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Παρασκευή, 5 Ιανουαρίου 2018

Proton beam therapy for skull base chordomas in 106 patients: A dose adaptive radiation protocol

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Publication date: Available online 6 January 2018
Source:Radiotherapy and Oncology
Author(s): Vivien Fung, Valentin Calugaru, Stéphanie Bolle, Hamid Mammar, Claire Alapetite, Philippe Maingon, Ludovic De Marzi, Sébastien Froelich, Jean-Louis Habrand, Rémi Dendale, Georges Noël, Loïc Feuvret
Background and purposeTo evaluate clinical results and safety of a dose adaptive protocol based on tumor volume coverage and critical structure constraints, for the treatment of skull base chordomas.Material and methodsBetween May 2006 and October 2012, 106 patients with skull base chordoma were treated by combined photon and proton irradiation. Prescribed dose levels were 68.4, 70.2, 72 and 73.8 Gy(RBE) in once daily fractionation of 1.8 Gy(RBE). Dose level and dosimetric constraints to organs at risk depended on postoperative residual Gross Tumor Volume (GTV) coverage. Local control (LC) and overall survival (OS) were evaluated using the Kaplan–Meier method.ResultsWith a median follow-up of 61 months, the 2-year, 4-year, and 5-year LC rates were 88.6%, 78.3%, and 75.1%, respectively. GTV > 25 mL (p = 0.034, HR = 2.22; 95%CI 1.06–4.62) was an independent unfavorable prognostic factor of LC.The 2-year, 4-year, and 5-year OS rates were 99%, 90.2%, and 88.3%, respectively.Grade 3–5 late toxicity was observed in 7 patients, resulting in 93% 5-year freedom from high-grade toxicity.ConclusionsThis study suggests that the probability of LC of skull base chordomas depends on postoperative GTV. The dose adaptive protocol achieves acceptable local control. Future studies should investigate whether further dose escalation to doses in excess of 74 Gy(RBE) would achieve better results.



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Identifying criteria for diagnosis of post-traumatic pain and altered sensation of the maxillary and mandibular branches of the trigeminal nerve: a systematic review

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Publication date: Available online 5 January 2018
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Maria Devine, Murtaza Hirani, Justin Durham, Donald R. Nixdorf, Tara Renton
Objective: To systematically identify criteria used to diagnose patients with trigeminal nerve injury. Study design: A systematic review of the literature registered in the PROSPERO database. Inclusion criteria: patients diagnosed with nerve injury of the sensory divisions of the maxillary or mandibular branches of the trigeminal nerve, with reported tests and criteria used for diagnosis and persistent pain or unpleasant sensation associated with nerve injury. Results: 28 articles included. Diagnostic tests included clinical neurosensory tests (CNT) (89%), thermal quantitative sensory testing (25%), electromyography (7%) and patient interview (14%). Neuropathic pain was assessed using visual analogue scale (39%), use of neuropathic medication (7%), questionnaires including McGill and PainDETECT (21%). Functional impact was assessed in 14% and psychological impact in 7% of articles. Methodology in performing CNT, application of diagnostic terms and diagnostic grading of nerve injury was not consistent among the included articles making direct comparison of results difficult. Conclusion: Recommendations for assessment and diagnosis of trigeminal nerve injury have been made based on the best available evidence from the review. There is an urgent requirement for a consensus in diagnostic criteria, criteria for assessment and outcome reporting between stakeholder organisations in order to progress knowledge in this field.



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Reviewers January 2017—December 2017



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Reviewers January 2017—December 2017



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Patient-specific estimation of detailed cochlear shape from clinical CT images

Abstract

Purpose

A personalized estimation of the cochlear shape can be used to create computational anatomical models to aid cochlear implant (CI) surgery and CI audio processor programming ultimately resulting in improved hearing restoration. The purpose of this work is to develop and test a method for estimation of the detailed patient-specific cochlear shape from CT images.

Methods

From a collection of temporal bone \(\mu \) CT images, we build a cochlear statistical deformation model (SDM), which is a description of how a human cochlea deforms to represent the observed anatomical variability. The model is used for regularization of a non-rigid image registration procedure between a patient CT scan and a \(\mu \) CT image, allowing us to estimate the detailed patient-specific cochlear shape.

Results

We test the accuracy and precision of the predicted cochlear shape using both \(\mu \) CT and CT images. The evaluation is based on classic generic metrics, where we achieve competitive accuracy with the state-of-the-art methods for the task. Additionally, we expand the evaluation with a few anatomically specific scores.

Conclusions

The paper presents the process of building and using the SDM of the cochlea. Compared to current best practice, we demonstrate competitive performance and some useful properties of our method.



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Identifying criteria for diagnosis of post-traumatic pain and altered sensation of the maxillary and mandibular branches of the trigeminal nerve: a systematic review

Objective: To systematically identify criteria used to diagnose patients with trigeminal nerve injury. Study design: A systematic review of the literature registered in the PROSPERO database. Inclusion criteria: patients diagnosed with nerve injury of the sensory divisions of the maxillary or mandibular branches of the trigeminal nerve, with reported tests and criteria used for diagnosis and persistent pain or unpleasant sensation associated with nerve injury. Results: 28 articles included. Diagnostic tests included clinical neurosensory tests (CNT) (89%), thermal quantitative sensory testing (25%), electromyography (7%) and patient interview (14%).

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RELIABILITY OF REGION OF INTEREST CALCULATIONS IN THE RIGHT ATRIUM ON POST-MORTEM CT

Publication date: Available online 4 January 2018
Source:Journal of Forensic Radiology and Imaging
Author(s): Linda Kelly, Tom Sutherland, Matthew Dimmock, Linda Iles, Chris O'Donnell




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HACE1 is essential for astrocyte mitochondrial function and influences Huntington disease phenotypes in vivo

Abstract
Oxidative stress is a prominent feature of Huntington disease (HD), and we have shown previously that reduced levels of hace1 (HECT domain and Ankyrin repeat containing E3 ubiquitin protein ligase 1) in patient striatum may contribute to the pathogenesis of HD. Hace1 promotes the stability of Nrf2 and thus plays an important role in antioxidant response mechanisms, which are dysfunctional in HD. Moreover, hace1 overexpression mitigates mutant huntingtin (mHTT)-induced oxidative stress in vitro through promotion of the Nrf2 antioxidant response. Here, we show that the genetic ablation of hace1 in the YAC128 mouse model of HD accelerates motor deficits and exacerbates cognitive and psychiatric phenotypes in vivo. We find that both the expression of mHTT and the ablation of hace1 alone are sufficient to cause deficits in astrocytic mitochondrial respiration. We confirm the crucial role of hace1 in astrocytes in vivo, since its ablation is sufficient to cause dramatic astrogliosis in wild-type FVB/N mice. Astrogliosis is not observed in the presence of mHTT but a strong dysregulation in the expression of astrocytic markers in HACE1−/− x YAC128 striatum suggests an additive effect of mHTT expression and hace1 loss on this cell type. HACE1−/− x YAC128 mice and primary cells derived from these animals therefore provide model systems that will allow for the further dissection of Nrf2 pathways and astrocyte dysfunction in the context of HD.

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Functional characterization of tektin-1 in motile cilia and evidence for TEKT1 as a new candidate gene for motile ciliopathies

Abstract
A child presenting with Mainzer-Saldino syndrome (MZSDS), characterized by renal, retinal and skeletal involvements, was also diagnosed with lung infections and airway ciliary dyskinesia. These manifestations suggested dysfunction of both primary and motile cilia, respectively. Targeted exome sequencing identified biallelic mutations in WDR19, encoding an IFT-A subunit previously associated with MZSDS-related chondrodysplasia, Jeune asphyxiating thoracic dysplasia and cranioectodermal dysplasia, linked to primary cilia dysfunction, and in TEKT1 which encodes tektin-1 an uncharacterized member of the tektin family, mutations of which may cause ciliary dyskinesia. Tektin-1 localizes at the centrosome in cycling cells, at basal bodies of both primary and motile cilia and to the axoneme of motile cilia in airway cells. The identified mutations impaired these localizations. In addition, airway cells from the affected individual showed severe motility defects without major ultrastructural changes. Knockdown of tekt1 in zebrafish resulted in phenotypes consistent with a function for tektin-1 in ciliary motility, which was confirmed by live imaging. Finally, experiments in the zebrafish also revealed a synergistic effect of tekt1 and wdr19. Altogether, our data show genetic interactions between WDR19 and TEKT1 likely contributing to the overall clinical phenotype observed in the affected individual and provide strong evidence for TEKT1 as a new candidate gene for primary ciliary dyskinesia.

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Location matters: distinct DNA methylation patterns in GABAergic interneuronal populations from separate microcircuits within the human hippocampus

Abstract
Recent studies describe distinct DNA methylomes among phenotypic subclasses of neurons in the human brain, but variation in DNA methylation between common neuronal phenotypes distinguished by their function within distinct neural circuits remains an unexplored concept. Studies able to resolve epigenetic profiles at the level of microcircuits are needed to illuminate chromatin dynamics in the regulation of specific neuronal populations and circuits mediating normal and abnormal behaviors. The Illumina HumanMethylation450 BeadChip was used to assess genome-wide DNA methylation in stratum oriens GABAergic interneurons sampled by laser-microdissection from two discrete microcircuits along the trisynaptic pathway in postmortem human hippocampus from eight control, eight schizophrenia, and eight bipolar disorder subjects. Data were analysed using the minfi Bioconductor package in R software version 3.3.2. We identified 11 highly significant differentially methylated regions associated with a group of genes with high construct-validity, including multiple zinc finger of the cerebellum gene family members and WNT signaling factors. Genomic locations of differentially methylated regions were highly similar between diagnostic categories, with a greater number of differentially methylated individual cytosine residues between circuit locations in bipolar disorder cases than in schizophrenia or control (42, 7, and 7 differentially methylated positions, respectively). These findings identify distinct DNA methylomes among phenotypically similar populations of GABAergic interneurons functioning within separate hippocampal subfields. These data compliment recent studies describing diverse epigenotypes among separate neuronal subclasses, extending this concept to distinct epigenotypes within similar neuronal phenotypes from separate microcircuits within the human brain.

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Reporting flu vaccine science

When reporting on medical studies, the popular press has a habit of sensationalising. So the muted response to a recent research paper reporting increased risk of miscarriage with influenza vaccines...
recent?d=yIl2AUoC8zA recent?d=dnMXMwOfBR0 recent?i=MIDQD6_cHjM:5uMOnoqPk1M:V_sGLiP recent?d=qj6IDK7rITs recent?i=MIDQD6_cHjM:5uMOnoqPk1M:gIN9vFw recent?d=l6gmwiTKsz0 recent?d=7Q72WNTAKBA recent?i=MIDQD6_cHjM:5uMOnoqPk1M:F7zBnMy recent?i=MIDQD6_cHjM:5uMOnoqPk1M:-BTjWOF


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Could Dutch style sex education reduce pregnancies among UK teenagers?

As the UK government opens a public consultation on what English schools should teach in sex education classes, Rutgers, an influential non-governmental organisation that promotes sexual and...
recent?d=yIl2AUoC8zA recent?d=dnMXMwOfBR0 recent?i=5vlwpJOsUJw:mtLUcbmjUZ0:V_sGLiP recent?d=qj6IDK7rITs recent?i=5vlwpJOsUJw:mtLUcbmjUZ0:gIN9vFw recent?d=l6gmwiTKsz0 recent?d=7Q72WNTAKBA recent?i=5vlwpJOsUJw:mtLUcbmjUZ0:F7zBnMy recent?i=5vlwpJOsUJw:mtLUcbmjUZ0:-BTjWOF


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Can oral ADS activity or arginine levels be a caries risk indicator? A systematic review and meta-analysis

Abstract

Objectives

The objective of this study was to evaluate the association between salivary and plaque arginine levels/ADS activities with dental caries.

Materials and methods

A systematic search was performed as per PRISMA statement using PubMed, Scopus, Cochrane Library, and Web of Science. Published studies that investigated adults and children (P) with caries-active status (E) and caries-free status (C), whereby arginine levels/ADS activity (O) was measured in saliva/plaque to analyze exposure-outcome association compared to the control group were deemed eligible for inclusion. Quality assessment was performed using combined Newcastle-Ottawa Scale and Modified RTI Item Bank scale. Meta-analysis was performed for effect size, precision estimation, and subgroup effects analysis.

Results

Of 233 records identified, seven (κ = 1.00) were included for qualitative synthesis (systematic review) and four for quantitative synthesis (meta-analysis). No specific bias could be identified in five studies assessed as per the Modified RTI Item Bank scale. Two studies received lower scores on the Newcastle Ottawa scale. Plaque ADS activity in adults (effect size = 0.93, p = 0.008), salivary ADS activity in adults and children (effect size = 0.85, p < 0.001), and salivary ADS activity in adults (effect size = 0.87, p < 0.001) identified a statistically significant effect size. Subgroup analysis demonstrated non-significant variance (Q value = 0.042, p = 0.838) between saliva and plaque ADS activities of adults.

Conclusions

The results of this review suggest the salivary and plaque ADS activities appear to be promising caries risk indicators for adults, while results remain inconclusive in children.

Clinical relevance

Measuring ADS activities (saliva or plaque) can be a potential caries risk indicator in adults. The protocol was registered on PROSPERO database: CRD42017060701.



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Milbenallergie im HNO-Bereich: Bedeutung, Diagnostik und Therapieoptionen.

Milbenallergie im HNO-Bereich: Bedeutung, Diagnostik und Therapieoptionen.

Laryngorhinootologie. 2018 Jan;97(1):56-69

Authors: Klimek L, Gröger M, Becker S

Abstract
Allergic rhinitis (AR) affects ca. 20% of the population. Approximately one third of patients affected by AR are suffering from perennial rhinitis due to mite allergy. Perennial rhinitis is the form of the disease that is most frequently associated with other allergy-related comorbidities such as asthma and atopic dermatitis, sleep disorders, chronic sinusitis, eustachian tube dysfunction and others.The often non-specific symptoms and the insidious course may lead to misinterpretations in diagnosing the disease.Therapeutic options include allergen avoidance with regard to environmental measures, encasings and personal actions. Drug therapy in mite-AR consists mainly in the administration of mast cell stabilizers, H1-antihistamines, glucocorticosteroids (GCS), leukotriene receptor antagonists and decongestants. It is particularly important to ensure a good antiinflammatory activity. Thus, a combination of H1-antihistamine and topical nasal GCS seems to be a rational approach. The only causal treatment form besides allergen avoidance is allergen-specific immunotherapy 1.

PMID: 29301162 [PubMed - in process]



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Changing Faces of OSA: Treatment Effects by Cluster Designation in the Icelandic Sleep Apnea Cohort.

Changing Faces of OSA: Treatment Effects by Cluster Designation in the Icelandic Sleep Apnea Cohort.

Sleep. 2018 Jan 02;:

Authors: Pien GW, Ye L, Keenan BT, Maislin G, Björnsdóttir E, Arnardottir ES, Benediktsdottir B, Gislason T, Pack AI

Abstract
Study Objectives: Distinct clinical phenotypes of obstructive sleep apnea (OSA) have been identified: Disturbed Sleep, Minimally Symptomatic, and Sleepy. Determining whether these phenotypes respond differently to standard treatment helps create a foundation for personalized therapies. We compared responses to positive airway pressure (PAP) therapy in these clinical OSA phenotypes.
Methods: The study sample included 706 patients from the Icelandic Sleep Apnea Cohort with moderate-to-severe OSA who were prescribed PAP. Linear and logistic mixed models were used to compare two-year changes in demographics, comorbid diseases, and sleep-related health issues within and across OSA clinical phenotypes. Relationships between changes in symptoms and PAP adherence were also examined.
Results: Overall, effect sizes were moderate to large when comparing sleepiness, insomnia-related, and apneic symptom changes in the Sleepy group to changes in other 2 groups, especially those in the Minimally Symptomatic group. Within the Disturbed Sleep group, PAP users and non-users demonstrated similar changes in insomnia-related symptoms. The Minimally Symptomatic group remained relatively asymptomatic, but reported significant decreases in daytime sleepiness and physical fatigue; PAP users generally had larger improvements. The Sleepy group had reductions in nearly all measured symptoms, including large reductions in drowsy driving; almost all of these improvements were greater among PAP users than non-users.
Conclusions: OSA treatment response patterns differed by initial clinical phenotype and PAP adherence. Individuals with insomnia-related symptoms may require additional targeted therapy for these complaints. These findings underscore the need for a personalized approach to management that recognizes patients with a range of OSA presentations.

PMID: 29301021 [PubMed - as supplied by publisher]



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Progesterone-Mediated Inhibition of the GnRH Pulse Generator: Differential Sensitivity as a Function of Sleep Status.

Progesterone-Mediated Inhibition of the GnRH Pulse Generator: Differential Sensitivity as a Function of Sleep Status.

J Clin Endocrinol Metab. 2017 Dec 28;:

Authors: Kim SH, Lundgren JA, Bhabhra R, Collins JS, Patrie JT, Burt Solorzano CM, Marshall JC, McCartney CR

Abstract
Context: During normal early puberty, luteinizing hormone (LH) pulse frequency is low while awake but increases during sleep. Mechanisms underlying such changes are unclear, but a small study in early pubertal girls suggested that differential wake-sleep sensitivity to progesterone negative feedback plays a role.
Objective: To test the hypothesis that progesterone acutely reduces waking LH pulse frequency more than sleep-associated pulse frequency in late pubertal girls.
Design: Randomized, placebo-controlled, double-blinded crossover study.
Setting: Academic clinical research unit.
Participants: 11 normal post-menarcheal girls, ages 12-15 years.
Intervention: Subjects completed two 18-hour admissions in separate menstrual cycles (cycle day 6-11). Frequent blood sampling for LH assessment was performed 1800-1200 h; sleep was encouraged 2300-0700 h. Either oral micronized progesterone (0.8 mg/kg per dose) or placebo was given at 0700, 1500, 2300, and 0700 h before and during the first admission. A second admission, performed at least two months later, was identical to the first except that placebo was exchanged for progesterone or vice versa (treatment crossover).
Main Outcome Measure: LH pulse frequency during waking and sleeping hours.
Results: Progesterone reduced waking LH pulse frequency by 26% (p = 0.019), with no change observed during sleep (p = 0.314). The interaction between treatment condition (progesterone vs. placebo) and sleep status (wake vs. sleep) was highly significant (p = 0.007).
Conclusions: In late pubertal girls, progesterone acutely reduced waking LH pulse frequency more than sleep-associated pulse frequency. Differential wake-sleep sensitivity to progesterone negative feedback may direct sleep-wake LH pulse frequency changes across puberty.

PMID: 29300925 [PubMed - as supplied by publisher]



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Peripheral Endocannabinoids Associated with Energy Expenditure in Native Americans of Southwestern Heritage.

Peripheral Endocannabinoids Associated with Energy Expenditure in Native Americans of Southwestern Heritage.

J Clin Endocrinol Metab. 2017 Dec 28;:

Authors: Heinitz S, Basolo A, Piaggi P, Piomelli D, Jumpertz von Schwartzenberg R, Krakoff J

Abstract
Context: The endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and the related acylethanolamide oleoylethanolamide (OEA) have been implicated in energy expenditure (EE)-regulation and metabolic diseases. Muscle (fat-free mass, FFM) and fat (fat mass, FM) are metabolically active compartments and main determinants of EE.
Objective: To assess whether human muscle, adipose, and plasma endocannabinoids correlate with EE.
Design: Muscle, adipose, and plasma AEA, 2-AG, and OEA concentrations were measured via liquid chromatography-mass spectrometry. EE was assessed by indirect whole-room calorimetry.
Setting: Clinical trial.
Participants: Obese/overweight Native Americans of full (n=35) and ≥ half (n=21) Southwestern heritage.
Main outcome measures: 24hour-EE, sleeping EE (SLEEP), resting EE (REE), respiratory quotient (RQ), macronutrient oxidation.
Results: In full Natives, muscle AEA concentration correlated with SLEEP (r = -0.65, P = 0.004) and REE (r = -0.53, P = 0.02). Muscle 2-AG was associated with SLEEP (r = -0.75, P = 0.0003). Adipose OEA concentration correlated with RQ (r = -0.47, P = 0.04) and lipid oxidation (r = 0.51, P = 0.03). Plasma OEA concentration was associated with SLEEP (r = -0.52, P = 0.04). After adjustment for major determinants, these lipids explained nearly 20% of the additional variance of the respective measure. Similarly, in Native Americans of ≥ half Southwestern heritage, investigated lipids correlated with EE measures.
Conclusion: Endocannabinoids in metabolically relevant peripheral tissues explained a large part of EE variation and may be involved in regulating EE. Dysregulation of peripheral endocannabinoids may predispose to metabolic diseases via an effect on EE and lipid oxidation.

PMID: 29300902 [PubMed - as supplied by publisher]



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Tissue Distribution of Suvorexant in Three Forensic Autopsy Cases.

Tissue Distribution of Suvorexant in Three Forensic Autopsy Cases.

J Anal Toxicol. 2017 Dec 28;:

Authors: Waters B, Hara K, Ikematsu N, Takayama M, Matsusue A, Kashiwagi M, Kubo SI

Abstract
Suvorexant (Belsomra®) is a relatively new insomnia medication that has been available in USA and Japan since 2014. It is a dual orexin receptor antagonist that promotes sleep by inhibiting the binding of orexin neurons to the OX1R and OX2R receptors. In this report, we describe the detection and quantitation of suvorexant from the postmortem specimens of three separate autopsy cases handled by our department. Suvorexant was identified by fast gas chromatography/mass spectrometry during routine screening, and quantitated by a fully validated liquid chromatography-tandem mass spectroscopy method. Quantitation was achieved by positive electrospray ionization in the selected reaction monitoring mode. Monitored transitions were m/z 451 > 186 for quantitation and m/z 451 > 104 for qualification. To our knowledge, this is the first instance of suvorexant being quantitated from actual autopsy cases. It is likely that this compound will be encountered more often by the forensic toxicology community going forward.

PMID: 29300899 [PubMed - as supplied by publisher]



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Physical activity, sleep and risk of respiratory infections: A Swedish cohort study.

Physical activity, sleep and risk of respiratory infections: A Swedish cohort study.

PLoS One. 2018;13(1):e0190270

Authors: Ghilotti F, Pesonen AS, Raposo SE, Winell H, Nyrén O, Trolle Lagerros Y, Plymoth A

Abstract
OBJECTIVES: Previous studies found higher levels of physical activity to be protective against infections and that short and long sleep negatively affects the immune response. However, these relationships remain debatable. We aimed to investigate if physical activity and sleep habits affect incidence of upper respiratory tract infections (URTI) in a prospective cohort study.
METHODS: A total of 2,038 adults aged 25-64 years served as a random sample of the gainfully employed population of an industrial town in Sweden. Physical activity and sleep habits were estimated through self-reported questionnaires. Physical activity was expressed as metabolic energy turnover hours per day. Sleep was assessed as number of hours slept per night and its perceived quality. URTI outcome was prospectively self-reported during a 9-month follow-up period. Associations of physical activity and sleep with URTI were estimated using hurdle regression models adjusted for potential confounders.
RESULTS: During 1,583 person-years 1,597 URTI occurred, resulting in an incidence of 1.01 infections/person-year (95% CI 0.96-1.06). The fitted regression models did not provide support for an association with physical activity or sleep habits. Factors positively associated with experiencing URTI were having children ≤ 6 years, female gender, higher education and treatment for allergy, asthma or lung cancer. Having children ≤ 6 years and female gender were related to a higher number of URTI among those experiencing URTI.
CONCLUSIONS: We did not find any association between physical activity, sleep duration or sleep quality and the occurrence of upper respiratory tract infections in adult Swedish population.

PMID: 29300730 [PubMed - in process]



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The efficacy and safety of mannitol challenge in a workplace setting for assessing asthma prevalence.

The efficacy and safety of mannitol challenge in a workplace setting for assessing asthma prevalence.

J Asthma. 2018 Jan 04;:1-8

Authors: de Menezes MB, Ferraz E, Brannan JD, Martinez EZ, Vianna EO

Abstract
OBJECTIVE: There is no standard definition of asthma for epidemiological purposes; most surveys use symptoms and bronchial hyperresponsiveness. Few studies tested mannitol challenge test (MCT) in occupational settings. We sought to determine efficacy and safety of MCT in detecting subjects with asthma symptoms in the workplace.
METHODS: In this cross-sectional study we recruited 908 workers in 2 universities; they underwent a respiratory questionnaire, spirometry, skin prick tests, and MCT.
RESULTS: Eight hundred and eleven subjects completed the study; 11.1% had a positive MCT; 8.14% had asthma. MCT had low sensitivity (35.4-61.9%) but high specificity (90.2-94.9%) to detect symptomatic individuals. The most prevalent symptom was wheezing in the last 12 months. Twenty-four of those with a positive MCT (26.7%) had no positive replies to the questions on asthma symptoms. Among subjects with a positive MCT, 71.9% achieved 95% of baseline FEV1 after 15 minutes of salbutamol recovery treatment. Nine subjects (1.1%) had adverse events that prevented the test from being completed.
CONCLUSIONS: MCT has high specificity but low sensitivity to detect symptomatic subjects in the workplace. It may detect subjects with hyperresponsiveness but no symptoms, who could be at risk of developing airway diseases. The test is safe and well tolerated.

PMID: 29300533 [PubMed - as supplied by publisher]



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Association of habitual dietary intake with morningness-eveningness and rotating shift work in Japanese female nurses.

Association of habitual dietary intake with morningness-eveningness and rotating shift work in Japanese female nurses.

Chronobiol Int. 2018 Jan 04;:1-13

Authors: Yoshizaki T, Komatsu T, Tada Y, Hida A, Kawano Y, Togo F

Abstract
Rotating shift workers are associated with imbalanced dietary intakes. Rotating shift workers and dietary intakes in adults who do not engage in night work have also been shown to be associated with chronotype. However, no studies have examined associations between morningness-eveningness (i.e., the degree to which people prefer to be active in the morning or the evening), rotating shift work and dietary intakes. Therefore, our first purpose was to elucidate the association between morningness-eveningness and habitual food group intakes in rotating shift workers. The second purpose was to elucidate the association of morningness-eveningness and rotating shift work with food group intakes, considering habitual sleep durations. Japanese nurses (1095 day workers and 1464 rotating shift workers) were studied using a self-administered questionnaire. The questionnaire covered habitual dietary intakes, morningness-eveningness and demographic characteristics of the participants. A Japanese version of the Morningness-Eveningness Questionnaire (MEQ) was used to measure self-rated morningness-eveningness. Dietary intakes over the previous 1 month were evaluated using a semi-quantitative food frequency questionnaire. Intakes of pulses, green/yellow vegetables, white vegetables, fruits, algae, eggs, confectioneries/savory snacks and sugar-sweetened beverages were significantly (p < 0.05) associated with the MEQ score in rotating shift workers. Among these food groups, intakes of green/yellow vegetables, white vegetables, fruits and algae were significantly (p < 0.05) lower in rotating shift workers than in day workers, and intakes of confectioneries/savory snacks and sugar-sweetened beverages were significantly (p < 0.05) higher in rotating shift workers than in day workers. Intakes of these food groups were also significantly (p < 0.05) associated with the MEQ score in day workers. In addition, the MEQ score was significantly (p < 0.05) lower in rotating shift workers than in day workers, indicating greater eveningness among rotating shift workers. Multivariate linear regression revealed that the MEQ scores were significantly (p < 0.05) associated with intakes of these food groups, while rotating shift work was associated only with confectioneries/savory snacks. These results suggest that morningness-eveningness is associated with unbalanced dietary intakes in rotating shift workers as well as day workers, which may partially explain associations between rotating shift work and unfavorable dietary intakes. These findings have important implications for the development of novel strategies for preventing poor health caused by imbalanced dietary intakes in rotating shift workers.

PMID: 29300497 [PubMed - as supplied by publisher]



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Reliability-Aware Cooperative Node Sleeping and Clustering in Duty-Cycled Sensors Networks.

Reliability-Aware Cooperative Node Sleeping and Clustering in Duty-Cycled Sensors Networks.

Sensors (Basel). 2018 Jan 04;18(1):

Authors: Song J, Miao Y, Song E, Hossain MS, Alhamid MF

Abstract
Duty-cycled sensor networks provide a new perspective for improvement of energy efficiency and reliability assurance of multi-hop cooperative sensor networks. In this paper, we consider the energy-efficient cooperative node sleeping and clustering problems in cooperative sensor networks where clusters of relay nodes jointly transmit sensory data to the next hop. Our key idea for guaranteeing reliability is to exploit the on-demand number of cooperative nodes, facilitating the prediction of personalized end-to-end (ETE) reliability. Namely, a novel reliability-aware cooperative routing (RCR) scheme is proposed to select k-cooperative nodes at every hop (RCR-selection). After selecting k cooperative nodes at every hop, all of the non-cooperative nodes will go into sleep status. In order to solve the cooperative node clustering problem, we propose the RCR-based optimal relay assignment and cooperative data delivery (RCR-delivery) scheme to provide a low-communication-overhead data transmission and an optimal duty cycle for a given number of cooperative nodes when the network is dynamic, which enables part of cooperative nodes to switch into idle status for further energy saving. Through the extensive OPNET-based simulations, we show that the proposed scheme significantly outperforms the existing geographic routing schemes and beaconless geographic routings in wireless sensor networks with a highly dynamic wireless channel and controls energy consumption, while ETE reliability is effectively guaranteed.

PMID: 29300329 [PubMed - in process]



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Obstructive sleep apnoea in adults: peri-operative considerations: A narrative review.

Obstructive sleep apnoea in adults: peri-operative considerations: A narrative review.

Eur J Anaesthesiol. 2018 Jan 02;:

Authors: Roesslein M, Chung F

Abstract
: Obstructive sleep apnoea (OSA) is a common breathing disorder of sleep with a prevalence increasing in parallel with the worldwide rise in obesity. Alterations in sleep duration and architecture, hypersomnolence, abnormal gas exchange and also associated comorbidities may all feature in affected patients.The peri-operative period poses a special challenge for surgical patients with OSA who are often undiagnosed, and are at an increased risk for complications including pulmonary and cardiovascular, during that time. In order to ensure the best peri-operative management, anaesthetists caring for these patients should have a thorough understanding of the disorder, and be aware of the individual's peri-operative risk constellation, which depends on the severity and phenotype of OSA, the invasiveness of the surgical procedure, anaesthesia and also the requirement for postoperative opioids.The objective of this review is to educate clinicians in the epidemiology, pathogenesis and diagnosis of OSA in adults and also to highlight specific tasks in the preoperative assessment, namely to select a suitable intra-operative anaesthesia regimen, and manage the extent and duration of postoperative care to facilitate the best peri-operative outcome.

PMID: 29300271 [PubMed - as supplied by publisher]



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Sleep Quality and Daytime Sleepiness Among Women With Urgency Predominant Urinary Incontinence.

Sleep Quality and Daytime Sleepiness Among Women With Urgency Predominant Urinary Incontinence.

Female Pelvic Med Reconstr Surg. 2018 Jan 03;:

Authors: Winkelman WD, Warsi A, Huang AJ, Schembri M, Rogers RG, Richter HE, Myers DL, Kraus SR, Johnson KC, Hess R, Gregory T, Bradley CS, Arya LA, Brown JS, Stone KL, Subak LL

Abstract
OBJECTIVE: The objective of this study was to examine the strength and direction of the association between urinary symptoms and both poor quality sleep and daytime sleepiness among women with urgency urinary incontinence.
METHODS: A planned secondary analysis of baseline characteristics of participants in a multicenter, double-blinded, 12-week randomized controlled trial of pharmacologic therapy for urgency-predominant urinary incontinence in ambulatory women self-diagnosed by the 3 Incontinence Questions was performed. Urinary symptoms were assessed by 3-day voiding diaries. Quality of sleep was assessed using the Pittsburgh Sleep Quality Index (PSQI) and daytime sleepiness using the Epworth Sleepiness Scale.
RESULTS: Of the 640 participants, mean (SD) age was 56 (±14) years and 68% were white. Participants reported an average of 3.9 (±3.0) urgency incontinence episodes per day and 1.3 (±1.3) episodes of nocturia per night. At baseline, 57% had poor sleep quality (PSQI score, >5) and 17% reported daytime sleepiness (Epworth Sleepiness Scale score, >10). Most women (69%) did not use sleeping medication during the prior month, whereas 13% reported use of sleeping medication 3 or more times per week. An increase in total daily incontinence episodes, total daily urgency incontinence episodes, total daily micturitions, and moderate to severe urge sensations were all associated with higher self-report of poor sleep quality according to the PSQI (all P ≤ 0.01). Higher scores on the Bother Scale and the Health-Related Quality of Life for overactive bladder on the Overactive Bladder Questionnaire were similarly associated with higher rates of poor sleep quality (both P ≤ 0.01). In subgroup analysis of those who took sleeping medications less than twice a week, there was still a significant relationship between incontinence measures and quality of sleep as measured by the PSQI. In multivariable analyses, greater frequency of nighttime urgency incontinence was associated with poor sleep quality (P = 0.03).
CONCLUSIONS: Among ambulatory women with urgency urinary incontinence, poor sleep quality is common and greater frequency of incontinence is associated with a greater degree of sleep dysfunction. Women seeking urgency urinary incontinence treatment should be queried about their sleeping habits so that they can be offered appropriate interventions.

PMID: 29300259 [PubMed - as supplied by publisher]



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Dedicated Afternoon Rounds for ICU Patients' Families and Family Satisfaction With Care.

Dedicated Afternoon Rounds for ICU Patients' Families and Family Satisfaction With Care.

Crit Care Med. 2018 Jan 03;:

Authors: Weber U, Johnson J, Anderson N, Knies AK, Nhundu B, Bautista C, Huang KB, Hamza M, White J, Coppola A, Akgün KM, Greer DM, Marcolini EG, Gilmore EJ, Petersen NH, Timario N, Poskus K, Sheth KN, Hwang DY

Abstract
OBJECTIVE: It was hypothesized that adding dedicated afternoon rounds for patients' families to supplement standard family support would improve overall family satisfaction with care in a neuroscience ICU.
DESIGN: Pre- and postimplementation (pre-I and post-I) design.
SETTING: Single academic neuroscience ICU.
PATIENTS: Patients in the neuroscience ICU admitted for longer than 72 hours or made comfort measures only at any point during neuroscience ICU admission.
INTERVENTION: The on-service attending intensivist and a neuroscience ICU nursing leader made bedside visits to families to address concerns during regularly scheduled, advertised times two afternoons each week.
MEASUREMENTS AND MAIN RESULTS: One family member per patient during the pre-I and post-I periods was recruited to complete the Family Satisfaction in the ICU 24 instrument. Post-I respondents indicated whether they had participated in the afternoon rounds. For primary outcome, the mean pre-I and post-I composite Family Satisfaction in the ICU 24 scores (on a 100-point scale) were compared. A total of 146 pre-I (March 2013 to October 2014; capture rate, 51.6%) and 141 post-I surveys (October 2014 to December 2015; 47.2%) were collected. There was no difference in mean Family Satisfaction in the ICU 24 score between groups (pre-I, 89.2 ± 11.2; post-I, 87.4 ± 14.2; p = 0.6). In a secondary analysis, there was also no difference in mean Family Satisfaction in the ICU 24 score between the pre-I respondents and the 39.0% of post-I respondents who participated in family rounds. The mean Family Satisfaction in the ICU 24 score of the post-I respondents who reported no participation trended lower than the mean pre-I score, with fewer respondents in this group reporting complete satisfaction with emotional support (75% vs. 54%; p = 0.002), coordination of care (82% vs. 68%; p = 0.03), and frequency of communication by physicians (60% vs. 43%; p = 0.03).
CONCLUSIONS: Dedicated afternoon rounds for families twice a week may not necessarily improve an ICU's overall family satisfaction. Increased dissatisfaction among families who do not or cannot participate is possible.

PMID: 29300237 [PubMed - as supplied by publisher]



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"Give Me Some Time": Facilitators of and Barriers to Uptake of Home-based HIV Testing During Household Contact Investigation for Tuberculosis in Kampala, Uganda.

"Give Me Some Time": Facilitators of and Barriers to Uptake of Home-based HIV Testing During Household Contact Investigation for Tuberculosis in Kampala, Uganda.

J Acquir Immune Defic Syndr. 2018 Jan 03;:

Authors: Armstrong-Hough M, Ggita J, Ayakaka I, Dowdy D, Cattamanchi A, Haberer JE, Katamba A, Davis JL

Abstract
BACKGROUND: Integrating home-based HIV counseling and testing (HCT) with tuberculosis (TB) evaluation could improve uptake of HIV testing among household contacts of patients with active TB. We sought to identify the facilitators of and barriers to HCT during household contact investigation for TB in Kampala, Uganda.
METHODS: We nested semi-structured interviews with 28 household contacts who were offered home-based HCT in a household-randomized trial of home-based strategies for TB contact investigation. Respondents reflected on their experiences of the home visit, the social context of the household, and their decision to accept or decline HIV testing. We used content analysis to identify and evaluate facilitators and barriers to testing, then categorized the emergent themes using the Capability, Opportunity, Motivation, and Behavior (COM-B) model.
RESULTS: Facilitators included a pre-existing desire to confirm HIV status or to show support for the index TB patient; a perception that home-based services are convenient; and positive perceptions of lay health workers. Key barriers included fear of results and feeling psychologically unprepared to receive results. The social influence of other household members operated as both a facilitator and a barrier.
CONCLUSIONS: Pre-existing motivation, psychological readiness to test, and the social context of the household are major contributors to the decision to test for HIV at home. Uptake might be improved by providing normalizing information about HCT prior to the visit, by offering a second HCT opportunity, by offering self-tests with follow-up counseling, or by introducing HCT using "opt-out" language.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.

PMID: 29300218 [PubMed - as supplied by publisher]



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Air pollution in India and related adverse respiratory health effects: past, present, and future directions.

Air pollution in India and related adverse respiratory health effects: past, present, and future directions.

Curr Opin Pulm Med. 2018 Jan 02;:

Authors: Khilnani GC, Tiwari P

Abstract
PURPOSE OF REVIEW: The review describes current status of air pollution in India, summarizes recent research on adverse health effects of ambient and household air pollution, and outlines the ongoing efforts and future actions required to improve air quality and reduce morbidity and mortality because of air pollution in India.
RECENT FINDINGS: Global burden of disease data analysis reveals more than one million premature deaths attributable to ambient air pollution in 2015 in India. More than one million additional deaths can be attributed to household air pollution. Particulate matter with diameter 2.5 μm or less has been causatively linked with most premature deaths. Acute respiratory tract infections, asthma, chronic obstructive pulmonary disease, exacerbations of preexisting obstructive airway disease and lung cancer are proven adverse respiratory effects of air pollution. Targeting air quality standards laid by WHO can significantly reduce morbidity and mortality because of air pollution in India.
SUMMARY: India is currently exposed to high levels of ambient and household air pollutants. Respiratory adverse effects of air pollution are significant contributors to morbidity and premature mortality in India. Substantial efforts are being made at legislative, administrative, and community levels to improve air quality. However, much more needs to be done to change the 'status quo' and attain the target air quality standards. VIDEO ABSTRACT: http://ift.tt/2CIep03.

PMID: 29300211 [PubMed - as supplied by publisher]



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Effectiveness of Sucrose Used Routinely for Pain Relief and Neonatal Clinical Risk in Preterm Infants: A Nonrandomized Study.

Effectiveness of Sucrose Used Routinely for Pain Relief and Neonatal Clinical Risk in Preterm Infants: A Nonrandomized Study.

Clin J Pain. 2018 Jan 03;:

Authors: Valeri BO, Gaspardo CM, Martinez FE, Linhares MBM

Abstract
BACKGROUND: Preterm infants (PI) requiring the Neonatal Intensive Care Unit (NICU) are exposed to early repetitive pain/distress. Little is known about how pain relief strategies interact with infants'clinical health status, such as severity of illness with pain responses. This study aimed to examine main and interactive effects of routine sucrose intervention and neonatal clinical risk (NCR) on biobehavioral pain reactivity-recovery in PI during painful blood collection procedures.
METHODS: Very-low birthweight PI (n=104) were assigned to Low and High Clinical Risk Groups, according to the Clinical Risk Index for Babies. Sucrose-Group (SG; n=52) received sucrose solution (25%; 0.5▒mL/Kg) two minutes before the procedures and Control-Group (CG) received standard-care. Biobehavioral pain reactivity-recovery was assessed according to the Neonatal Facial Coding System, Sleep-wake state scale, crying time, and heart rate (HR) at five phases (Baseline, Antisepsis, Puncture, Recovery-Dressing and Recovery-Resting). Repeated measure ANOVA with mixed-design was performed considering pain assessment phases, intervention group, and NCR.
RESULTS: Independent of NCR, sucrose presented main effect in decreasing neonates' facial activity pain responses and crying time, during Puncture and Recovery-Resting. Independent of NCR level or routine sucrose intervention, all neonates displayed activated state in Puncture and decreased biobehavioral responses in Recovery-Resting phase. Although no sucrose or NCR effects were observed on physiological reactivity, all neonates exhibited physiological recovery 10 minutes after puncture, reaching the same HR patterns as the Baseline.
CONCLUSIONS: Independent of NCR level, sucrose intervention for pain relief during acute painful procedures was effective to reduce pain intensity and increase biobehavioral regulation.

PMID: 29300197 [PubMed - as supplied by publisher]



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Improving the diagnosis of obstructive sleep apnea in children with nocturnal oximetry-based evaluations.

Improving the diagnosis of obstructive sleep apnea in children with nocturnal oximetry-based evaluations.

Expert Rev Respir Med. 2018 Jan 04;:

Authors: Van Eyck A, Verhulst SL

PMID: 29300109 [PubMed - as supplied by publisher]



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Bed-Sharing in the First 8 Weeks of Life: An Australian Study.

Related Articles

Bed-Sharing in the First 8 Weeks of Life: An Australian Study.

Matern Child Health J. 2018 Jan 03;:

Authors: Cunningham HM, Vally H, Bugeja L

Abstract
Background As the evidence continues to emerge about the relationship between sudden unexpected death in infancy (SUDI) and the way an infant sleeps, providing consistent and evidence-informed recommendations on how best to sleep infants is an ongoing challenge. A recent case series study in the state of Victoria, Australia, identified 45.8% of sleep-related infant deaths occurred whilst bed-sharing. This study prompted the need for further exploration of infant sleeping practices, including bed-sharing, in this population. Methods A cross-sectional survey of 2745 mothers attending the Maternal and Child Health (MCH) Service across Victoria, Australia was conducted. Data included the prevalence and circumstances of bed-sharing, family demographics, and SUDI risk and protective factors. Associations between bed-sharing and SUDI risk and protective factors were examined using univariate and multivariate analyses. Results Bed-sharing prevalence was found to be 44.7%, with 21.5% reporting that this was intended. Multivariate analyses showed bed-sharing was less likely amongst those with an annual household income above $AUS104, 000 (OR 0.72; 95% CI 0.54-0.96) and more likely amongst mothers who breastfed (OR 1.71; 95% CI 1.23-2.37). Conclusions Bed-sharing prevalence in this population compares closely with the Victorian case series study and a previous cross-sectional study in the state of Queensland, Australia, in 2002. Noted gaps in how families are implementing current recommendations about reducing the risk of SUDI were identified for sleep position, sleep location and the sleep environment. Further consideration needs to be given to addressing these gaps and applying these findings of current bed-sharing practices to the development of infant safe sleeping policy and programs.

PMID: 29299793 [PubMed - as supplied by publisher]



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Thermoregulatory postures limit antipredator responses in peafowl [RESEARCH ARTICLE]

Jessica L. Yorzinski, Jennifer Lam, Rachel Schultz, and Melissa Davis

Many animals inhabit environments where they experience temperature fluctuations. One way in which animals can adjust to these temperature changes is through behavioral thermoregulation. However, we know little about the thermal benefits of postural changes and the costs they may incur. In this study, we examined the thermoregulatory role of two postures, the head-tuck and leg-tuck posture, in peafowl (Pavo cristatus) and evaluated whether the head-tuck posture imposes a predation cost. The heads and legs of peafowl are significantly warmer when the birds exhibit these postures, demonstrating that these postures serve an important thermoregulatory role. In addition, the birds are slower to respond to an approaching threat when they display the head-tuck posture, suggesting that a thermoregulatory posture can limit antipredator behavior.



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An attenuated quadruple gene mutant of Mycobacterium tuberculosis imparts protection against tuberculosis in guinea pigs [RESEARCH ARTICLE]

Ritika Kar Bahal, Shubhita Mathur, Priyanka Chauhan, and Anil K. Tyagi

Previously we had developed a triple gene mutant of Mycobacterium tuberculosis (Mtbmms) harboring disruption in three genes, namely mptpA, mptpB and sapM. Though vaccination with Mtbmms strain induced protection in the lungs of guinea pigs, the mutant strain failed to control the hematogenous spread of the challenge strain to the spleen. Additionally, inoculation with Mtbmms resulted in some pathological damage to the spleens in the early phase of infection. In order to generate a strain that overcomes the pathology caused by Mtbmms in spleen of guinea pigs and controls dissemination of the challenge strain, Mtbmms was genetically modified by disrupting bioA gene to generate Mtbmmsb strain. Further, in vivo attenuation of Mtbmmsb was evaluated and its protective efficacy was assessed against virulent M. tuberculosis challenge in guinea pigs. Mtbmmsb mutant strain was highly attenuated for growth and virulence in guinea pigs. Vaccination with Mtbmmsb mutant generated significant protection in comparison to sham-immunized animals at 4 and 12 weeks post-infection in lungs and spleen of infected animals. However, the protection imparted by Mtbmmsb was significantly less in comparison to BCG immunized animals. This study indicates the importance of attenuated multiple gene deletion mutants of M. tuberculosis for generating protection against tuberculosis.



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A novel assessment of the traction forces upon settlement of two typical marine fouling invertebrates using PDMS micropost arrays [RESEARCH ARTICLE]

Kang Xiao, Wen-Bin Cao, Cu-Huang Rong, Lian-Guo Chen, Xiao-Xue Yang, Wei-Jia Wen, Pei-Yuan Qian, Zhang-Li Hu, Ying Xu, and Yu Zhang

Marine biofouling poses a severe threat to maritime and aquaculture industries. To prevent the attachment of marine biofouling organisms on man-made structures, countless cost and effort was spent annually. In particular, most attention has been paid on the development of efficient and environmentally friendly fouling-resistant coatings, as well as larval settlement mechanism of several major biofouling invertebrates. In this study, polydimethylsiloxane (PDMS) micropost arrays were utilized as the settlement substrata and opposite tractions were identified during early settlement of the barnacle Amphibalanus amphitrite and the bryozoan Bugula neritina. The settling A. amphitrite pushed the periphery microposts with an average traction force of 376.2 nN, while settling B. neritina pulled the periphery microposts with an average traction force of 205.9 nN. These micropost displacements are consistent with the body expansion of A. amphitrite during early post-settlement metamorphosis stage and elevation of wall epithelium of B. neritina during early pre-ancestrula stage, respectively. As such, the usage of micropost array may supplement the traditional histological approach to indicate the early settlement stages or even the initiation of larval settlement of marine fouling organisms, and could finally aid in the development of automatic monitoring platform for the real-time analysis on this complex biological process.



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Cardiac-enriched BAF chromatin-remodeling complex subunit Baf60c regulates gene expression programs essential for heart development and function [RESEARCH ARTICLE]

Xin Sun, Swetansu K. Hota, Yu-Qing Zhou, Stefanie Novak, Dario Miguel-Perez, Danos Christodoulou, Christine E. Seidman, J. G. Seidman, Carol C. Gregorio, R. Mark Henkelman, Janet Rossant, and Benoit G. Bruneau

How chromatin-remodeling complexes modulate gene networks to control organ-specific properties is not well understood. For example, Baf60c (Smarcd3) encodes a cardiac-enriched subunit of the SWI/SNF-like BAF chromatin complex, but its role in heart development is not fully understood. We found that constitutive loss of Baf60c leads to embryonic cardiac hypoplasia and pronounced cardiac dysfunction. Conditional deletion of Baf60c in cardiomyocytes resulted in postnatal dilated cardiomyopathy with impaired contractile function. Baf60c regulates a gene expression program that includes genes encoding contractile proteins, modulators of sarcomere function, and cardiac metabolic genes. Many of the genes deregulated in Baf60c null embryos are targets of the MEF2/SRF co-factor Myocardin (MYOCD). In a yeast two-hybrid screen, we identified MYOCD as a BAF60c interacting factor; we showed that BAF60c and MYOCD directly and functionally interact. We conclude that Baf60c is essential for coordinating a program of gene expression that regulates the fundamental functional properties of cardiomyocytes.



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Transcriptional retargeting of herpes simplex virus for cell-specific replication to control cancer

Abstract

Introduction

Oncolytic virotherapy has emerged as a novel frontier in the treatment of cancer. Among the viruses that entered clinical trials are the oncolytic herpes simplex virus-1 (HSV-1). Current oncolytic HSV-1 approved for clinical practice, and those in clinical trials are attenuated viruses, often deleted in the neurovirulence gene γ134.5, and in additional genes, which may result in a much more attenuated virus with reduced replication efficiency. Therefore, the transcriptional retargeting strategy by modifying the regulator elements flanking essential viral genes to achieve tumor-specific replication while maintaining as much of the viral genome has been representing alternative promising oncolytic virotherapy modality.

Materials and methods

In this communication, we aimed to review extensive studies on transcriptional retargeting strategy with HSV-1 genome engineered on immediate–early ICP4 gene, late γ134.5 gene or early ICP6 gene as well as multiple-regulated oncolytic HSV1 through combining transcriptional retargeting and translational control. Design modality based on differential cellular background, advantage, and potential clinic limitation of the innovative oncolytic HSV-1 was described, and prospective and challenge of transcriptional retargeting strategy were collectively summarized.

Conclusion

Transcriptional retargeting strategy holds great promise in retaining tumor specificity as well as full replication capacity of oncolytic virus in the target cell as urgently required by clinical trials. Future efforts should be aimed toward the development of multiple-component targeted oncolytic virus such as combing the transcriptional retargeting strategy and genetically attenuated modulation or post-transcriptional control that will be the most effective at generating truly tumor selective vectors.



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Metastatic Intimal Sarcoma of the Pulmonary Artery Sensitive to Carboplatin-Vinorelbine Chemotherapy: Case Report and Literature Review

Pulmonary artery intimal sarcoma (PAIS) is a very rare tumour with a very poor prognosis. In advanced stages, chemotherapy and radiotherapy are poorly efficient, and no standard chemotherapy guideline is currently available. Here, we report on a 37-year-old woman with PAIS initially treated with surgical resection who developed metastatic relapse refractory to anthracycline-based chemotherapy, then trabectedin, then pazopanib. The patient was then given carboplatin-vinorelbine chemotherapy. The treatment was well tolerated, and, rapidly, a CT scan showed an objective response that lasted 8 months despite the 4th therapeutic line. We review the literature and show that our case is the second one that provides evidence of the efficacy of platinum-vinorelbine regimens in this aggressive tumour.
Case Rep Oncol 2018;11:21–28

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Antimicrobial activity of silver nanoparticles encapsulated in poly-N-isopropylacrylamide-based polymeric nanoparticles

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Nano-graphene oxide composite for in vivo imaging

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Vocal Fry and Vowel Height in Simulated Room Acoustics

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Purpose: The purpose of this study was to investigate the influence of room acoustics in the relationship between vowel height and vocal fry. Methods: This was a cross-sectional study. Participants (college students, n = 40) read the first six sentences of “The Rainbow Passage” under nine simulated room acoustic conditions. Using two words with low vowels (act, pot) and two words with high vowels (shape, strikes) preceding a voiceless stop, the presence/absence of vocal fry was assessed using an automatic detection script. Generalized estimation equations were used to investigate the relationship between percentage of vocal fry, vowel height, and room acoustics. Results: The percentage of vocal fry was significantly higher for the low-height vowels compared with the high-height vowels (β = 1.21; standard er ror = 0.35), and for pink background noise present (β = 0.89; standard error = 0.35) compared with the condition without artificial noise added. Conclusion: The results of this study indicate that young college students are more likely to produce fry phonation when producing low-height vowels under pink background noise condition compared with no noise conditions and high-height vowels. This result is of special interest for voice clinicians when designing therapy plans and vocal assessment protocols with fry-like components.
Folia Phoniatr Logop 2017;69:118–124

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Investigation of brain structure in the 1-month infant

Abstract

The developing brain undergoes systematic changes that occur at successive stages of maturation. Deviations from the typical neurodevelopmental trajectory are hypothesized to underlie many early childhood disorders; thus, characterizing the earliest patterns of normative brain development is essential. Recent neuroimaging research provides insight into brain structure during late childhood and adolescence; however, few studies have examined the infant brain, particularly in infants under 3 months of age. Using high-resolution structural MRI, we measured subcortical gray and white matter brain volumes in a cohort (N = 143) of 1-month infants and examined characteristics of these volumetric measures throughout this early period of neurodevelopment. We show that brain volumes undergo age-related changes during the first month of life, with the corresponding patterns of regional asymmetry and sexual dimorphism. Specifically, males have larger total brain volume and volumes differ by sex in regionally specific brain regions, after correcting for total brain volume. Consistent with findings from studies of later childhood and adolescence, subcortical regions appear more rightward asymmetric. Neither sex differences nor regional asymmetries changed with gestation-corrected age. Our results complement a growing body of work investigating the earliest neurobiological changes associated with development and suggest that asymmetry and sexual dimorphism are present at birth.



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Protein levels of clusterin and glutathione synthetase in platelets allow for early detection of colorectal cancer

Abstract

Colorectal cancer (CRC) is one of the most frequent malignancies in the Western world. Early tumor detection and intervention are important determinants on CRC patient survival. During early tumor proliferation, dissemination and angiogenesis, platelets store and segregate proteins actively and selectively. Hence, the platelet proteome is a potential source of biomarkers denoting early malignancy. By comparing protein profiles of platelets between healthy volunteers (n = 12) and patients with early- (n = 7) and late-stage (n = 5) CRCs using multiplex fluorescence two-dimensional gel electrophoresis (2D-DIGE), we aimed at identifying differentially regulated proteins within platelets. By inter-group comparisons, 94 differentially expressed protein spots were detected (p < 0.05) between healthy controls and patients with early- and late-stage CRCs and revealed distinct separations between all three groups in principal component analyses. 54 proteins of interest were identified by mass spectrometry and resulted in high-ranked Ingenuity Pathway Analysis networks associated with Cellular function and maintenance, Cellular assembly and organization, Developmental disorder and Organismal injury and abnormalities (p < 0.0001 to p = 0.0495). Target proteins were validated by multiplex fluorescence-based Western blot analyses using an additional, independent cohort of platelet protein samples [healthy controls (n = 15), early-stage CRCs (n = 15), late-stage CRCs (n = 15)]. Two proteins—clusterin and glutathione synthetase (GSH-S)—featured high impact and were subsequently validated in this independent clinical cohort distinguishing healthy controls from patients with early- and late-stage CRCs. Thus, the potential of clusterin and GSH-S as platelet biomarkers for early detection of CRC could improve existing screening modalities in clinical application and should be confirmed in a prospective multicenter trial.



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Mechanisms regulating immune surveillance of cellular stress in cancer

Abstract

The purpose of this review is to explore immune-mediated mechanisms of stress surveillance in cancer, with particular emphasis on the idea that all cancers have classical hallmarks (Hanahan and Weinberg in Cell 100:57–70, 67; Cell 144:646–674, 68) that could be interrelated. We postulate that hallmarks of cancer associated with cellular stress pathways (Luo et al. in Cell 136:823–837, 101) including oxidative stress, proteotoxic stress, mitotic stress, DNA damage, and metabolic stress could define and modulate the inflammatory component of cancer. As such, the overarching goal of this review is to define the types of cellular stress that cancer cells undergo, and then to explore mechanisms by which immune cells recognize, respond to, and are affected by each stress response.



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Mechanisms of protein homeostasis (proteostasis) maintain stem cell identity in mammalian pluripotent stem cells

Abstract

Protein homeostasis, or proteostasis, is essential for cell function, development, and organismal viability. The composition of the proteome is adjusted to the specific requirements of a particular cell type and status. Moreover, multiple metabolic and environmental conditions challenge the integrity of the proteome. To maintain the quality of the proteome, the proteostasis network monitors proteins from their synthesis through their degradation. Whereas somatic stem cells lose their ability to maintain proteostasis with age, immortal pluripotent stem cells exhibit a stringent proteostasis network associated with their biological function and intrinsic characteristics. Moreover, growing evidence indicates that enhanced proteostasis mechanisms play a central role in immortality and cell fate decisions of pluripotent stem cells. Here, we will review new insights into the melding fields of proteostasis and pluripotency and their implications for the understanding of organismal development and survival.



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Current knowledge on exosome biogenesis and release

Abstract

Exosomes are nanosized membrane vesicles released by fusion of an organelle of the endocytic pathway, the multivesicular body, with the plasma membrane. This process was discovered more than 30 years ago, and during these years, exosomes have gone from being considered as cellular waste disposal to mediate a novel mechanism of cell-to-cell communication. The exponential interest in exosomes experienced during recent years is due to their important roles in health and disease and to their potential clinical application in therapy and diagnosis. However, important aspects of the biology of exosomes remain unknown. To explore the use of exosomes in the clinic, it is essential that the basic molecular mechanisms behind the transport and function of these vesicles are better understood. We have here summarized what is presently known about how exosomes are formed and released by cells. Moreover, other cellular processes related to exosome biogenesis and release, such as autophagy and lysosomal exocytosis are presented. Finally, methodological aspects related to exosome release studies are discussed.



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Stress-induced changes in miRNA biogenesis and functioning

Abstract

MicroRNAs (miRNAs) are small, noncoding RNAs that play key roles in the regulation of cellular homeostasis in eukaryotic organisms. There is emerging evidence that some of these processes are influenced by various forms of cellular stresses, including DNA damage, pathogen invasion or chronic stress associated with diseases. Many reports over the last decade demonstrate examples of stress-induced miRNA deregulation at the level of transcription, processing, subcellular localization and functioning. Moreover, core miRNA biogenesis proteins and their interactions with partners can be selectively regulated in response to stress signaling. However, little is known about the role of isomiRs and the interactions of miRNA with non-canonical targets in the context of the stress response. In this review, we summarize the current knowledge on miRNA functions under various stresses, including chronic stress and miRNA deregulation in the pathogenesis of age-associated neurodegenerative disorders.



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Role of noncoding RNAs in regulation of cardiac cell death and cardiovascular diseases

Abstract

Loss of functional cardiomyocytes is a major underlying mechanism for myocardial remodeling and heart diseases, due to the limited regenerative capacity of adult myocardium. Apoptosis, programmed necrosis, and autophagy contribute to loss of cardiac myocytes that control the balance of cardiac cell death and cell survival through multiple intricate signaling pathways. In recent years, non-coding RNAs (ncRNAs) have received much attention to uncover their roles in cell death of cardiovascular diseases, such as myocardial infarction, cardiac hypertrophy, and heart failure. In addition, based on the view that mitochondrial morphology is linked to three types of cell death, ncRNAs are able to regulate mitochondrial fission/fusion of cardiomyocytes by targeting genes involved in cell death pathways. This review focuses on recent progress regarding the complex relationship between apoptosis/necrosis/autophagy and ncRNAs in the context of myocardial cell death in response to stress. This review also provides insight into the treatment for heart diseases that will guide novel therapies in the future.



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The mitochondrial epitranscriptome: the roles of RNA modifications in mitochondrial translation and human disease

Abstract

Mitochondrial protein synthesis is essential for the production of components of the oxidative phosphorylation system. RNA modifications in the mammalian mitochondrial translation apparatus play key roles in facilitating mitochondrial gene expression as they enable decoding of the non-conventional genetic code by a minimal set of tRNAs, and efficient and accurate protein synthesis by the mitoribosome. Intriguingly, recent transcriptome-wide analyses have also revealed modifications in mitochondrial mRNAs, suggesting that the concept of dynamic regulation of gene expression by the modified RNAs (the “epitranscriptome”) extends to mitochondria. Furthermore, it has emerged that defects in RNA modification, arising from either mt-DNA mutations or mutations in nuclear-encoded mitochondrial modification enzymes, underlie multiple mitochondrial diseases. Concomitant advances in the identification of the mitochondrial RNA modification machinery and recent structural views of the mitochondrial translation apparatus now allow the molecular basis of such mitochondrial diseases to be understood on a mechanistic level.



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Genes, Vol. 9, Pages 12: Transcription Factor and lncRNA Regulatory Networks Identify Key Elements in Lung Adenocarcinoma

Genes, Vol. 9, Pages 12: Transcription Factor and lncRNA Regulatory Networks Identify Key Elements in Lung Adenocarcinoma

Genes doi: 10.3390/genes9010012

Authors: Dan Li William Yang Jialing Zhang Jack Yang Renchu Guan Mary Yang

Lung cancer is the second most commonly diagnosed carcinoma and is the leading cause of cancer death. Although significant progress has been made towards its understanding and treatment, unraveling the complexities of lung cancer is still hampered by a lack of comprehensive knowledge on the mechanisms underlying the disease. High-throughput and multidimensional genomic data have shed new light on cancer biology. In this study, we developed a network-based approach integrating somatic mutations, the transcriptome, DNA methylation, and protein-DNA interactions to reveal the key regulators in lung adenocarcinoma (LUAD). By combining Bayesian network analysis with tissue-specific transcription factor (TF) and targeted gene interactions, we inferred 15 disease-related core regulatory networks in co-expression gene modules associated with LUAD. Through target gene set enrichment analysis, we identified a set of key TFs, including known cancer genes that potentially regulate the disease networks. These TFs were significantly enriched in multiple cancer-related pathways. Specifically, our results suggest that hepatitis viruses may contribute to lung carcinogenesis, highlighting the need for further investigations into the roles that viruses play in treating lung cancer. Additionally, 13 putative regulatory long non-coding RNAs (lncRNAs), including three that are known to be associated with lung cancer, and nine novel lncRNAs were revealed by our study. These lncRNAs and their target genes exhibited high interaction potentials and demonstrated significant expression correlations between normal lung and LUAD tissues. We further extended our study to include 16 solid-tissue tumor types and determined that the majority of these lncRNAs have putative regulatory roles in multiple cancers, with a few showing lung-cancer specific regulations. Our study provides a comprehensive investigation of transcription factor and lncRNA regulation in the context of LUAD regulatory networks and yields new insights into the regulatory mechanisms underlying LUAD. The novel key regulatory elements discovered by our research offer new targets for rational drug design and accompanying therapeutic strategies.



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FDA issues Breakthrough Therapy designation for ribociclib for premenopausal women with HR /HER2- advanced breast cancer

Ribociclib has received US Food and Drug Administration (FDA) Breakthrough Therapy designation for initial endocrine-based treatment of pre- or perimenopausal women with hormone-receptor positive, human epidermal growth factor receptor-2 negative (HR...

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Große thorakale Raumforderung



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Ein seltener, gastrointestinaler Notfall



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Near-Infrared Photoimmunotherapy Targeting EGFR - Shedding New Light on Glioblastoma Treatment

Abstract

Glioblastomas (GBM) are high-grade brain tumours, differentially driven by alterations (amplification, deletion, or missense mutations) in the epidermal growth factor receptor (EGFR), that carry a poor prognosis of just 12-15 months following standard therapy. A combination of interventions targeting tumor-specific cell surface regulators along with convergent downstream signalling pathways may enhance treatment efficacy. Against this background, we investigated a novel photoimmunotherapy approach combining the cytotoxicity of photodynamic therapy with the specificity of immunotherapy.

An EGFR-specific affibody (ZEGFR:03115) was conjugated to the phthalocyanine dye, IR700DX, which when excited with near-infrared light produces a cytotoxic response. ZEGFR:03115-IR700DX EGFR-specific binding was confirmed by FACS analysis and confocal microscopy. The conjugate showed effective targeting of EGFR positive GBM cells in the brain. The therapeutic potential of the conjugate was assessed both in vitro, in GBM cell lines and spheroids by the CellTiter-Glo® assay, and in vivo using subcutaneous U87-MGvIII xenografts. In addition, mice were imaged pre- and post-PIT using the IVIS/Spectrum/CT to monitor treatment response.

Binding of the conjugate correlated to the level of EGFR expression in GBM cell lines. The cell proliferation assay revealed a receptor-dependent response between the tested cell lines. Inhibition of EGFRvIII+ve tumor growth was observed following administration of the immunoconjugate and irradiation. Importantly, this response was not seen in control tumors.

In conclusion, the ZEGFR:03115-IR700DX showed specific uptake in vitro and enabled imaging of EGFR expression in the orthotopic brain tumor model. Moreover, the proof-of-concept in vivo PIT study demonstrated therapeutic efficacy of the conjugate in subcutaneous glioma xenografts. This article is protected by copyright. All rights reserved.



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Whole Blood FPR1 mRNA Expression Predicts Both Non-Small Cell and Small Cell Lung Cancer

Abstract

While long-term survival rates for early-stage lung cancer are high, most cases are diagnosed in later stages that can negatively impact survival rates. We aim to design a simple, single biomarker blood test for early-stage lung cancer that is robust to preclinical variables and can be readily implemented in the clinic. Whole blood was collected in PAXgene tubes from a training set of 29 patients, and a validation set of 260 patients, of which samples from 58 patients were prospectively collected in a clinical trial specifically for this study. After RNA was extracted, the expression of FPR1 and a reference gene were quantified by an automated one-step Taqman RT-PCR assay. Elevated levels of FPR1 mRNA in whole blood predicted lung cancer status with a sensitivity of 55% and a specificity of 87% on all validation specimens. The prospectively collected specimens had a significantly higher 68% sensitivity and 89% specificity. Results from patients with benign nodules were similar to healthy volunteers. No meaningful correlation was present between our test results and any clinical characteristic other than lung cancer diagnosis. FPR1 mRNA levels in whole blood can predict the presence of lung cancer. Using this as a reflex test for positive lung cancer screening computed tomography (CT) scans has the potential to increase the positive predictive value. This marker can be easily measured in an automated process utilizing off-the-shelf equipment and reagents. Further work is justified to explain the source of this biomarker. This article is protected by copyright. All rights reserved.



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MI (2-methyl-4-isothiazolin-3-one) contained in detergents is not detectable in machine washed textiles

European legislation has banned the preservative methylisothiazolinone (MI) from inclusion in leave-on cosmetics. However, the risk for allergic reactions depends on exposure. The aim of this study was to dete...

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A phase I study for adjuvant chemotherapy of gemcitabine plus S-1 in patients with biliary tract cancer undergoing curative resection without major hepatectomy (KHBO1202)

Abstract

Purpose

To determine the recommended dose (RD) of gemcitabine (GEM) plus S-1 (GS) in curatively resected biliary tract cancer (BTC) patients without major hepatectomy.

Methods

A standard 3 + 3 dose-escalation design was used with planned dose levels (mg/m2) of GEM (administered intravenously on days 1 and 8) and S-1 (administered orally twice daily on days 1–14, with a 1-week rest, every 3 weeks for up to 24 weeks) of 1000/80 (Level 2), 1000/65 (Level 1), 800/65 (Level − 1), and 800/50 (Level − 2).

Results

Thirty-one patients (17 men and 14 women; median age, 70 years) were enrolled. Level 1 was chosen as the starting dose. Three of seven patients developed dose-limiting toxicities at Level 1 and the dose was de-escalated to Level − 1. Five of 12 patients developed Grade 4 neutropenia at Level − 1 and the dose was de-escalated to Level − 2. One patient developed Grade 4 neutropenia at Level − 2. Another patient was unable to receive the day 8 dose due to Grade 3 neutropenia at Level − 2. Level − 1 was confirmed as the maximum tolerated dose and Level − 2 the RD for this regimen. The 1- and 2-year recurrence-free survival rates were 77.0 and 54.0%, respectively. The recurrence-free survival rate of patients in the GS completion group was significantly higher than that of the GS discontinuation group.

Conclusions

Level − 2 was confirmed as the RD (GEM 800 mg/m2 and S-1 50 mg/m2) for GS adjuvant chemotherapy in curatively resected BTC patients without major hepatectomy.



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Biosensors for Alzheimer's disease biomarker detection: A review

Publication date: Available online 4 January 2018
Source:Biochimie
Author(s): Bingqing Shui, Dan Tao, Anca Florea, Jing Cheng, Qin Zhao, Yingying Gu, Wen Li, Nicole Jaffrezic-Renault, Yong Mei, Zhenzhong Guo
Alzheimer's disease (AD) is a chronic disease amongst people aged 65 and older. Increasing evidence has illustrated that early diagnosis holds the key to effective treatment of AD. A variety of detection techniques have been developed. Biosensors are excellent analytical tools which have applications in detecting the biomarkers of AD. This review includes appropriate bioreceptors to achieve highly sensitive and selective quantification of AD biomarkers by using transducers. AD biomarkers such as tau protein, amyloid β peptides and apolipoprotein E4, are firstly summarized. The most commonly used bioreceptors, including aptamers and antibodies, are also reviewed. We introduce aptamers specific to AD biomarkers, list the sequences of aptamers designed to capture AD biomarkers and compare the properties of aptamers with those of antibodies with regard to their efficiency as bio-recognition elements. We discuss the recent progress of aptamer systems' applications in AD biomarkers in biosensing. The review also discusses novel strategies used for signal amplification in sensing AD biomarkers.



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Structure-function analyses reveal key features in Staphylococcus aureus IsdB-associated unfolding of the heme-binding pocket of human hemoglobin [Protein Structure and Folding]

IsdB is a receptor on the surface of the bacterial pathogen Staphylococcus aureus that extracts heme from hemoglobin (Hb) to enable growth on Hb as a sole iron source. IsdB is critically important both for in vitro growth on Hb and in infection models and is also highly up-regulated in blood, serum, and tissue infection models, indicating a key role of this receptor in bacterial virulence. However, structural information for IsdB is limited. We present here a crystal structure of a complex between human Hb and IsdB. In this complex, the α subunits of Hb are refolded with the heme displaced to the interface with IsdB. We also observe that atypical residues of Hb, His58 and His89 of αHb, coordinate to the heme iron, which is poised for transfer into the heme-binding pocket of IsdB. Moreover, the porphyrin ring interacts with IsdB residues Tyr440 and Tyr444. Previously, Tyr440 was observed to coordinate heme iron in an IsdB·heme complex structure. A Y440F/Y444F IsdB variant we produced was defective in heme transfer yet formed a stable complex with Hb (Kd = 6 ± 2 μm) in solution with spectroscopic features of the bis-His species observed in the crystal structure. Haptoglobin binds to a distinct site on Hb to inhibit heme transfer to IsdB and growth of S. aureus, and a ternary complex of IsdB·Hb·Hp was observed. We propose a model for IsdB heme transfer from Hb that involves unfolding of Hb and heme iron ligand exchange.

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An improved Escherichia coli screen for Rubisco identifies a protein-protein interface that can enhance CO2-fixation kinetics [Plant Biology]

An overarching goal of photosynthesis research is to identify how components of the process can be improved to benefit crop productivity, global food security, and renewable energy storage. Improving carbon fixation has mostly focused on enhancing the CO2 fixing enzyme ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco). This grand challenge has mostly proved ineffective because of catalytic mechanism constraints and required chaperone complementarity that hinder Rubisco biogenesis in alternative hosts. Here we refashion Escherichia coli metabolism by expressing a phosphoribulokinase-neomycin phosphotransferase fusion protein to produce a high-fidelity, high-throughput Rubisco-directed evolution (RDE2) screen that negates false-positive selection. Successive evolution rounds using the plant-like Te-Rubisco from the cyanobacterium Thermosynechococcus elongatus BP1 identified two large subunit and six small subunit mutations that improved carboxylation rate, efficiency, and specificity. Structural analysis revealed the amino acids clustered in an unexplored subunit interface of the holoenzyme. To study its effect on plant growth, the Te-Rubisco was transformed into tobacco by chloroplast transformation. As previously seen for Synechocccus PCC6301 Rubisco, the specialized folding and assembly requirements of Te-Rubisco hinder its heterologous expression in leaf chloroplasts. Our findings suggest that the ongoing efforts to improve crop photosynthesis by integrating components of a cyanobacteria CO2-concentrating mechanism will necessitate co-introduction of the ancillary molecular components required for Rubisco biogenesis.

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“HETE”ing up mitochondria in human heart failure [Metabolism]

A decade of research has established the phospholipase iPLA2γ as being involved in cardiomyocyte dysfunction and necrosis leading to heart failure, but the mechanisms by which iPLA2γ acts and its interaction with the mitochondrial permeability transition pore (mPTP) that is critical for cardiac homeostasis are unclear. New investigations by Moon et al. demonstrate that mitochondria in failing hearts undergo dynamic shifts in PLA2 isoform expression, leading to a redistribution of eicosanoid composition that contributes to pathologic mPTP opening.

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Stilbenoid prenyltransferases define key steps in the diversification of peanut phytoalexins [Enzymology]

Defense responses of peanut (Arachis hypogaea) to biotic and abiotic stresses include the synthesis of prenylated stilbenoids. Members of this compound class show several protective activities in human disease studies, and the list of potential therapeutic targets continues to expand. Despite their medical and biological importance, the biosynthetic pathways of prenylated stilbenoids remain to be elucidated, and the genes encoding stilbenoid-specific prenyltransferases have yet to be identified in any plant species. In this study, we combined targeted transcriptomic and metabolomic analyses to discover prenyltransferase genes in elicitor-treated peanut hairy root cultures. Transcripts encoding five enzymes were identified, and two of these were functionally characterized in a transient expression system consisting of Agrobacterium-infiltrated leaves of Nicotiana benthamiana. We observed that one of these prenyltransferases, AhR4DT-1, catalyzes a key reaction in the biosynthesis of prenylated stilbenoids, in which resveratrol is prenylated at its C-4 position to form arachidin-2, whereas another, AhR3′DT-1, added the prenyl group to C-3′ of resveratrol. Each of these prenyltransferases was highly specific for stilbenoid substrates, and we confirmed their subcellular location in the plastid by fluorescence microscopy. Structural analysis of the prenylated stilbenoids suggested that these two prenyltransferase activities represent the first committed steps in the biosynthesis of a large number of prenylated stilbenoids and their derivatives in peanut. In summary, we have identified five candidate prenyltransferases in peanut and confirmed that two of them are stilbenoid-specific, advancing our understanding of this specialized enzyme family and shedding critical light onto the biosynthesis of bioactive stilbenoids.

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Role of the PWWP domain of lens epithelium-derived growth factor (LEDGF)/p75 cofactor in lentiviral integration targeting. [Withdrawals/Retractions]

VOLUME 286 (2011) PAGES 41812–41825This article has been withdrawn by the authors. The authors have become aware of a duplication of two lanes (the PWWPHRP2-LEDGF and HDGF-LEDGF325–530 lanes) in Fig. 2 of this manuscript and withdraw the article in the interests of maintaining their publication standards and those of the journal.

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An ultra-stable single-chain insulin analog resists thermal inactivation and exhibits biological signaling duration equivalent to the native protein [Molecular Biophysics]

Thermal degradation of insulin complicates its delivery and use. Previous efforts to engineer ultra-stable analogs were confounded by prolonged cellular signaling in vivo, of unclear safety and complicating mealtime therapy. We therefore sought an ultra-stable analog whose potency and duration of action on intravenous bolus injection in diabetic rats are indistinguishable from wild-type (WT) insulin. Here, we describe the structure, function, and stability of such an analog, a 57-residue single-chain insulin (SCI) with multiple acidic substitutions. Cell-based studies revealed native-like signaling properties with negligible mitogenic activity. Its crystal structure, determined as a novel zinc-free hexamer at 2.8 Å, revealed a native insulin fold with incomplete or absent electron density in the C domain; complementary NMR studies are described in the accompanying article. The stability of the analog (ΔGU 5.0(±0.1) kcal/mol at 25 °C) was greater than that of WT insulin (3.3(±0.1) kcal/mol). On gentle agitation, the SCI retained full activity for >140 days at 45 °C and >48 h at 75 °C. These findings indicate that marked resistance to thermal inactivation in vitro is compatible with native duration of activity in vivo. Further, whereas WT insulin forms large and heterogeneous aggregates above the standard 0.6 mm pharmaceutical strength, perturbing the pharmacokinetic properties of concentrated formulations, dynamic light scattering, and size-exclusion chromatography revealed only limited SCI self-assembly and aggregation in the concentration range 1–7 mm. Such a combination of favorable biophysical and biological properties suggests that SCIs could provide a global therapeutic platform without a cold chain.

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The actin-organizing formin protein Fhod3 is required for postnatal development and functional maintenance of the adult heart in mice [Developmental Biology]

Cardiac development and function require actin–myosin interactions in the sarcomere, a highly organized contractile structure. Sarcomere assembly mediated by formin homology 2 domain-containing 3 (Fhod3), a member of formins that directs formation of straight actin filaments, is essential for embryonic cardiogenesis. However, the role of Fhod3 in the neonatal and adult stages has remained unknown. Here, we generated floxed Fhod3 mice to bypass the embryonic lethality of an Fhod3 knockout (KO). Perinatal KO of Fhod3 in the heart caused juvenile lethality at around day 10 after birth with enlarged hearts composed of severely impaired myofibrils, indicating that Fhod3 is crucial for postnatal heart development. Tamoxifen-induced conditional KO of Fhod3 in the adult heart neither led to lethal effects nor did it affect sarcomere structure and localization of sarcomere components. However, adult Fhod3-deleted mice exhibited a slight cardiomegaly and mild impairment of cardiac function, conditions that were sustained over 1 year without compensation during aging. In addition to these age-related changes, systemic stimulation with the α1-adrenergic receptor agonist phenylephrine, which induces sustained hypertension and hypertrophy development, induced expression of fetal cardiac genes that was more pronounced in adult Fhod3-deleted mice than in the control mice, suggesting that Fhod3 modulates hypertrophic changes in the adult heart. We conclude that Fhod3 plays a crucial role in both postnatal cardiac development and functional maintenance of the adult heart.

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Solution structure of an ultra-stable single-chain insulin analog connects protein dynamics to a novel mechanism of receptor binding [Molecular Biophysics]

Domain-minimized insulin receptors (IRs) have enabled crystallographic analysis of insulin-bound “micro-receptors.” In such structures, the C-terminal segment of the insulin B chain inserts between conserved IR domains, unmasking an invariant receptor-binding surface that spans both insulin A and B chains. This “open” conformation not only rationalizes the inactivity of single-chain insulin (SCI) analogs (in which the A and B chains are directly linked), but also suggests that connecting (C) domains of sufficient length will bind the IR. Here, we report the high-resolution solution structure and dynamics of such an active SCI. The hormone's closed-to-open transition is foreshadowed by segmental flexibility in the native state as probed by heteronuclear NMR spectroscopy and multiple conformer simulations of crystallographic protomers as described in the companion article. We propose a model of the SCI's IR-bound state based on molecular-dynamics simulations of a micro-receptor complex. In this model, a loop defined by the SCI's B and C domains encircles the C-terminal segment of the IR α-subunit. This binding mode predicts a conformational transition between an ultra-stable closed state (in the free hormone) and an active open state (on receptor binding). Optimization of this switch within an ultra-stable SCI promises to circumvent insulin's complex global cold chain. The analog's biphasic activity, which serendipitously resembles current premixed formulations of soluble insulin and microcrystalline suspension, may be of particular utility in the developing world.

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