Titanium dioxide particle – induced goblet cell hyperplasia : association with mast cells and IL-13

BACKGROUND: Inhalation of particles aggravates respiratory symptoms including mucus hypersecretion in patients with chronic airway disease and induces goblet cell hyperplasia (GCH) in experimental animal models. However, the underlying mechanisms remain poorly understood. METHODS: To understand this, the numbers of goblet cells, Muc5ac (+) expressing epithelial cells and IL-13 expressing mast cells were measured in the trachea of sham or TiO(2 )particles – treated rats using periodic acid-Schiff, toluidine blue and immunohistochemical staining. RT-PCR for Muc-1, 2 and 5ac gene transcripts was done using RNA extracted from the trachea. Differential cell count and IL-13 levels were measured in bronchoalveolar lavage (BAL) fluid. In pretreatment groups, cyclophosphamide (CPA) or dexamethasone (DEX) was given before instillation of TiO(2). TiO(2 )treatment markedly increased Muc5ac mRNA expression, and Muc5ac (+) or PAS (+) epithelial cells 48 h following treatment. RESULTS: The concentration of IL-13 in BAL fluids was higher in TiO(2 )treated – rats when compared to those in sham rats (p < 0.05). Pretreatment with cyclophosphamide (CPA) decreased the number of neutrophils and eosinophils in BAL fluid of TiO(2 )treated – rats (p < 0.05), but affected neither the percentage of PAS (+) cells, nor IL-13 levels in the BAL fluids (p > 0.05). In contrast, pretreatment with dexamethasone (DEX) diminished the percentage of PAS (+) cells and the levels of IL-13 (p < 0.05). TiO(2 )treatment increased the IL-13 (+) mast cells (p < 0.05) in the trachea, which was suppressed by DEX (p < 0.05), but not by CPA pretreatment (p > 0.05). In addition there were significant correlations of IL-13 (+) rate of mast cells in the trachea with IL-13 concentration in BAL fluid (p < 0.01) and with the percentage of Muc5ac (+) cells in the sham and TiO(2 )treated rats (p < 0.05). CONCLUSION: In conclusion, TiO(2 )instillation induces GCH and Muc5ac expression, and this process may be associated with increased production of IL-13 by mast cells

The smallest of the small: short-term outcomes of profoundly growth restricted and profoundly low birth weight preterm infants

ObjectiveSurvival of preterm and very low birth weight (VLBW) infants has steadily improved. However, the rates of mortality and morbidity among the very smallest infants are poorly characterized.Study designData from the California Perinatal Quality Care Collaborative for the years 2005 to 2012 were used to compare the mortality and morbidity of profoundly low birth weight (ProLBW, birth weight 300 to 500 g) and profoundly small for gestational age (ProSGA, &lt;1st centile for weight-for-age) infants with very low birth weight (VLBW, birth weight 500 to 1500 g) and appropriate for gestational age (AGA, 5th to 95th centile for weight-for-age) infants, respectively.ResultData were available for 44 561 neonates of birth weight &lt;1500 g. Of these, 1824 were ProLBW and 648 were ProSGA. ProLBW and ProSGA differed in their antenatal risk factors from the comparison groups and were less likely to receive antenatal steroids or to be delivered by cesarean section. Only 14% of ProSGA and 21% of ProLBW infants survived to hospital discharge, compared with &gt;80% of AGA and VLBW infants. The largest increase in mortality in ProSGA and ProLBW infants occurred prior to 12 h of age, and most mortality happened in this time period. Survival of the ProLBW and ProSGA infants was positively associated with higher gestational age, receipt of antenatal steroids, cesarean section delivery and singleton birth.ConclusionSurvival of ProLBW and ProSGA infants is uncommon, and survival without substantial morbidity is rare. Survival is positively associated with receipt of antenatal steroids and cesarean delivery

Metabolic responses to high pCO2 conditions at a CO2 vent site in juveniles of a marine isopod species assemblage

We are starting to understand the relationship between metabolic rate responses and species' ability to respond to exposure to high pCO2. However, most of our knowledge has come from investigations of single species. The examination of metabolic responses of closely related species with differing distributions around natural elevated CO2 areas may be useful to inform our understanding of their adaptive significance. Furthermore, little is known about the physiological responses of marine invertebrate juveniles to high pCO2, despite the fact they are known to be sensitive to other stressors, often acting as bottlenecks for future species success. We conducted an in situ transplant experiment using juveniles of isopods found living inside and around a high pCO2 vent (Ischia, Italy): the CO2 'tolerant' Dynamene bifida and 'sensitive' Cymodoce truncata and Dynamene torelliae. This allowed us to test for any generality of the hypothesis that pCO2 sensitive marine invertebrates may be those that experience trade-offs between energy metabolism and cellular homoeostasis under high pCO2 conditions. Both sensitive species were able to maintain their energy metabolism under high pCO2 conditions, but in C. truncata this may occur at the expense of [carbonic anhydrase], confirming our hypothesis. By comparison, the tolerant D. bifida appeared metabolically well adapted to high pCO2, being able to upregulate ATP production without recourse to anaerobiosis. These isopods are important keystone species; however, given they differ in their metabolic responses to future pCO2, shifts in the structure of the marine ecosystems they inhabit may be expected under future ocean acidification conditions

Evolutionary History of Rabies in Ghana

Rabies virus (RABV) is enzootic throughout Africa, with the domestic dog (Canis familiaris) being the principal vector. Dog rabies is estimated to cause 24,000 human deaths per year in Africa, however, this estimate is still considered to be conservative. Two sub-Saharan African RABV lineages have been detected in West Africa. Lineage 2 is present throughout West Africa, whereas Africa 1a dominates in northern and eastern Africa, but has been detected in Nigeria and Gabon, and Africa 1b was previously absent from West Africa. We confirmed the presence of RABV in a cohort of 76 brain samples obtained from rabid animals in Ghana collected over an eighteen-month period (2007–2009). Phylogenetic analysis of the sequences obtained confirmed all viruses to be RABV, belonging to lineages previously detected in sub-Saharan Africa. However, unlike earlier reported studies that suggested a single lineage (Africa 2) circulates in West Africa, we identified viruses belonging to the Africa 2 lineage and both Africa 1 (a and b) sub-lineages. Phylogeographic Bayesian Markov chain Monte Carlo analysis of a 405 bp fragment of the RABV nucleoprotein gene from the 76 new sequences derived from Ghanaian animals suggest that within the Africa 2 lineage three clades co-circulate with their origins in other West African countries. Africa 1a is probably a western extension of a clade circulating in central Africa and the Africa 1b virus a probable recent introduction from eastern Africa. We also developed and tested a novel reverse-transcription loop-mediated isothermal amplification (RT-LAMP) assay for the detection of RABV in African laboratories. This RT-LAMP was shown to detect both Africa 1 and 2 viruses, including its adaptation to a lateral flow device format for product visualization. These data suggest that RABV epidemiology is more complex than previously thought in West Africa and that there have been repeated introductions of RABV into Ghana. This analysis highlights the potential problems of individual developing nations implementing rabies control programmes in the absence of a regional programme

Long-term carbon sink in Borneo's forests halted by drought and vulnerable to edge effects

Less than half of anthropogenic carbon dioxide emissions remain in the atmosphere. While carbon balance models imply large carbon uptake in tropical forests, direct on-the-ground observations are still lacking in Southeast Asia. Here, using long-term plot monitoring records of up to half a century, we find that intact forests in Borneo gained 0.43 Mg C ha‾¹ per year (95% CI 0.14—0.72, mean period 1988-2010) above-ground live biomass. These results closely match those from African and Amazonian plot networks, suggesting that the world's remaining intact tropical forests are now en masse out-of-equilibrium. Although both pan-tropical and long-term, the sink in remaining intact forests appears vulnerable to climate and land use changes. Across Borneo the 1997-1998 El Niño drought temporarily halted the carbon sink by increasing tree mortality, while fragmentation persistently offset the sink and turned many edge-affected forests into a carbon source to the atmosphere

hTERT promoter activity and CpG methylation in HPV-induced carcinogenesis

<p>Abstract</p> <p>Background</p> <p>Activation of telomerase resulting from deregulated hTERT expression is a key event during high-risk human papillomavirus (hrHPV)-induced cervical carcinogenesis. In the present study we examined hTERT promoter activity and its relation to DNA methylation as one of the potential mechanisms underlying deregulated hTERT transcription in hrHPV-transformed cells.</p> <p>Methods</p> <p>Using luciferase reporter assays we analyzed hTERT promoter activity in primary keratinocytes, HPV16- and HPV18-immortalized keratinocyte cell lines and cervical cancer cell lines. In the same cells as well as cervical specimens we determined hTERT methylation by bisulfite sequencing analysis of the region spanning -442 to +566 (relative to the ATG) and quantitative methylation specific PCR (qMSP) analysis of two regions flanking the hTERT core promoter.</p> <p>Results</p> <p>We found that in most telomerase positive cells increased hTERT core promoter activity coincided with increased hTERT mRNA expression. On the other hand basal hTERT promoter activity was also detected in telomerase negative cells with no or strongly reduced hTERT mRNA expression levels. In both telomerase positive and negative cells regulatory sequences flanking both ends of the core promoter markedly repressed exogenous promoter activity.</p> <p>By extensive bisulfite sequencing a strong increase in CpG methylation was detected in hTERT positive cells compared to cells with no or strongly reduced hTERT expression. Subsequent qMSP analysis of a larger set of cervical tissue specimens revealed methylation of both regions analyzed in 100% of cervical carcinomas and 38% of the high-grade precursor lesions, compared to 9% of low grade precursor lesions and 5% of normal controls.</p> <p>Conclusions</p> <p>Methylation of transcriptionally repressive sequences in the hTERT promoter and proximal exonic sequences is correlated to deregulated hTERT transcription in HPV-immortalized cells and cervical cancer cells. The detection of DNA methylation at these repressive regions may provide an attractive biomarker for early detection of cervical cancer.</p

The legal framework for financial advertising:curbing behavioural exploitation

Policy makers and behavioural finance scholars express growing concern that marketing practices by financial institutions exploit retail investors’ behavioural biases. Investor protection regulation should thus address these marketing practices and include mechanisms curbing behavioural exploitation. That raises the question whether the marketing communications regime of the new Markets in Financial Instruments Directive can live up to this demand. This article develops a regulatory model that integrates behavioural finance insights into the new marketing communications regime. It then determines how regulatory authorities can apply this model when they interpret and apply specific regulatory requirements. It demonstrates how a regulatory authority or a court can translate empirical behavioural finance research findings into legal arguments when assessing whether marketing practices can significantly distort a model investor’s decision-making process. The article further establishes that the detailed requirements imposed on investment firms by the new Markets in Financial Instruments Directive are necessary in order to protect investors from behavioural exploitation. Finally, the article submits policy proposals that aim to protect investors more effectively from behavioural exploitation

Insights into pathogenic events of HIV-associated Kaposi sarcoma and immune reconstitution syndrome related Kaposi sarcoma

A decrease in the incidence of human immune deficiency virus-associated Kaposi sarcoma (HIV-KS) and regression of some established HIV-KS lesions is evident after the introduction of highly active anti-retroviral treatment (HAART), and is attributed to generalized immune restoration, to the reconstitution of human herpesvirus (HHV)-8 specific cellular immune responses, and to the decrease in HIV Tat protein and HHV-8 loads following HAART. However, a small subset of HIV-seropositive subjects with a low CD4+ T cell count at the time of introduction of HAART, may develop HIV-KS as immune reconstitution inflammatory syndrome (IRIS) within 8 weeks thereafter

Rogdi Defines GABAergic Control of a Wake-promoting Dopaminergic Pathway to Sustain Sleep in Drosophila

Kohlschutter-Tonz syndrome (KTS) is a rare genetic disorder with neurological dysfunctions including seizure and intellectual impairment. Mutations at the Rogdi locus have been linked to development of KTS, yet the underlying mechanisms remain elusive. Here we demonstrate that a Drosophila homolog of Rogdi acts as a novel sleep-promoting factor by supporting a specific subset of gamma-aminobutyric acid (GABA) transmission. Rogdi mutant flies displayed insomnia-like behaviors accompanied by sleep fragmentation and delay in sleep initiation. The sleep suppression phenotypes were rescued by sustaining GABAergic transmission primarily via metabotropic GABA receptors or by blocking wake-promoting dopaminergic pathways. Transgenic rescue further mapped GABAergic neurons as a cell-autonomous locus important for Rogdi-dependent sleep, implying metabotropic GABA transmission upstream of the dopaminergic inhibition of sleep. Consistently, an agonist specific to metabotropic but not ionotropic GABA receptors titrated the wake-promoting effects of dopaminergic neuron excitation. Taken together, these data provide the first genetic evidence that implicates Rogdi in sleep regulation via GABAergic control of dopaminergic signaling. Given the strong relevance of GABA to epilepsy, we propose that similar mechanisms might underlie the neural pathogenesis of Rogdi-associated KTS