80 research outputs found
Are ‘cultures of worklessness' passed down the generations?
This report critically investigates the idea of ‘intergenerational cultures of worklessness ’ and that there may be families where ‘three generations have never worked’. Although there is relatively little solid research evidence to support them, these ideas are said to help explain worklessness in the UK and continue to inform recent and current government policy agendas. Our study used qualitative research methods, with families in Middlesbrough and Glasgow. The report: • explores the existence of permanent worklessness across generations within families; • concludes that even two generations of extensive or permanent worklessness in the same family is a rare phenomenon; • examines whether families experiencing long-term worklessness can be described as having a ‘culture of worklessness’; • shows how the impact of complex and multiple problems, rooted in long-term experiences of deep poverty, can distance people from the labour market; and • argues that policy makers should abandon theories – and policies that flow from them – that see worklessness as primarily the outcome of a ‘culture of worklessness’, held in families and passed down the generations
Assessment of Type I Interferon Signaling in Pediatric Inflammatory Disease
International audiencePURPOSE: Increased type I interferon is considered relevant to the pathology of a number of monogenic and complex disorders spanning pediatric rheumatology, neurology, and dermatology. However, no test exists in routine clinical practice to identify enhanced interferon signaling, thus limiting the ability to diagnose and monitor treatment of these diseases. Here, we set out to investigate the use of an assay measuring the expression of a panel of interferon-stimulated genes (ISGs) in children affected by a range of inflammatory diseases. DESIGN, SETTING, AND PARTICIPANTS: A cohort study was conducted between 2011 and 2016 at the University of Manchester, UK, and the Institut Imagine, Paris, France. RNA PAXgene blood samples and clinical data were collected from controls and symptomatic patients with a genetically confirmed or clinically well-defined inflammatory phenotype. The expression of six ISGs was measured by quantitative polymerase chain reaction, and the median fold change was used to calculate an interferon score (IS) for each subject compared to a previously derived panel of 29 controls (where +2 SD of the control data, an IS of \textgreater2.466, is considered as abnormal). Results were correlated with genetic and clinical data. RESULTS: Nine hundred ninety-two samples were analyzed from 630 individuals comprising symptomatic patients across 24 inflammatory genotypes/phenotypes, unaffected heterozygous carriers, and controls. A consistent upregulation of ISG expression was seen in 13 monogenic conditions (455 samples, 265 patients; median IS 10.73, interquartile range (IQR) 5.90-18.41), juvenile systemic lupus erythematosus (78 samples, 55 patients; median IS 10.60, IQR 3.99-17.27), and juvenile dermatomyositis (101 samples, 59 patients; median IS 9.02, IQR 2.51-21.73) compared to controls (78 samples, 65 subjects; median IS 0.688, IQR 0.427-1.196), heterozygous mutation carriers (89 samples, 76 subjects; median IS 0.862, IQR 0.493-1.942), and individuals with non-molecularly defined autoinflammation (89 samples, 69 patients; median IS 1.07, IQR 0.491-3.74). CONCLUSIONS AND RELEVANCE: An assessment of six ISGs can be used to define a spectrum of inflammatory diseases related to enhanced type I interferon signaling. If future studies demonstrate that the IS is a reactive biomarker, this measure may prove useful both in the diagnosis and the assessment of treatment efficacy
Reduced cytochrome P4501A activity and recovery from oxidative stress during subchronic benzo[a]pyrene and benzo[e]pyrene treatment of rainbow trout
Author Posting. © The Author(s), 2011. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Toxicology and Applied Pharmacology 254 (2011): 1-7, doi:10.1016/j.taap.2011.04.015.This
study
assessed
the
role
of
aryl
hydrocarbon
receptor
(AHR)
affinity,
and
cytochrome
P4501A
(CYP1A)
protein
and
activity
in
polyaromatic
hydrocarbon
(PAH)-‐induced
oxidative
stress.
In
the
1-‐100
nM
concentration
range
benzo[a]pyrene
(BaP)
but
not
benzo[e]pyrene
(BeP)
competitively
displaced
2
nM
[3H]2,
3,
7,
8-‐tetrachloro-‐dibenzo-‐p-‐dioxin
from
rainbow
trout
AHR2α.
Based
on
appearance
of
fluorescent
aromatic
compounds
in
bile
over
3,
7,
14,
28
or
50
days
of
feeding
3
μg
of
BaP
or
BeP/g
fish/day,
rainbow
trout
liver
readily
excreted
these
polyaromatic
hydrocarbons
(PAHs)
and
their
metabolites
at
near
steady
state
rates.
CYP1A
proteins
catalyzed
more
than
98%
of
ethoxyresorufin-‐O-‐deethylase
(EROD)
activity
in
rainbow
trout
hepatic
microsomes.
EROD
activity
of
hepatic
microsomes
initially
increased
and
then
decreased
to
control
activities
after
50
days
of
feeding
both
PAHs.
Immunohistochemistry
of
liver
confirmed
CYP1A
protein
increased
in
fish
fed
both
PAHs
after
3
days
and
remained
elevated
for
up
to
28
days.
Neither
BaP
nor
BeP
increased
hepatic
DNA
adduct
concentrations
at
any
time
up
to
50
days
of
feeding
these
PAHs.
Comet
assays
of
blood
cells
demonstrated
marked
DNA
damage
after
14
days
of
feeding
both
PAHs
that
was
not
significant
after
50
days.
There
was
a
strong
positive
correlation
between
hepatic
EROD
activity
and
DNA
damage
in
blood
cells
over
time
for
both
PAHs.
Neither
CYP1A
protein
nor
3-‐
nitrotyrosine
(a
biomarker
for
oxidative
stress)
immunostaining
in
trunk
kidney
were
significantly
altered
by
BaP
or
BeP
after
3,
7,
14,
or
28
days.
There
was
no
clear
association
between
AHR2α
affinity
and
BaP
and
BeP-‐induced
oxidative
stress.The
Oregon
Agricultural
Experiment
Station,
Northwest
Fisheries
Science
Center,
and
RO1ES006272
from
the
National
Institute
of
Health
supported
this
work
Spondyloenchondrodysplasia Due to Mutations in ACP5: A Comprehensive Survey
Purpose: Spondyloenchondrodysplasia is a rare immuno-osseous dysplasia caused by biallelic mutations in ACP5. We aimed to provide a survey of the skeletal, neurological and immune manifestations of this disease in a cohort of molecularly confirmed cases. Methods: We compiled clinical, genetic and serological data from a total of 26 patients from 18 pedigrees, all with biallelic ACP5 mutations. Results: We observed a variability in skeletal, neurological and immune phenotypes, which was sometimes marked even between affected siblings. In total, 22 of 26 patients manifested autoimmune disease, most frequently autoimmune thrombocytopenia and systemic lupus erythematosus. Four patients were considered to demonstrate no clinical autoimmune disease, although two were positive for autoantibodies. In the majority of patients tested we detected upregulated expression of interferon-stimulated genes (ISGs), in keeping with the autoimmune phenotype and the likely immune-regulatory function of the deficient protein tartrate resistant acid phosphatase (TRAP). Two mutation positive patients did not demonstrate an upregulation of ISGs, including one patient with significant autoimmune disease controlled by immunosuppressive therapy. Conclusions: Our data expand the known phenotype of SPENCD. We propose that the OMIM differentiation between spondyloenchondrodysplasia and spondyloenchondrodysplasia with immune dysregulation is no longer appropriate, since the molecular evidence that we provide suggests that these phenotypes represent a continuum of the same disorder. In addition, the absence of an interferon signature following immunomodulatory treatments in a patient with significant autoimmune disease may indicate a therapeutic response important for the immune manifestations of spondyloenchondrodysplasia
Barriers to identifying eating disorders in pregnancy and in the postnatal period: a qualitative approach.
BACKGROUND: Eating Disorders (ED) are mental health disorders that typically effect women of childbearing age and are associated with adverse maternal and infant outcomes. UK healthcare guidance recommends routine enquiry for current and past mental illness in antenatal and postnatal care for all women, and that pregnant women with a known ED are offered enhanced monitoring and support. Midwives and health visitors are ideally placed to identify and support women with ED as they are often the primary point of contact during the antenatal and postnatal periods. However, research on the barriers to identifying ED in the perinatal period is limited. This study aimed to understand the barriers to disclosure and identification of ED in pregnancy and postnatally as perceived by women with past or current ED, and midwives and health visitors working in the UK National Health Service. METHODS: Two studies were undertaken: mixed-measures survey of pregnant and postnatal women with current or past ED; focus groups with student and qualified midwives and health visitors. RESULTS: Five themes emerged on the barriers to disclosure in pregnancy as perceived by women: stigma, lack of opportunity, preference for self-management, current ED symptomatology and illness awareness. Four themes were identified on the barriers to identification of ED in pregnancy and in the postnatal period as perceived by health professionals: system constraints, recognition of role, personal attitudes, and stigma and taboo. CONCLUSIONS: Several barriers to the identification of ED during and after pregnancy were described, the main factors were stigma and poor professional training. Perinatal mental health is becoming increasingly prioritised within national policy initiatives; however, ED continue to be neglected and increased awareness is needed. Similarly, clinical guidance aimed at responding to the rising prevalence of obesity focus on changing nutrition but not on assessing for the presence of ED behaviours that might be affecting nutrition. Improving education and training for health professionals may contribute to reducing stigma and increase confidence in identifying ED. The barriers identified in this research need to be addressed if recognition and response to women with ED during the perinatal period is to improve
Genetic, Phenotypic, and Interferon Biomarker Status in ADAR1-Related Neurological Disease
International audienceWe investigated the genetic, phenotypic, and interferon status of 46 patients from 37 families with neurological disease due to mutations in ADAR1. The clinicoradiological phenotype encompassed a spectrum of Aicardi–Goutières syndrome, isolated bilateral striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive spastic dystonic motor disorder, and adult-onset psychological difficulties with intracranial calcification. Homozygous missense mutations were recorded in five families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of 23 families with compound heterozygous mutations. We also ascertained 11 cases from nine families with a p.Gly1007Arg dominant-negative mutation, which occurred de novo in four patients, and was inherited in three families in association with marked phenotypic variability. In 50 of 52 samples from 34 patients, we identified a marked upregulation of type I interferon-stimulated gene transcripts in peripheral blood, with a median interferon score of 16.99 (interquartile range [IQR]: 10.64–25.71) compared with controls (median: 0.93, IQR: 0.57–1.30). Thus, mutations in ADAR1 are associated with a variety of clinically distinct neurological phenotypes presenting from early infancy to adulthood, inherited either as an autosomal recessive or dominant trait. Testing for an interferon signature in blood represents a useful biomarker in this context
Genetic and phenotypic spectrum associated with IFIH1 gain-of-function
IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi–Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate
GABAA receptor subtype involvement in addictive behaviour
GABAA receptors form the major class of inhibitory neurotransmitter receptors in the mammalian brain. This review sets out to summarise the evidence that variations in genes encoding GABAA receptor isoforms are associated with aspects of addictive behaviour in humans, while animal models of addictive behaviour also implicate certain subtypes of GABAA receptor. In addition to outlining the evidence for the involvement of specific subtypes in addiction, we summarise the particular contributions of these isoforms in control over the functioning of brain circuits, especially the mesolimbic system, and make a first attempt to bring together evidence from several fields to understanding potential involvement of GABAA Receptor Subtypes in addictive behaviour. While the weight of the published literature is on alcohol dependency, the underlying principles outlined are relevant across a number of different aspects of addictive behaviour
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