Modulation of Allergic Inflammation in the Nasal Mucosa of Allergic Rhinitis Sufferers With Topical Pharmaceutical Agents

Allergic rhinitis (AR) is a chronic upper respiratory disease estimated to affect between 10 and 40% of the worldwide population. The mechanisms underlying AR are highly complex and involve multiple immune cells, mediators, and cytokines. As such, the development of a single drug to treat allergic inflammation and/or symptoms is confounded by the complexity of the disease pathophysiology. Complete avoidance of allergens that trigger AR symptoms is not possible and without a cure, the available therapeutic options are typically focused on achieving symptomatic relief. Topical therapies offer many advantages over oral therapies, such as delivering greater concentrations of drugs to the receptor sites at the source of the allergic inflammation and the reduced risk of systemic side effects. This review describes the complex pathophysiology of AR and identifies the mechanism(s) of action of topical treatments including antihistamines, steroids, anticholinergics, decongestants and chromones in relation to AR pathophysiology. Following the literature review a discussion on the future therapeutic strategies for AR treatment is provided

Genome-wide mapping of cystitis due to Streptococcus agalactiae and Escherichia coli in mice identifies a unique bladder transcriptome that signifies pathogen-specific antimicrobial defense against urinary tract infection

The most common causes of urinary tract infections (UTIs) are Gram-negative pathogens such as Escherichia coli; however, Gram-positive organisms, including Streptococcus agalactiae, or group B streptococcus (GBS), also cause UTI. In GBS infection, UTI progresses to cystitis once the bacteria colonize the bladder, but the host responses triggered in the bladder immediately following infection are largely unknown. Here, we used genome-wide expression profiling to map the bladder transcriptome of GBS UTI in mice infected transurethrally with uropathogenic GBS that was cultured from a 35-year-old women with cystitis. RNA from bladders was applied to Affymetrix Gene-1.0ST microarrays; quantitative reverse transcriptase PCR (qRT-PCR) was used to analyze selected gene responses identified in array data sets. A surprisingly small significant-gene list of 172 genes was identified at 24 h; this compared to 2,507 genes identified in a side-by-side comparison with uropathogenic E. coli (UPEC). No genes exhibited significantly altered expression at 2 h in GBS-infected mice according to arrays despite high bladder bacterial loads at this early time point. The absence of a marked early host response to GBS juxtaposed with broad-based bladder responses activated by UPEC at 2 h. Bioinformatics analyses, including integrative system-level network mapping, revealed multiple activated biological pathways in the GBS bladder transcriptome that regulate leukocyte activation, inflammation, apoptosis, and cytokine-chemokine biosynthesis. These findings define a novel, minimalistic type of bladder host response triggered by GBS UTI, which comprises collective antimicrobial pathways that differ dramatically from those activated by UPEC. Overall, this study emphasizes the unique nature of bladder immune activation mechanisms triggered by distinct uropathogens

Assessing road effects on bats: the role of landscape, road features, and bat activity on road-kills

Recent studies suggest that roads can significantly impact bat populations. Though bats are one of the most threatened groups of European vertebrates, studies aiming to quantify bat mortality and determine the main factors driving it remain scarce. Between March 16 and October 31 of 2009, we surveyed road-killed bats daily along a 51-km-long transect that incorporates different types of roads in southern Portugal. We found 154 road-killed bats of 11 species. The two most common species in the study area, Pipistrellus kuhlii and P. pygmaeus, were also the most commonly identified road-kill, representing 72 % of the total specimens collected. About two-thirds of the total mortality occurred between mid July and late September, peaking in the second half of August. We also recorded casualties of threatened and rare species, including Miniopterus schreibersii, Rhinolophus ferrumequinum, R. hipposideros, Barbastella barbastellus, and Nyctalus leisleri. These species were found mostly in early autumn, corresponding to the mating and swarming periods. Landscape features were the most important variable subset for explaining bat casualties. Road stretches crossing or in the vicinity of high-quality habitats for bats—including dense Mediterranean woodland (‘‘montado’’) areas, water courses with riparian gallery, and water reservoirs—yielded a significantly higher number of casualties. Additionally, more roadkilled bats were recorded on high-traffic road stretches with viaducts, in areas of higher bat activity and near known roosts

Assessment of the proliferative, apoptotic and cellular renovation indices of the human mammary epithelium during the follicular and luteal phases of the menstrual cycle

Introduction During the menstrual cycle, the mammary gland goes through sequential waves of proliferation and apoptosis. in mammary epithelial cells, hormonal and non-hormonal factors regulate apoptosis. To determine the cyclical effects of gonadal steroids on breast homeostasis, we evaluated the apoptotic index ( AI) determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling ( TUNEL) staining in human mammary epithelial cells during the spontaneous menstrual cycle and correlated it with cellular proliferation as determined by the expression of Ki-67 during the same period.Methods Normal breast tissue samples were obtained from 42 randomly selected patients in the proliferative ( n = 21) and luteal ( n = 21) phases. Menstrual cycle phase characterization was based on the date of the last and subsequent menses, and on progesterone serum levels obtained at the time of biopsy.Results the proliferation index ( PI), defined as the number of Ki-67-positive nuclei per 1,000 epithelial cells, was significantly larger in the luteal phase (30.46) than in the follicular phase (13.45; P = 0.0033). the AI was defined as the number of TUNEL-positive cells per 1,000 epithelial cells. the average AI values in both phases of the menstrual cycle were not statistically significant ( P = 0.21). However, the cell renewal index ( CRI = PI/AI) was significantly higher in the luteal phase ( P = 0.033). A significant cyclical variation of PI, AI and CRI was observed. PI and AI peaks occurred on about the 24th day of the menstrual cycle, whereas the CRI reached higher values on the 28th day.Conclusions We conclude that proliferative activity is dependent mainly on hormonal fluctuations, whereas apoptotic activity is probably regulated by hormonal and non-hormonal factors.Universidade Federal de São Paulo, Dept Gyneol, Mastol Div, São Paulo, BrazilStanford Univ, Sch Med, Dept Neurosurg, Stanford, CA 94305 USAAPC Pathol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Gyneol, Mastol Div, São Paulo, BrazilWeb of Scienc

The OASIS Mission

The Orbiting Astrophysical Observatory in Space (OASIS) is a mission to investigate Galactic Cosmic Rays (GCRs), a major feature of our galaxy. OASIS will use measurements of GCRs to determine the cosmic ray source, where they are accelerated, to investigate local accelerators and to learn what they can tell us about the interstellar medium and the processes that occur in it. OASIS will determine the astrophysical sources of both the material and acceleration of GCRs by measuring the abundances of the rare actinide nuclei and make direct measurements of the spectrum and anisotropy of electrons at energies up to approx.10 TeV, well beyond the range of the Fermi and AMS missions. OASIS has two instruments. The Energetic Trans-Iron Composition Experiment (ENTICE) instrument measures elemental composition. It resolves individual elements with atomic number (Z) from 10 to 130 and has a collecting power of 60m2.str.yrs, >20 times larger than previous instruments, and with improved resolution. The sample of 10(exp 10) GCRs collected by ENTICE will include .100 well-resolved actinides. The High Energy Particle Calorimeter Telescope (HEPCaT) is an ionization calorimeter that will extend the electron spectrum into the TeV region for the first time. It has 7.5 sq m.str.yrs of collecting power. This talk will describe the scientific objectives of the OASIS mission and its discovery potential. The mission and its two instruments which have been designed to accomplish this investigation will also be described

Migratory Dermal Dendritic Cells Act as Rapid Sensors of Protozoan Parasites

Dendritic cells (DC), including those of the skin, act as sentinels for intruding microorganisms. In the epidermis, DC (termed Langerhans cells, LC) are sessile and screen their microenvironment through occasional movements of their dendrites. The spatio-temporal orchestration of antigen encounter by dermal DC (DDC) is not known. Since these cells are thought to be instrumental in the initiation of immune responses during infection, we investigated their behavior directly within their natural microenvironment using intravital two-photon microscopy. Surprisingly, we found that, under homeostatic conditions, DDC were highly motile, continuously crawling through the interstitial space in a Gαi protein-coupled receptor–dependent manner. However, within minutes after intradermal delivery of the protozoan parasite Leishmania major, DDC became immobile and incorporated multiple parasites into cytosolic vacuoles. Parasite uptake occurred through the extension of long, highly dynamic pseudopods capable of tracking and engulfing parasites. This was then followed by rapid dendrite retraction towards the cell body. DDC were proficient at discriminating between parasites and inert particles, and parasite uptake was independent of the presence of neutrophils. Together, our study has visualized the dynamics and microenvironmental context of parasite encounter by an innate immune cell subset during the initiation of the immune response. Our results uncover a unique migratory tissue surveillance program of DDC that ensures the rapid detection of pathogens

Second Order Perturbations in the Randall-Sundrum Infinite Brane-World Model

We discuss the non-linear gravitational interactions in the Randall-Sundrum single brane model. If we naively write down the 4-dimensional effective action integrating over the fifth dimension with the aid of the decomposition with respect to eigen modes of 4-dimensional d'Alembertian, the Kaluza-Klein mode coupling seems to be ill-defined. We carefully analyze second order perturbations of the gravitational field induced on the 3-brane under the assumption of the static and axial-symmetric 5-dimensional metric. It is shown that there remains no pathological feature in the Kaluza-Klein mode coupling after the summation over all different mass modes. Furthermore, the leading Kaluza-Klein corrections are shown to be sufficiently suppressed in comparison with the leading order term which is obtained by the zero mode truncation. We confirm that the 4-dimensional Einstein gravity is approximately recovered on the 3-brane up to second order perturbations.Comment: 15 pages, 2 figures, comment and reference added, typos correcte

TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions

Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes

Penetrance of variants in monogenic disease and clinical utility of common polygenic variation has not been well explored on a large-scale. Here, the authors use exome sequencing data from 77,184 individuals to generate penetrance estimates and assess the utility of polygenic variation in risk prediction of monogenic variants