double blind cross over RCT. 16 patients were recruited in each arm, given atorvastatin 80mg or placebo for 3months, followed by a washout period for 6weeks, crossed over and administered the alternative therapy for 3months. 27 patients completed the study. Atorvastatin did not significantly improve the primary endpoint of cough as measured by Leicester Cough Questionnaire [mean difference=1.92, 95% CI for difference (-0.57, 4.41), p=0.12]. However, atorvastatin treatment resulted in improved St Georges Respiratory Questionnaire (-5.62points, p=0.016), reduced serum CXCL8 (p=0.04), TNF (p=0.01) and ICAM1 (p=0.04). There was a trend towards improvement in serum CRP and serum neutrophil counts (p=0.07 and p=0.06 respectively). In vitro, we demonstrated that atorvastatin 10μM reduced fMLF induced upregulation of CD11b expression and changes in calcium flux reflecting an ability to decrease neutrophil activation. We demonstrated that atorvastatin reduced systemic inflammation and improved quality of life in bronchiectasis patients infected with P. aeruginosa. These effects may be due to an ability of atorvastatin to modulate neutrophil activation. Copyright © 2017. Published by Elsevier Inc.
Analysis of risk factors for infant mortality in the 1992-3 and 2002-3 birth cohorts in rural Guinea-Bissau
May 25, 2017   PloS One
Byberg S, Østergaard MD, Rodrigues A, Martins C, Benn CS, Aaby P, Fisker AB
Analysis of risk factors for infant mortality in the 1992-3 and 2002-3 birth cohorts in rural Guinea-Bissau
May 25, 2017
PloS One
Though still high, the infant mortality rate in Guinea-Bissau has declined. We aimed to identify risk factors including vaccination coverage, for infant mortality in the rural population of Guinea-Bissau and assess whether these risk factors changed from 1992-3 to 2002-3. The Bandim Health Project (BHP) continuously surveys children in rural Guinea-Bissau. We investigated the association between maternal and infant factors (especially DTP and measles coverage) and infant mortality. Hazard ratios (HR) were calculated using Cox regression. We tested for interactions with sex, age groups (defined by current vaccination schedule) and cohort to assess whether the risk factors were the same for boys and girls, in different age groups in 1992-3 and in 2002-3. The infant mortality rate declined from 148/1000 person years (PYRS) in 1992-3 to 124/1000 PYRS in 2002-3 (HR = 0.88;95%CI:0.77-0.99); this decline was significant for girls (0.77;0.64-0.94) but not for boys (0.97;0.82-1.15) (p = 0.10 for interaction). Risk factors did not differ significantly by cohort in either distribution or effect. Mortality decline was most marked among girls aged 9-11 months (0.56;0.37-0.83). There was no significant mortality decline for girls 1.5-8 months of age (0.93;0.68-1.28) (p = 0.05 for interaction). DTP and measles coverage increased from 1992-3 to 2002-3. Risk factors did not change with the decline in mortality. Due to beneficial non-specific effects for girls, the increased coverage of measles vaccination may have contributed to the disproportional decline in mortality by sex and age group.
A-kinase anchoring protein BIG3 coordinates oestrogen signalling in breast cancer cells
May 30, 2017   Nature Communications
Yoshimaru T, Ono M, Bando Y, Chen YA, Mizuguchi K, Shima H, Komatsu M, Imoto I, Izumi K, Honda J, Miyoshi Y, Sasa M, Katagiri T
A-kinase anchoring protein BIG3 coordinates oestrogen signalling in breast cancer cells
May 30, 2017
Nature Communications
Approximately 70% of breast cancer cells express oestrogen receptor alpha (ERα). Previous studies have shown that the Brefeldin A-inhibited guanine nucleotide-exchange protein 3-prohibitin 2 (BIG3-PHB2) complex has a crucial role in these cells. However, it remains unclear how BIG3 regulates the suppressive activity of PHB2. Here we demonstrate that BIG3 functions as an A-kinase anchoring protein that binds protein kinase A (PKA) and the α isoform of the catalytic subunit of protein phosphatase 1 (PP1Cα), thereby dephosphorylating and inactivating PHB2. E2-induced PKA-mediated phosphorylation of BIG3-S305 and -S1208 serves to enhance PP1Cα activity, resulting in E2/ERα signalling activation via PHB2 inactivation due to PHB2-S39 dephosphorylation. Furthermore, an analysis of independent cohorts of ERα-positive breast cancers patients reveal that both BIG3 overexpression and PHB2-S39 dephosphorylation are strongly associated with poor prognosis. This is the first demonstration of the mechanism of E2/ERα signalling activation via the BIG3-PKA-PP1Cα tri-complex in breast cancer cells.
Resistance to malaria through structural variation of red blood cell invasion receptors
May 19, 2017   Science (New York, N.Y.)
Leffler EM, Band G, Busby GBJ, Kivinen K, Le QS,   . . . . . .   , Rowlands K, Rockett KA, Spencer CCA, Kwiatkowski DP, Malaria Genomic Epidemiology Network
Resistance to malaria through structural variation of red blood cell invasion receptors
May 19, 2017
Science (New York, N.Y.)
The malaria parasite Plasmodium falciparum invades human red blood cells by a series of interactions between host and parasite surface proteins. By analyzing genome sequence data from human populations, including 1269 individuals from sub-Saharan Africa, we identify a diverse array of large copy-number variants affecting the host invasion receptor genes GYPA and GYPB We find that a nearby association with severe malaria is explained by a complex structural rearrangement involving the loss of GYPB and gain of two GYPB-A hybrid genes, which encode a serologically distinct blood group antigen known as Dantu. This variant reduces the risk of severe malaria by 40% and has recently increased in frequency in parts of Kenya, yet it appears to be absent from west Africa. These findings link structural variation of red blood cell invasion receptors with natural resistance to severe malaria. Copyright © 2017, American Association for the Advancement of Science.
Prediction of disease activity in models of multiple sclerosis by molecular magnetic resonance imaging of P-selectin
May 23, 2017   Proceedings Of The National Academy Of Sciences Of The United States Of America
Fournier AP, Quenault A, Martinez de Lizarrondo S, Gauberti M, Defer G, Vivien D, Docagne F, Macrez R
Prediction of disease activity in models of multiple sclerosis by molecular magnetic resonance imaging of P-selectin
May 23, 2017
Proceedings Of The National Academy Of Sciences Of The United States Of America
New strategies for detecting disease activity in multiple sclerosis are being investigated to ameliorate diagnosis and follow-up of patients. Today, although magnetic resonance imaging (MRI) is widely used to diagnose and monitor multiple sclerosis, no imaging tools exist to predict the evolution of disease and the efficacy of therapeutic strategies. Here, we show that molecular MRI targeting the endothelial adhesion molecule P-selectin unmasks the pathological events that take place in the spinal cord of mice subjected to chronic or relapsing experimental autoimmune encephalomyelitis. This approach provides a quantitative spatiotemporal follow-up of disease course in relation to clinical manifestations. Moreover, it predicts relapse in asymptomatic mice and remission in symptomatic animals. Future molecular MRI targeting P-selectin may be used to improve diagnosis, follow-up of treatment, and management of relapse/remission cycles in multiple sclerosis patients by providing information currently inaccessible through conventional MRI techniques.
Anti-MAdCAM antibody (PF-00547659) for ulcerative colitis (TURANDOT): a phase 2, randomised, double-blind, placebo-controlled trial
May 21, 2017   Lancet (London, England)
Vermeire S, Sandborn WJ, Danese S, Hébuterne X, Salzberg BA,   . . . . . .   , Pradhan V, Hassan-Zahraee M, Clare R, Cataldi F, Reinisch W
Anti-MAdCAM antibody (PF-00547659) for ulcerative colitis (TURANDOT): a phase 2, randomised, double-blind, placebo-controlled trial
May 21, 2017
Lancet (London, England)
PF-00547659 is a fully human monoclonal antibody that binds to human mucosal addressin cell adhesion molecule-1 (MAdCAM-1) to selectively reduce lymphocyte homing to the intestinal tract. We aimed to assess the efficacy and safety of PF-00547659 in patients with moderate to severe ulcerative colitis. This phase 2, randomised, double-blind, placebo-controlled clinical trial recruited patients aged 18-65 years from 105 centres in 21 countries, with a history (≥3 months) of active ulcerative colitis extending more than 15 cm beyond the anal verge (with a total Mayo score ≥6 and a Mayo endoscopic subscore ≥2) who had failed or were intolerant to at least one conventional therapy. Patients were stratified by previous anti-TNFα treatment, and randomly assigned by a computer-generated randomisation schedule to receive a subcutaneous injection of 7·5 mg, 22·5 mg, 75 mg, or 225 mg PF-00547659 or placebo at baseline, then every 4 weeks. Patients, investigators, and sponsors were blinded to the treatment. The primary endpoint was the proportion of patients achieving remission (total Mayo score ≤2 with no individual subscore >1 and rectal bleeding subscore ≤1) at week 12. The efficacy analysis included all patients who received at least one dose of the randomised treatment; the safety analysis was done according to treatment received. All p values were one-sided and multiplicity-adjusted. This study is registered with ClinicalTrials.gov, number NCT01620255. Between Nov 2, 2012, and Feb 4, 2016, we screened 587 patients; 357 were eligible and randomly assigned to receive placebo (n=73) or PF-00547659 at doses of 7·5 mg (n=71), 22·5 mg (n=72), 75 mg (n=71), or 225 mg (n=70). Remission rates at week 12 were significantly greater in three of four active-treatment groups than in the placebo group (2·7% [two of 73]): 7·5 mg (11·3% [eight of 71]), 22·5 mg (16·7% [12 of 72]), 75 mg (15·5% [11 of 71]), and 225 mg (5·7% [four of 70]). These rates corresponded to a stratum-adjusted (anti-TNFα-naive and anti-TNFα-experienced) risk difference versus placebo of 8·0% for 7·5 mg (90% CI 1·9 to 14, p=0·0425), 12·8% for 22·5 mg (5·6 to 19·9, p=0·0099), 11·8% for 75 mg (4·8 to 18·8, p=0·0119), and 2·6% for 225 mg (-1·2 to 6·4, p=0·1803). Four of 73 (5·5%) patients had a serious adverse event in the placebo group, ten of 71 (14·1%) in the 7·5 mg group, one of 70 (1·4%) in the 22·5 mg group, three of 73 (4·1%) in the 75 mg group, and three of 70 (4·3%) in the 225 mg group. No safety signal was observed for the study drug. PF-00547659 was safe and well tolerated in this patient population, and better than placebo for induction of remission in patients with moderate to severe ulcerative colitis. The greatest clinical effects were observed with the 22·5 mg and 75 mg doses. Pfizer. Copyright © 2017 Elsevier Ltd. All rights reserved.
STREAM characterisation correction - Authors' reply
May 31, 2017   Lancet (London, England)
Reed GW, Cannon CP
REM sleep and memory
May 25, 2017   Current Opinion In Neurobiology
Boyce R, Williams S, Adamantidis A
REM sleep and memory
May 25, 2017
Current Opinion In Neurobiology
Memory consolidation, a process which stabilizes recently acquired information into long-term storage, is thought to be optimized during sleep. Although recent evidence indicates that non-rapid-eye movement sleep (NREMs) is directly involved in memory consolidation, the role of rapid-eye movement sleep (REMs) in this process has remained controversial due to the extreme difficulty in experimentally isolating neural activity during REMs. Using a combination of electrophysiological recording and optogenetic techniques, recent work demonstrated for the first time that neural activity occurring specifically during REMs is required for spatial and contextual memory consolidation. Identifying the underlying mechanisms behind these observations, precisely how they translate to humans, and clarifying the extent of REMs' role in other modalities of memory are important challenges of future research with implications for human health. Copyright © 2017. Published by Elsevier Ltd.
Melanin-concentrating hormone and sleep
May 20, 2017   Current Opinion In Neurobiology
Ferreira JGP, Bittencourt JC, Adamantidis A
Melanin-concentrating hormone and sleep
May 20, 2017
Current Opinion In Neurobiology
The melanin-concentrating hormone (MCH) is an essential neuromodulator involved with homeostatic regulation and motivated behaviors. The majority of MCH neurons are localized within the zona incerta, lateral hypothalamic and incerto-hypothalamic areas but others regions, as the olfactory turbecle, the laterodorsal tegmental nucleus, the paramediam pontine reticular formation and the medial preoptic area, can also express the peptide depending on the gender and metabolic state of the animal. If the MCH on these novel sites of expression are also related with the control of wake-sleep cycle will be discuss in this review. Copyright © 2017. Published by Elsevier Ltd.
Sex Bias in Pathogenesis of Autoimmune Neuroinflammation: Relevance for Dimethyl Fumarate Immunomodulatory/Anti-oxidant Action
May 23, 2017   Molecular Neurobiology
Stojić-Vukanić Z, Kotur-Stevuljević J, Nacka-Aleksić M, Kosec D, Vujnović I, Pilipović I, Dimitrijević M, Leposavić G
Sex Bias in Pathogenesis of Autoimmune Neuroinflammation: Relevance for Dimethyl Fumarate Immunomodulatory/Anti-oxidant Action
May 23, 2017
Molecular Neurobiology
In the present study, upon showing sexual dimorphism in dimethyl fumarate (DMF) efficacy to moderate the clinical severity of experimental autoimmune encephalomyelitis (EAE) in Dark Agouti rats, cellular and molecular substrate of this dimorphism was explored. In rats of both sexes, DMF administration from the day of immunization attenuated EAE severity, but this effect was more prominent in males leading to loss of the sexual dimorphism observed in vehicle-administered controls. Consistently, in male rats, DMF was more efficient in diminishing the number of CD4+ T lymphocytes infiltrating spinal cord (SC) and their reactivation, the number of IL-17+ T lymphocytes and particularly cellularity of their highly pathogenic IFN-γ+GM-CSF+IL-17+ subset. This was linked with changes in SC CD11b+CD45+TCRαβ- microglia/proinflammatory monocyte progeny, substantiated in a more prominent increase in the frequency of anti-inflammatory phygocyting CD163+ cells and the cells expressing high surface levels of immunoregulatory CD83 molecule (associated with apoptotic cells phagocytosis and implicated in downregulation of CD4+ T lymphocyte reactivation) among CD11b+CD45+TCRαβ- cells in male rat SC. These changes were associated with greater increase in the nuclear factor (erythroid-derived 2)-like 2 expression in male rats administered with DMF. In accordance with the previous findings, DMF diminished reactive nitrogen and oxygen species generation and consistently, SC level of advanced oxidation protein products, to the greater extent in male rats. Overall, our study indicates sex-specificity in the sensitivity of DMF cellular and molecular targets and encourages sex-based clinical research to define significance of sex for action of therapeutic agents moderating autoimmune neuroinflammation-/oxidative stress-related nervous tissue damage.

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