205 research outputs found
Risk factors for admission and the role of respiratory syncytial virus-specific cytotoxic T-lymphocyte responses in children with acute bronchiolitis
Background. Risk factors for admission of children with acute bronchiolitis have remained controversial. Technological advances in the measurements of cytotoxic T-lymphocyte (CTL) activity, enable respiratory syncytial virus (RSV)-specific CTL activity to be studied in infants with bronchiolitis for the first time. We evaluated risk factors for admission of children with acute bronchiolitis and determined the role of CTL responses in those infected with RSV.Method. Children between 3 and 24 months of age presenting with bronchiolitis to the paediatric outpatient department at King Edward VIII Hospital, Durban, over a 1-year period were enrolled. Management included clinical evaluation, nasopharyngeal aspiration, standard treatment and hospitalisation if indicated. Secretions were tested with monoclonal antibodies for RSV and pooled respiratory viruses; shell vial cultures were also established. Permission was requested from parents of RSV-infected subjects for blood draws for specific cytotoxic T-cell assays and CD4/CD8 cells on admission and repeat CTL on day 7.Results. Viruses were identified in 55 of the 114 subjects studied (48.2%). RSV was seen in 41 cases (74.5%). Twenty three infants (20.2%) required admission. Risk factors associated with inpatient admissions on univariate analysis included younger mean age (7.6 months v. 10.1 months), overcrowding (p < 0.01) and indoor exposure to products of combustion of cooking fuels (p = 0.05). Only the former two were significant on multivariate analysis. RSV-specific CTL responses were obtained in 21 children (51.2%). Responses were either very weak (N = 7) or negative (N = 14) on day 0 and did not alter significantly on day 7. The mean CD4/CD8 ratios in this group were 2.27:1. The highest frequency of CTL was directed against the proteins 'M4/5/6', with counts ranging from 100 to 400 spot forming cells (sfc)/million.Conclusion. Measures to address risk factors identified in this study may decrease the need for hospitalisation from bronchiolitis. The lack of RSV-specific CTL responses in peripheral blood of immunocompetent RSV-infected children suggest an alternative method of induction of immunity or compartmentalisation of immune cells
Death effector domain-containing protein induces vulnerability to cell cycle inhibition in triple-negative breast cancer
Lacking targetable molecular drivers, triple-negative breast cancer (TNBC) is the most clinically challenging subtype of breast cancer. In this study, we reveal that Death Effector Domain-containing DNA-binding protein (DEDD), which is overexpressed in > 60% of TNBCs, drives a mitogen-independent G1/S cell cycle transition through cytoplasm localization. The gain of cytosolic DEDD enhances cyclin D1 expression by interacting with heat shock 71 kDa protein 8 (HSC70). Concurrently, DEDD interacts with Rb family proteins and promotes their proteasome-mediated degradation. DEDD overexpression renders TNBCs vulnerable to cell cycle inhibition. Patients with TNBC have been excluded from CDK 4/6 inhibitor clinical trials due to the perceived high frequency of Rb-loss in TNBCs. Interestingly, our study demonstrated that, irrespective of Rb status, TNBCs with DEDD overexpression exhibit a DEDD-dependent vulnerability to combinatorial treatment with CDK4/6 inhibitor and EGFR inhibitor in vitro and in vivo. Thus, our study provided a rationale for the clinical application of CDK4/6 inhibitor combinatorial regimens for patients with TNBC
GAD1 Upregulation Programs Aggressive Features of Cancer Cell Metabolism in the Brain Metastatic Microenvironment
The impact of altered amino acid metabolism on cancer progression is not fully understood. We hypothesized that a metabolic transcriptome shift during metastatic evolution is crucial for brain metastasis. Here, we report a powerful impact in this setting caused by epigenetic upregulation of glutamate decarboxylase 1 (GAD1), a regulator of the GABA neurotransmitter metabolic pathway. In cell-based culture and brain metastasis models, we found that downregulation of the DNA methyltransferase DNMT1 induced by the brain microenvironment-derived clusterin resulted in decreased GAD1 promoter methylation and subsequent upregulation of GAD1 expression in brain metastatic tumor cells. In a system to dynamically visualize cellular metabolic responses mediated by GAD1, we monitored the cytosolic NADH:NAD+ equilibrium in tumor cells. Reducing GAD1 in metastatic cells by primary glia cell coculture abolished the capacity of metastatic cells to utilize extracellular glutamine, leading to cytosolic accumulation of NADH and increased oxidative status. Similarly, genetic or pharmacologic disruption of the GABA metabolic pathway decreased the incidence of brain metastasis in vivo Taken together, our results show how epigenetic changes in GAD1 expression alter local glutamate metabolism in the brain metastatic microenvironment, contributing to a metabolic adaption that facilitates metastasis outgrowth in that setting
Risk factors for admission and the role of respiratory syncytial virus-specific cytotoxic T-lymphocyte responses in children with acute bronchiolitis
Electron and hole states in quantum-dot quantum wells within a spherical 8-band model
In order to study heterostructures composed both of materials with strongly
different parameters and of materials with narrow band gaps, we have developed
an approach, which combines the spherical 8-band effective-mass Hamiltonian and
the Burt's envelope function representation. Using this method, electron and
hole states are calculated in CdS/HgS/CdS/H_2O and CdTe/HgTe/CdTe/H_2O
quantum-dot quantum-well heterostructures. Radial components of the wave
functions of the lowest S and P electron and hole states in typical quantum-dot
quantum wells (QDQWs) are presented as a function of radius. The 6-band-hole
components of the radial wave functions of an electron in the 8-band model have
amplitudes comparable with the amplitude of the corresponding 2-band-electron
component. This is a consequence of the coupling between the conduction and
valence bands, which gives a strong nonparabolicity of the conduction band. At
the same time, the 2-band-electron component of the radial wave functions of a
hole in the 8-band model is small compared with the amplitudes of the
corresponding 6-band-hole components. It is shown that in the CdS/HgS/CdS/H_2O
QDQW holes in the lowest states are strongly localized in the well region
(HgS). On the contrary, electrons in this QDQW and both electron and holes in
the CdTe/HgTe/CdTe/H_2O QDQW are distributed through the entire dot. The
importance of the developed theory for QDQWs is proven by the fact that in
contrast to our rigorous 8-band model, there appear spurious states within the
commonly used symmetrized 8-band model.Comment: 15 pages, 5 figures, E-mail addresses: [email protected],
[email protected]
Rationales, design and recruitment for the Elfe longitudinal study
Background
Many factors act simultaneously in childhood to influence health status, life chances and well being, including pre-birth influences, the environmental pollutants of early life, health status but also the social influences of family and school. A cohort study is needed to disentangle these influences and explore attribution.
Methods
Elfe will be a nationally representative cohort of 20 000 children followed from birth to adulthood using a multidisciplinary approach. The cohort will be based on the INSEE Permanent Demographic Panel (EDP) established using census data and civil records. The sample size has been defined in order to match the representativeness criteria and to obtain some prevalence estimation, but also to address the research area of low exposure/rare effects. The cohort will be based on repeated surveys by face to face or phone interview (at birth and each year) as well as medical interview (at 2 years) and examination (at 6 years). Furthermore, biological samples will be taken at birth to evaluate the foetal exposition to toxic substances, environmental sensors will be placed in the child's homes. Pilot studies have been initiated in 2007 (500 children) with an overall acceptance rate of 55% and are currently under progress, the 2-year survey being carried out in October this year.
Discussion
The longitudinal study will provide a unique source of data to analyse the development of children in their environment, to study the various factors interacting throughout the life course up to adulthood and to determine the impact of childhood experience on the individual's physical, psychological, social and professional development
Diurnal Rhythms in Neurexins Transcripts and Inhibitory/Excitatory Synapse Scaffold Proteins in the Biological Clock
The neurexin genes (NRXN1/2/3) encode two families (α and β) of highly polymorphic presynaptic proteins that are involved in excitatory/inhibitory synaptic balance. Recent studies indicate that neuronal activation and memory formation affect NRXN1/2/3α expression and alternative splicing at splice sites 3 and 4 (SS#3/SS#4). Neurons in the biological clock residing in the suprachiasmatic nuclei of the hypothalamus (SCN) act as self-sustained oscillators, generating rhythms in gene expression and electrical activity, to entrain circadian bodily rhythms to the 24 hours day/night cycles. Cell autonomous oscillations in NRXN1/2/3α expression and SS#3/SS#4 exons splicing and their links to rhythms in excitatory/inhibitory synaptic balance in the circadian clock were explored. NRXN1/2/3α expression and SS#3/SS#4 splicing, levels of neurexin-2α and the synaptic scaffolding proteins PSD-95 and gephyrin (representing excitatory and inhibitory synapses, respectively) were studied in mRNA and protein extracts obtained from SCN of C3H/J mice at different times of the 24 hours day/night cycle. Further studies explored the circadian oscillations in these components and causality relationships in immortalized rat SCN2.2 cells. Diurnal rhythms in mNRXN1α and mNRXN2α transcription, SS#3/SS#4 exon-inclusion and PSD-95 gephyrin and neurexin-2α levels were found in the SCN in vivo. No such rhythms were found with mNRXN3α. SCN2.2 cells also exhibited autonomous circadian rhythms in rNRXN1/2 expression SS#3/SS#4 exon inclusion and PSD-95, gephyrin and neurexin-2α levels. rNRXN3α and rNRXN1/2β were not expressed. Causal relationships were demonstrated, by use of specific siRNAs, between rNRXN2α SS#3 exon included transcripts and gephyrin levels in the SCN2.2 cells. These results show for the first time dynamic, cell autonomous, diurnal rhythms in expression and splicing of NRXN1/2 and subsequent effects on the expression of neurexin-2α and postsynaptic scaffolding proteins in SCN across the 24-h cycle. NRXNs gene transcripts may have a role in coupling the circadian clock to diurnal rhythms in excitatory/inhibitory synaptic balance
Constant light enhances synchrony among circadian clock cells and promotes behavioral rhythms in VPAC(2)-signaling deficient mice
Individual neurons in the suprachiasmatic nuclei (SCN) contain an intracellular molecular clock and use intercellular signaling to synchronize their timekeeping activities so that the SCN can coordinate brain physiology and behavior. The neuropeptide vasoactive intestinal polypeptide (VIP) and its VPAC2 receptor form a key component of intercellular signaling systems in the SCN and critically control cellular coupling. Targeted mutations in either the intracellular clock or intercellular neuropeptide signaling mechanisms, such as VIP-VPAC2 signaling, can lead to desynchronization of SCN neuronal clocks and loss of behavioral rhythms. An important goal in chronobiology is to develop interventions to correct deficiencies in circadian timekeeping. Here we show that extended exposure to constant light promotes synchrony among SCN clock cells and the expression of ~24 h rhythms in behavior in mice in which intercellular signaling is disrupted through loss of VIP-VPAC2 signaling. This study highlights the importance of SCN synchrony for the expression of rhythms in behavior and reveals how non-invasive manipulations in the external environment can be used to overcome neurochemical communication deficits in this important brain system
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