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1.
Anal Chim Acta ; 1107: 113-126, 2020 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-32200885

RESUMO

Quadrupole based mass spectrometry based detection has experienced enormous improvements in terms of sensitivity over the last centuries. This development has not been equally matched with improvements in selectivity. Hence, the use of unit mass based MS/MS transitions or high resolution (HRMS) based extracted ion chromatograms is gradually becoming insufficient in the field of high sensitivity multi-residue analysis (e.g. pesticides in food). As a consequence, commercial instruments hyphenating ion mobility (IMS) with low or high resolution mass spectrometry based detection have appeared. The use of such an additional (frequently claimed to be orthogonal) dimension is intended to increase selectivity. In addition, IMS derived collision cross section (CCS) has been proposed to be used as an additional identification point for the unambiguous identification of trace compounds in complex matrices. It is the topic of this paper to investigate the benefit of using such a hyphenated technique for trace analysis of small molecules in complex matrices. The potential of CCS to serve as additional identification point has been critically evaluated. Discussed are the effect of CCS data on false detects and missing detects of analytes present at trace levels. This involves the investigation of the physical resolving power provided by HRMS, IMS and chromatography as well as the correlation among these parameters (orthogonality). It is the conclusion that currently commercially available travelling wave and linear drift tube based IMS devices with a resolving power of up to 50 permit a reduction of false detects, yet this comes at the price of a higher likelihood of missing detects. The reduction of missing detects and the use of CCS as potential confirmatory information would require IMS resolving powers above 100.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32188073

RESUMO

In some countries, obesity rates among police officers are higher than the general public, despite physically demanding jobs. Obesity rates based on body mass index (BMI) may lack accuracy as BMI does not directly address body composition. Since data are lacking for obesity rates among Russian police officers, this study documented and compared officer obesity rates to the adult Russian population and compared the accuracy of body mass index (BMI) for obesity classification to two direct measures of body composition. Moscow region police officers (N = 182, 84% men) underwent height, weight, waist circumference (WC), and body fat percentage (BF%) bioelectrical impedance measurements during annual medical examinations. BMI-defined obesity rates were 4.6% for men and 17.2% for women, which were >3 and >1.8 times lower than Russian adults, respectively. WC-defined obesity rates were similar to BMI (3.3% for men and 10.3% for women), but BF%-defined obesity rates were much higher (22.2% for men and 55.2% for women). Although obesity rates were lower than those found among police officers in other countries, BMI alone was not a particularly accurate method for classifying weight status among Russian police officers.

3.
Br J Dermatol ; 2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-32034956

RESUMO

BACKGROUND: Scabies is a common parasitic skin condition that causes considerable morbidity globally. Clinical and epidemiological research for scabies have been limited by a lack of standardisation of diagnostic methods. OBJECTIVES: We aimed to develop consensus criteria for the diagnosis of common scabies that could be implemented in a variety of settings. METHODS: Consensus diagnostic criteria were developed through a Delphi study of international experts. Detailed recommendations were collected from the expert panel to define the criteria features and guide their implementation. These comments were then combined with a comprehensive review of available literature and opinion of an expanded group of international experts to develop detailed, evidence-based definitions and diagnostic methods. RESULTS: The 2020 IACS Consensus Criteria for the Diagnosis of Scabies include three levels of diagnostic certainty and eight subcategories. Confirmed Scabies (Level A) requires direct visualisation of the mite or its products. Clinical Scabies (Level B) and Suspected Scabies (Level C) rely on clinical assessment of signs and symptoms. Evidence-based, consensus methods for microscopy, visualisation and clinical symptoms and signs were developed, along with a media library. CONCLUSIONS: The 2020 IACS Criteria represent a pragmatic, yet robust set of diagnostic features and methods. The criteria may be implemented in a range of research, public health and clinical settings by selecting the appropriate diagnostic levels and subcategories. These criteria may provide greater consistency and standardisation for scabies diagnoses. Validation studies and development of training materials and development of survey methods are now required.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31993663

RESUMO

While rodent research suggests that the bed nucleus of the stria terminalis (BNST) and centromedial amygdala (CM) coordinate the hormonal stress response, little is known about the BNST's role in the human stress response. The human BNST responds to negatively-valenced stimuli, which likely subserves its role in responding to threat. Thus, variation in BNST reactivity to negatively-valenced stimuli may relate to differences in the stress response. We measured participants' blood-oxygenated-level-dependent response to affective images, and salivary cortisol and α-amylase (AA) levels in response to a subsequent Trier Social Stress Test (TSST). Greater BNST activation to emotionally evocative images was associated with a larger TSST-evoked AA, but not cortisol response. This association remained after controlling for CM activation, which was not related to the cortisol or AA response. These results suggest that the BNST response to negatively-valenced images subserves its role in coordinating the stress response, a BNST role in the stress response independent from the CM, and highlight the need for investigation of the conditions under which BNST activation predicts the cortisol response. Our findings are critical for the future study of mood and anxiety disorders, as dysregulation of the stress system plays a key role in their pathogenesis.

5.
Horm Behav ; 117: 104610, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31669457

RESUMO

Early-life stress exposure can confer vulnerability for development of psychiatric illnesses and impaired cognition in adulthood. It is well-known that early-life stress can dysregulate the hypothalamic-pituitary-adrenal (HPA) axis in a sex-dependent manner. Specifically, uniparental rodent models of prolonged disrupted mother-offspring relationships (e.g., maternal separation) have demonstrated greater alterations in stress responsivity in adult males, compared to females. Also, chronic early-life stressors (e.g., limited bedding model) impair cognitive function in males more than females. However, the sex-dependent effects of early-life stress and later-life chronic HPA axis activation on cognition have not been well-characterized. Here, we utilized the biparental California mouse (Peromyscus californicus) to model the early-life adversity of paternal deprivation (PD). Fathers either remained in the nest (biparental care) or were permanently removed (PD) on postnatal day (PND) 1. Adult offspring were exposed to daily handling (control) or chronic variable stress (CVS; three stressors for seven days). Twenty-four hours after the final stressor, the novel object recognition (NOR) task commenced, followed by serum collection for corticosterone (CORT) analysis. Independent of sex or rearing, CVS increased CORT. Exploration during acquisition for the NOR task was increased as a result of CVS and PD. During NOR testing, non-stressed females exhibited greater difference scores (i.e., increased recognition memory), compared to non-stressed males. However, the addition of CVS diminished difference scores in females - an effect not observed in CVS-exposed males. Overall, these data suggest that neonatal paternal experience, sex, and chronic stress contribute to exploratory behavior, cognition, and stress hormone concentrations in a biparental species.

6.
Mol Ther ; 28(1): 52-63, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31704085

RESUMO

Enhancing natural killer (NK) cell cytotoxicity by blocking inhibitory signaling could lead to improved NK-based cancer immunotherapy. Thus, we have developed a highly efficient method for editing the genome of human NK cells using CRISPR/Cas9 to knock out inhibitory signaling molecules. Our method efficiently edits up to 90% of primary peripheral blood NK cells. As a proof-of-principle we demonstrate highly efficient knockout of ADAM17 and PDCD1, genes that have a functional impact on NK cells, and demonstrate that these gene-edited NK cells have significantly improved activity, cytokine production, and cancer cell cytotoxicity. Furthermore, we were able to expand cells to clinically relevant numbers, without loss of activity. We also demonstrate that our CRISPR/Cas9 method can be used for efficient knockin of genes by delivering homologous recombination template DNA using recombinant adeno-associated virus serotype 6 (rAAV6). Our platform represents a feasible method for generating engineered primary NK cells as a universal therapeutic for cancer immunotherapy.

7.
Neuroimage ; 207: 116428, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31809887

RESUMO

The bed nucleus of the stria terminalis (BNST) and central nucleus of the amygdala (CeA) are hypothesized to be the output nodes of the extended amygdala threat response, integrating multiple signals to coordinate the threat response via outputs to the hypothalamus and brainstem. The BNST and CeA are structurally and functionally connected, suggesting interactions between these regions may regulate how the response to provocation unfolds. However, the relationship between human BNST-CeA connectivity and the behavioral response to affective stimuli is little understood. To investigate whether individual differences in BNST-CeA connectivity are related to the affective response to negatively valenced stimuli, we tested relations between resting-state BNST-CeA connectivity and both facial electromyographic (EMG) activity of the corrugator supercilii muscle and eyeblink startle magnitude during affective image presentation within the Refresher sample of the Midlife in the United States (MIDUS) study. We found that higher right BNST-CeA connectivity was associated with greater corrugator activity to negative, but not positive, images. There was a trend-level association between right BNST-CeA connectivity and trait negative affect. Eyeblink startle magnitude was not significantly related to BNST-CeA connectivity. These results suggest that functional interactions between BNST and CeA contribute to the behavioral response to negative emotional events.

9.
Nat Commun ; 10(1): 5519, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31801954

RESUMO

Identification of genetic biomarkers associated with autism spectrum disorders (ASDs) could improve recurrence prediction for families with a child with ASD. Here, we describe clinical microarray findings for 253 longitudinally phenotyped ASD families from the Baby Siblings Research Consortium (BSRC), encompassing 288 infant siblings. By age 3, 103 siblings (35.8%) were diagnosed with ASD and 54 (18.8%) were developing atypically. Thirteen siblings have copy number variants (CNVs) involving ASD-relevant genes: 6 with ASD, 5 atypically developing, and 2 typically developing. Within these families, an ASD-related CNV in a sibling has a positive predictive value (PPV) for ASD or atypical development of 0.83; the Simons Simplex Collection of ASD families shows similar PPVs. Polygenic risk analyses suggest that common genetic variants may also contribute to ASD. CNV findings would have been pre-symptomatically predictive of ASD or atypical development in 11 (7%) of the 157 BSRC siblings who were eventually diagnosed clinically.

11.
Artigo em Inglês | MEDLINE | ID: mdl-31820811

RESUMO

Relative to the centromedial amygdala (CM), the bed nucleus of the stria terminalis (BNST) may exhibit more sustained activation toward threat, sensitivity to unpredictability, and activation during anxious anticipation. These factors are often intertwined. For example, greater BNST (vs. CM) activation during a block of aversive stimuli may reflect either more sustained activation to the stimuli, or greater activation due to the anticipation of upcoming stimuli. To further investigate these questions, we had participants (19 females, 9 males) complete a task adapted from Somerville et al. (2013) during high-resolution 7-Tesla fMRI BOLD acquisition. We found a larger response to negative vs. neutral blocks (sustained threat) than to images (transient) in the BNST, but not the CM. However, in an additional analysis, we also found BNST, but not CM, activation to the onset of the anticipation period on negative vs. neutral trials, possibly contributing to BNST activation across negative blocks. Predictability did not affect CM or BNST activation. These results suggest a BNST role in anxious anticipation and highlight the need for further research clarifying the temporal response characteristics of these regions.

13.
Nat Commun ; 10(1): 5222, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31745080

RESUMO

The fusion of genome engineering and adoptive cellular therapy holds immense promise for the treatment of genetic disease and cancer. Multiplex genome engineering using targeted nucleases can be used to increase the efficacy and broaden the application of such therapies but carries safety risks associated with unintended genomic alterations and genotoxicity. Here, we apply base editor technology for multiplex gene modification in primary human T cells in support of an allogeneic CAR-T platform and demonstrate that base editor can mediate highly efficient multiplex gene disruption with minimal double-strand break induction. Importantly, multiplex base edited T cells exhibit improved expansion and lack double strand break-induced translocations observed in T cells edited with Cas9 nuclease. Our findings highlight base editor as a powerful platform for genetic modification of therapeutically relevant primary cell types.

14.
Front Integr Neurosci ; 13: 56, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31632248

RESUMO

Background: Individuals with premutation alleles of the FMR1 gene are at risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative condition affecting sensorimotor function. Information on quantitative symptom traits associated with aging in premutation carriers is needed to clarify neurodegenerative processes contributing to FXTAS. Materials and Methods: 26 FMR1 premutation carriers ages 44-77 years and 31 age-matched healthy controls completed rapid (2 s) and sustained (8 s) visually guided precision gripping tasks. Individuals pressed at multiple force levels to determine the impact of increasing the difficulty of sensorimotor actions on precision behavior. During initial pressing, reaction time, the rate at which individuals increased their force, the duration of pressing, and force accuracy were measured. During sustained gripping, the complexity of the force time series, force variability, and mean force were examined. During relaxation, the rate at which individuals decreased their force was measured. We also examined the relationships between visuomotor behavior and cytosine-guanine-guanine (CGG) repeat length and clinically rated FXTAS symptoms. Results: Relative to controls, premutation carriers showed reduced rates of initial force generation during rapid motor actions and longer durations of their initial pressing with their dominant hand. During sustained force, premutation carriers demonstrated reduced force complexity, though this effect was specific to younger premutation carries during dominant hand pressing and was more severe for younger relative to older premutation carriers at low and medium force levels. Increased reaction time and lower sustained force complexity each were associated with greater CGG repeat length for premutation carriers. Increased reaction time and increased sustained force variability were associated with more severe clinically rated FXTAS symptoms. Conclusion: Overall our findings suggest multiple sensorimotor processes are disrupted in aging premutation carriers, including initial force control guided by feedforward mechanisms and sustained sensorimotor behaviors guided by sensory feedback control processes. Results indicating that sensorimotor issues in aging premutation carriers relate to both greater CGG repeat length and clinically rated FXTAS symptoms suggest that quantitative tests of precision sensorimotor ability may serve as key targets for monitoring FXTAS risk and progression.

15.
Br J Dermatol ; 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31621065
16.
J Asthma ; : 1-7, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31550948

RESUMO

Objective: To improve asthma morbidity and mortality in the UK, national asthma guidelines recommend referral to \ specialist care for the following high-risk groups, after a hospital admission for asthma, ≥3 courses of oral corticosteroids (OCS) in 12 months, an incident high-dose inhaled corticosteroid (ICS) prescription or addition of a fourth asthma drug to a patient's maintenance regimen. We sought to assess the prevalence and temporal change of referrals to identify unmet needs. Methods: We used UK electronic healthcare records, 2006-2017, to identify high-risk asthma patients managed within primary care. Referrals to respiratory clinics in secondary care were measured, within 3 months before or 6 months after, an incident ICS, third OCS in a year, or fourth asthma drug; or 12 months after a hospital admission for asthma. A nested case-control and conditional logistic regression was used to evaluate factors associated with receiving a referral. Results: A total of 246,116 asthma patients were eligible. There was a slight increase in secondary care referrals from 2014 onwards but the percentage remained low with <20% in each high-risk group referred for specialist care. The factors in the past year that were most strongly associated with receiving a referral were a hospital admission or A&E visit for asthma, ≥3 OCS courses, ≥2 add-on drugs, or high-dose ICS prescription. Conclusions: The majority of high-risk asthma patients were not referred for specialist care, as recommended by national guidelines. Compared to other risk factors, those admitted to hospital were most likely to receive a referral. Abbreviations A&E accident and emergency BTS British Thoracic Society CPRD Clinical Practice Research Datalink COPD chronic obstructive pulmonary disease GP general practice HES Hospital Episode Statistics ICS inhaled corticosteroids IMD Index of Multiple Deprivation ISAC Independent Scientific Advisory Committee LABA long-acting beta-agonist LAMA long-acting antimuscarinic LTRA leukotriene receptor antagonist NICE National Institute for Health and Care NRAD National Review of Asthma Deaths OCS oral corticosteroids SIGN Scottish Intercollegiate Guideline Network.

17.
Epidemiol Infect ; 147: e250, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31496448

RESUMO

Currently no national guidelines exist for the management of scabies outbreaks in residential or nursing care homes for the elderly in the United Kingdom. In this setting, diagnosis and treatment of scabies outbreaks is often delayed and optimal drug treatment, environmental control measures and even outcome measures are unclear. We undertook a systematic review to establish the efficacy of outbreak management interventions and determine evidence-based recommendations. Four electronic databases were searched for relevant studies, which were assessed using a quality assessment tool drawing on STROBE guidelines to describe the quality of observational data. Nineteen outbreak reports were identified, describing both drug treatment and environmental management measures. The quality of data was poor; none reported all outcome measures and only four described symptom relief measures. We were unable to make definitive evidence-based recommendations. We draw on the results to propose a framework for data collection in future observational studies of scabies outbreaks. While high-quality randomised controlled trials are needed to determine optimal drug treatment, evidence on environmental measures will need augmentation through other literature studies. The quality assessment tool designed is a useful resource for reporting of outcome measures including patient-reported measures in future outbreaks.

18.
J Occup Environ Med ; 61(10): 841-848, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31348415

RESUMO

OBJECTIVE: The aim of this study was to determine the efficacy of an occupationally tailored, web-based health and wellness program, The First Twenty® (TF20), for weight change among volunteer firefighters. METHODS: The impact of TF20 on firefighters' 6-month weight change was tested in a cluster, randomized controlled trial, using a crossover design of firefighters in 10 departments. TF20 has web-based nutrition, physical activity, and behavioral health components. RESULTS: An adjusted treatment-induced weight loss from 1.7 to 2.8 lb was observed for all participants and 2.3 to 3.1 lb among overweight and obese participants. An average weight gain was observed among firefighters in the control condition and weight loss for those in the treatment condition. CONCLUSIONS: TF20 supports firefighters' weight loss. Firefighters need wellness interventions to improve nutrition and physical activity given their high prevalence of obesity.

19.
Clin Epigenetics ; 11(1): 103, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31311581

RESUMO

BACKGROUND: Autism spectrum disorder (ASD) is a common and etiologically heterogeneous neurodevelopmental disorder. Although many genetic causes have been identified (> 200 ASD-risk genes), no single gene variant accounts for > 1% of all ASD cases. A role for epigenetic mechanisms in ASD etiology is supported by the fact that many ASD-risk genes function as epigenetic regulators and evidence that epigenetic dysregulation can interrupt normal brain development. Gene-specific DNAm profiles have been shown to assist in the interpretation of variants of unknown significance. Therefore, we investigated the epigenome in patients with ASD or two of the most common genomic variants conferring increased risk for ASD. Genome-wide DNA methylation (DNAm) was assessed using the Illumina Infinium HumanMethylation450 and MethylationEPIC arrays in blood from individuals with ASD of heterogeneous, undefined etiology (n = 52), and individuals with 16p11.2 deletions (16p11.2del, n = 9) or pathogenic variants in the chromatin modifier CHD8 (CHD8+/-, n = 7). RESULTS: DNAm patterns did not clearly distinguish heterogeneous ASD cases from controls. However, the homogeneous genetically-defined 16p11.2del and CHD8+/- subgroups each exhibited unique DNAm signatures that distinguished 16p11.2del or CHD8+/- individuals from each other and from heterogeneous ASD and control groups with high sensitivity and specificity. These signatures also classified additional 16p11.2del (n = 9) and CHD8 (n = 13) variants as pathogenic or benign. Our findings that DNAm alterations in each signature target unique genes in relevant biological pathways including neural development support their functional relevance. Furthermore, genes identified in our CHD8+/- DNAm signature in blood overlapped differentially expressed genes in CHD8+/- human-induced pluripotent cell-derived neurons and cerebral organoids from independent studies. CONCLUSIONS: DNAm signatures can provide clinical utility complementary to next-generation sequencing in the interpretation of variants of unknown significance. Our study constitutes a novel approach for ASD risk-associated molecular classification that elucidates the vital cross-talk between genetics and epigenetics in the etiology of ASD.

20.
Womens Health Issues ; 29(5): 432-439, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31229361

RESUMO

OBJECTIVES: Firefighters play a crucial role in protecting the lives and property of the communities they serve. Health and readiness for duty among women firefighters is of great concern because they are a significantly understudied group in this critical occupation. A tobacco-free fire service has been strongly promoted, but there are no published data on the extent and types of tobacco use among women firefighters. METHODS: Data were collected as part of a national online study of the health of women in the fire service. RESULTS: A total of 1,712 women firefighters completed questions regarding tobacco use. Unadjusted smoking and smokeless tobacco rates were 5.1% and 1.2%, respectively. Age standardized smoking rates were lower than those of male firefighters and U.S. adult women. Smokeless tobacco use prevalence was very low compared with male firefighters, but comparable with U.S. adult women. Tobacco users were more likely to have lower education and income and were younger when compared with those who did not use tobacco. There was a strong association between tobacco use and problem and binge drinking. CONCLUSIONS: Current findings suggest that the rates of cigarette and smokeless tobacco use are relatively low among women firefighters. Unhealthy lifestyle behaviors such as problem and binge drinking were strongly associated with tobacco use.

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