12 research outputs found
Heterozygous deletion of FOXA2 segregates with disease in a family with heterotaxy, panhypopituitarism, and biliary atresia
No full textBiliary atresia (BA) is a pediatric cholangiopathy with unknown etiology occurring in isolated and syndromic forms. Laterality defects affecting the cardiovascular and gastrointestinal systems are the most common features present in syndromic BA. Most cases are sporadic, although reports of familial cases have led to the hypothesis of genetic susceptibility in some patients. We identified a child with BA, malrotation, and interrupted inferior vena cava whose father presented with situs inversus, polysplenia, panhypopituitarism, and mildly dysmorphic facial features. Chromosomal microarray analysis demonstrated a 277 kb heterozygous deletion on chromosome 20, which included a single gene, FOXA2, in the proband and her father. This deletion was confirmed to be de novo in the father. The proband and her father share a common diagnosis of heterotaxy, but they also each presented with a variety of other issues. Further genetic screening revealed that the proband carried an additional protein-altering polymorphism (rs1904589; p.His165Arg) in the NODAL gene that is not present in the father, and this variant has been shown to decrease expression of the gene. As FOXA2 can be a regulator of NODAL expression, we propose that haploinsufficiency for FOXA2 combined with a decreased expression of NODAL is the likely cause for syndromic BA in this proband
Compound heterozygous mutations in NEK8 in siblings with end-stage renal disease with hepatic and cardiac anomalies
No full textWe studied two brothers who presented in the newborn period with cardiac, renal, and hepatic anomalies that were initially suggestive of ALGS, although no mutations in JAG1 or NOTCH2 were identified. Exome sequencing demonstrated compound heterozygous mutations intheNEK8gene (Never in mitosis A-related Kinase 8), a ciliary kinase indispensable for cardiac and renal development based on murine studies. The mutations included a c.2069_2070insC variant (p.Ter693LeufsTer86), and a c.1043C>T variant (p.Thr348Met) in the highly conserved RCC1 (Regulation of Chromosome Condensation 1) domain. The RCC1 domain is crucial for localization of the NEK8 protein to the centrosomes and cilia. Mutations in NEK8 have been previously reported in three fetuses (from a single family) with renal-hepatic-pancreatic dysplasia 2 (RHPD2), similar to Ivemark syndrome, and in three individuals with nephronophthisis (NPHP9). This is the third report of disease-causing mutations in the NEK8 gene in humans and only the second describing multi-organ involvement. The clinical features we describe differ from those in the previously published report in that (1) a pancreatic phenotype was not observed in the individuals reported here, (2) there were more prominent cardiac findings, (consistent with observations in murine models), and (3) we observed bile duct hypoplasia rather than ductal plate malformation.The patients reported here expand our understanding of the NEK8-associated phenotype. Our findings highlight the variable phenotypic expressivity and the spectrum of clinical manifestations due to mutations in the NEK8 gen
The virtual image : Brazilian literature in English translation
No full textThe
aim of this thesis is to
examine
how the virtual
image
of Brazil
and
its literature is
constructed
in the Anglo-American world. To this
end, a survey of
Brazilian literary
works
in English translation was
carried out.
Having
gathered this data, it became
possible to establish
correlations
between the historical
moments when such translations
were made, when their number
increased,
and the events occurring at
those times in the international
panorama, as well as to look into the
role of sponsors, publishers and translators in the
selection and
production of such translations.
The data
also allowed a profile of
Brazilian literary
works
in
English translation to be drawn. It became
possible to suggest that
such works
fall into four
main categories:
`authorial
works',
'topical
works',
`ambassadorial
works'
and `consumer-oriented
works'.
In
order
to look
more closely
into how the translation process
has helped to
shape
the
virtual
image
of Brazilian literary
works
in
the Anglo-American world, an analysis of a sample of
translations
of
such works was made. Included in this
sample were
the translations
of works
by Machado de Asis, by Indianist
and
Regionalist
wirters,
culminating
in
an examination of translations of
GuimarAes Rosa's
works.
Having looked
at these aspects of
the translation
process, what
remained
to be done
was to investigate
to what extent
Brazilian
literary
works
in English translation
are read
by the English-
speaking public.
To this
end, a survey of availability and
library
readership was undertaken. Finally,
a reading experiment was carried
out
in
which native speakers of
English
were asked to read the short
story
'A terceira
margem
do
rio',
by GuimarAes Rosa.
The
conclusion attempts to pull all these threads together and
to indicate directions for further
research
Honey as an antiviral agent against respiratory syncytial virus
No full textRespiratory syncytial virus is the most frequent cause of hospitalization for viral respiratory infections in infants and young children worldwide. It also severely affects immunocompromised adults and the elderly, however, despite decades of efforts, there is no proven effective treatment for RSV infection and attempts at vaccine development have been hampered by several major obstacles. A large amount of research has established the potent antibacterial activity of honey, but its activity against viral species has been the subject of only a small number of studies. These were with viruses which cause localised infections in which honey could be used topically. Recent studies demonstrating the safety of intrapulmonary administration of honey in sheep and humans raised the possibility of using honey to treat respiratory infections. The aim of this study, therefore, was to extend the knowledge obtained from previous studies of honey’s antiviral activity to its action against RSV. A variety of tests using cell culture were developed to evaluate the susceptibility of RSV to honey. Each test monitored and scored the development of morphological changes to the cells caused by RSV infection to determine whether the honey had any inhibitory effect on these changes. These included tests for: inhibition, where honey was used to treat infected cells; protection, in which the cells were treated with honey prior to infection; neutralisation, in which the virus was directly exposed to the honey for a defined period before being used to inoculate the cells. Pre-treatment of the cells had no effect on the consequent development of cytopathic effect, while the inhibition and neutralisation experiments showed a significant inhibitory effect on the progression of infection, suggesting a direct effect on the virus rather than on the cells, however, further studies are required to confirm this. A wide range of honey types were tested for their inhibitory and neutralising capabilities against RSV and the results suggested that the antiviral activity may be characteristic of more than one type of honey. The activity observed did vary, however, with some types of honey causing greater inhibition of RSV than others. Enzyme-linked immunosorbent assays were also used to quantitatively measure the number of viral antigens in honey-treated and untreated cells. The results confirmed that treatment with honey had caused inhibition of viral replication, there being very little virus detected in honey-treated cells compared with untreated cells infected with RSV. Experiments using quantitative PCR also demonstrated the inhibitory effect of honey on RSV at the transcription level, with significant differences in the mRNA copy numbers of two out of the three viral genes examined. Attempts at isolating the antiviral component in honey demonstrated that the sugar was not responsible for the inhibition of RSV, but that methylglyoxal may play a part in the greater potency of Manuka honeys against RSV. It is concluded from the findings in this study that honey may possibly be an effective antiviral treatment for the therapy of respiratory viral infections, and provides justification for future in vitro studies and clinical trials
Discordant clinical phenotype in monozygotic twins with Alagille syndrome: Possible influence of non‐genetic factors
No full textThe impact of illness and the impact of school closure on social contact patterns.
No full textBACKGROUND: Mathematical models, based on data describing normal patterns of social mixing, are used to understand epidemics in order to predict patterns of disease spread and plan interventions and responses. However, individuals who are ill show behavioural changes that affect their social mixing patterns and predictive models should take into account these changes if they are to be effective. OBJECTIVES: To describe and quantify the changes in (1) social contact behaviour experienced by individuals when they are ill with pandemic H1N1 influenza (swine flu) and (2) mixing patterns of school children that take place as a result of swine flu-related school closures. METHODS: For the first part of the study, a self-completed questionnaire-based study was carried out in the autumn/winter of 2009-10. The study population was individuals who had been diagnosed with swine flu and who received a swine flu antiviral prescription from an antiviral distribution centre (ADC). It consisted of an initial survey to be filled in when participants were symptomatic with swine flu and a follow-up survey to be filled in when they had recovered. Each part of the questionnaire had two sections: patient details and a contact diary. The second part of the study was adapted to quantify the difference in mixing patterns of pupils between the school term and the half-term holiday as school closures did not occur during the study period. Eight schools participated and questionnaire packs were distributed to them, containing two surveys: one to be filled in during the school term and one during the spring half-term holiday. RESULTS: For the patient study, approximately 3800 surveys were distributed by 31 ADCs. Overall, 317 responses to the initial survey were received and 179 participants returned the follow-up survey. For all types of a contact, except contacts made at home, there were highly significant differences in contact behaviour (Wilcoxon signed-rank test, p < 0.001). Individuals made substantially fewer contacts when they were ill than when they were well. Analysis showed that returning to work was the most significant predictor of increased numbers of contacts. Also, the greater the change in the number of symptoms reported, the greater the change in the number of contacts. For the school study, approximately 1100 questionnaire packs were distributed and 134 responses were received, with 119 paired contact diaries. Pupils reported on average 18.51 contacts each day during term time and 9.24 during the half-term holiday - a reduction of over 50% and a highly significant change (Wilcoxon signed-rank test, p < 0.0001). CONCLUSIONS: The evidence from this study suggests that ill individuals make substantial changes to their social contact patterns. These changes are strongly linked to absence from work and the severity of the reported illness. Epidemiological modellers should therefore consider the implications of illness-related behavioural changes on model predictions. Future studies to measure the extent of behavioural change in a broader cross-section of infected cases could be valuable, along with more detailed studies of the social contact patterns of school children, focusing on differences between school terms and school holidays
Global patterns in monthly activity of influenza virus, respiratory syncytial virus, parainfluenza virus, and metapneumovirus: a systematic analysis
No full textBackground Influenza virus, respiratory syncytial virus, parainfluenza virus, and metapneumovirus are the most common viruses associated with acute lower respiratory infections in young children (= 65 years). A global report of the monthly activity of these viruses is needed to inform public health strategies and programmes for their control.Methods In this systematic analysis, we compiled data from a systematic literature review of studies published between Jan 1, 2000, and Dec 31, 2017; online datasets; and unpublished research data. Studies were eligible for inclusion if they reported laboratory-confirmed incidence data of human infection of influenza virus, respiratory syncytial virus, parainfluenza virus, or metapneumovirus, or a combination of these, for at least 12 consecutive months (or 52 weeks equivalent); stable testing practice throughout all years reported; virus results among residents in well-defined geographical locations; and aggregated virus results at least on a monthly basis. Data were extracted through a three-stage process, from which we calculated monthly annual average percentage (AAP) as the relative strength of virus activity. We defined duration of epidemics as the minimum number of months to account for 75% of annual positive samples, with each component month defined as an epidemic month. Furthermore, we modelled monthly AAP of influenza virus and respiratory syncytial virus using site-specific temperature and relative humidity for the prediction of local average epidemic months. We also predicted global epidemic months of influenza virus and respiratory syncytial virus on a 5 degrees by 5 degrees grid. The systematic review in this study is registered with PROSPERO, number CRD42018091628.Findings We initally identified 37 335 eligible studies. Of 21 065 studies remaining after exclusion of duplicates, 1081 full-text articles were assessed for eligibility, of which 185 were identified as eligible. We included 246 sites for influenza virus, 183 sites for respiratory syncytial virus, 83 sites for parainfluenza virus, and 65 sites for metapneumovirus. Influenza virus had clear seasonal epidemics in winter months in most temperate sites but timing of epidemics was more variable and less seasonal with decreasing distance from the equator. Unlike influenza virus, respiratory syncytial virus had clear seasonal epidemics in both temperate and tropical regions, starting in late summer months in the tropics of each hemisphere, reaching most temperate sites in winter months. In most temperate sites, influenza virus epidemics occurred later than respiratory syncytial virus (by 0.3 months [95% CI -0.3 to 0.9]) while no clear temporal order was observed in the tropics. Parainfluenza virus epidemics were found mostly in spring and early summer months in each hemisphere. Metapneumovirus epidemics occurred in late winter and spring in most temperate sites but the timing of epidemics was more diverse in the tropics. Influenza virus epidemics had shorter duration (3.8 months [3.6 to 4.0]) in temperate sites and longer duration (5.2 months [4.9 to 5.5]) in the tropics. Duration of epidemics was similar across all sites for respiratory syncytial virus (4.6 months [4.3 to 4.8]), as it was for metapneumovirus (4.8 months [4.4 to 5.1]). By comparison, parainfluenza virus had longer duration of epidemics (6.3 months [6.0 to 6.7]). Our model had good predictability in the average epidemic months of influenza virus in temperate regions and respiratory syncytial virus in both temperate and tropical regions. Through leave-one-out cross validation, the overall prediction error in the onset of epidemics was within 1 month (influenza virus -0.2 months [-0.6 to 0.1]; respiratory syncytial virus 0.1 months [-0.2 to 0.4]).Interpretation This study is the first to provide global representations of month-by-month activity of influenza virus, respiratory syncytial virus, parainfluenza virus, and metapneumovirus. Our model is helpful in predicting the local onset month of influenza virus and respiratory syncytial virus epidemics. The seasonality information has important implications for health services planning, the timing of respiratory syncytial virus passive prophylaxis, and the strategy of influenza virus and future respiratory syncytial virus vaccination. Copyright (C) 2019 The Author(s). Published by Elsevier Ltd
Global patterns in monthly activity of influenza virus, respiratory syncytial virus, parainfluenza virus, and metapneumovirus: a systematic analysis
No full textAbstract: Background Influenza virus, respiratory syncytial virus, parainfluenza virus, and metapneumovirus are the most common viruses associated with acute lower respiratory infections in young children (= 65 years). A global report of the monthly activity of these viruses is needed to inform public health strategies and programmes for their control. Methods In this systematic analysis, we compiled data from a systematic literature review of studies published between Jan 1, 2000, and Dec 31, 2017; online datasets; and unpublished research data. Studies were eligible for inclusion if they reported laboratory-confirmed incidence data of human infection of influenza virus, respiratory syncytial virus, parainfluenza virus, or metapneumovirus, or a combination of these, for at least 12 consecutive months (or 52 weeks equivalent); stable testing practice throughout all years reported; virus results among residents in well-defined geographical locations; and aggregated virus results at least on a monthly basis. Data were extracted through a three-stage process, from which we calculated monthly annual average percentage (AAP) as the relative strength of virus activity. We defined duration of epidemics as the minimum number of months to account for 75% of annual positive samples, with each component month defined as an epidemic month. Furthermore, we modelled monthly AAP of influenza virus and respiratory syncytial virus using site-specific temperature and relative humidity for the prediction of local average epidemic months. We also predicted global epidemic months of influenza virus and respiratory syncytial virus on a 5 degrees by 5 degrees grid. The systematic review in this study is registered with PROSPERO, number CRD42018091628. Findings We initally identified 37 335 eligible studies. Of 21 065 studies remaining after exclusion of duplicates, 1081 full-text articles were assessed for eligibility, of which 185 were identified as eligible. We included 246 sites for influenza virus, 183 sites for respiratory syncytial virus, 83 sites for parainfluenza virus, and 65 sites for metapneumovirus. Influenza virus had clear seasonal epidemics in winter months in most temperate sites but timing of epidemics was more variable and less seasonal with decreasing distance from the equator. Unlike influenza virus, respiratory syncytial virus had clear seasonal epidemics in both temperate and tropical regions, starting in late summer months in the tropics of each hemisphere, reaching most temperate sites in winter months. In most temperate sites, influenza virus epidemics occurred later than respiratory syncytial virus (by 0.3 months [95% CI -0.3 to 0.9]) while no clear temporal order was observed in the tropics. Parainfluenza virus epidemics were found mostly in spring and early summer months in each hemisphere. Metapneumovirus epidemics occurred in late winter and spring in most temperate sites but the timing of epidemics was more diverse in the tropics. Influenza virus epidemics had shorter duration (3.8 months [3.6 to 4.0]) in temperate sites and longer duration (5.2 months [4.9 to 5.5]) in the tropics. Duration of epidemics was similar across all sites for respiratory syncytial virus (4.6 months [4.3 to 4.8]), as it was for metapneumovirus (4.8 months [4.4 to 5.1]). By comparison, parainfluenza virus had longer duration of epidemics (6.3 months [6.0 to 6.7]). Our model had good predictability in the average epidemic months of influenza virus in temperate regions and respiratory syncytial virus in both temperate and tropical regions. Through leave-one-out cross validation, the overall prediction error in the onset of epidemics was within 1 month (influenza virus -0.2 months [-0.6 to 0.1]; respiratory syncytial virus 0.1 months [-0.2 to 0.4]). Interpretation This study is the first to provide global representations of month-by-month activity of influenza virus, respiratory syncytial virus, parainfluenza virus, and metapneumovirus. Our model is helpful in predicting the local onset month of influenza virus and respiratory syncytial virus epidemics. The seasonality information has important implications for health services planning, the timing of respiratory syncytial virus passive prophylaxis, and the strategy of influenza virus and future respiratory syncytial virus vaccination. Copyright (C) 2019 The Author(s). Published by Elsevier Ltd
