Neuroinflammation and structural injury of the fetal ovine brain following intra-amniotic Candida albicans exposure.

BackgroundIntra-amniotic Candida albicans (C. Albicans) infection is associated with preterm birth and high morbidity and mortality rates. Survivors are prone to adverse neurodevelopmental outcomes. The mechanisms leading to these adverse neonatal brain outcomes remain largely unknown. To better understand the mechanisms underlying C. albicans-induced fetal brain injury, we studied immunological responses and structural changes of the fetal brain in a well-established translational ovine model of intra-amniotic C. albicans infection. In addition, we tested whether these potential adverse outcomes of the fetal brain were improved in utero by antifungal treatment with fluconazole.MethodsPregnant ewes received an intra-amniotic injection of 10(7) colony-forming units C. albicans or saline (controls) at 3 or 5 days before preterm delivery at 0.8 of gestation (term ~ 150 days). Fetal intra-amniotic/intra-peritoneal injections of fluconazole or saline (controls) were administered 2 days after C. albicans exposure. Post mortem analyses for fungal burden, peripheral immune activation, neuroinflammation, and white matter/neuronal injury were performed to determine the effects of intra-amniotic C. albicans and fluconazole treatment.ResultsIntra-amniotic exposure to C. albicans caused a severe systemic inflammatory response, illustrated by a robust increase of plasma interleukin-6 concentrations. Cerebrospinal fluid cultures were positive for C. albicans in the majority of the 3-day C. albicans-exposed animals whereas no positive cultures were present in the 5-day C. albicans-exposed and fluconazole-treated animals. Although C. albicans was not detected in the brain parenchyma, a neuroinflammatory response in the hippocampus and white matter was seen which was characterized by increased microglial and astrocyte activation. These neuroinflammatory changes were accompanied by structural white matter injury. Intra-amniotic fluconazole reduced fetal mortality but did not attenuate neuroinflammation and white matter injury.ConclusionsIntra-amniotic C. albicans exposure provoked acute systemic and neuroinflammatory responses with concomitant white matter injury. Fluconazole treatment prevented systemic inflammation without attenuating cerebral inflammation and injury

On the Origin of the UV Upturn in Elliptical Galaxies. I. Sensitivity of UV Population Synthesis to Various Input Parameters

We present models of the late stages of stellar evolution intended to explain the UV upturn phenomenon in elliptical galaxies. Such models are sensitive to values of a number of poorly-constrained physical parameters, including metallicity, age, stellar mass loss, helium enrichment, and the distribution of stars on the zero age horizontal branch (HB). We explore the sensitivity of the results to values of these parameters, and reach the following conclusions. Old, metal rich galaxies, such as giant ellipticals, naturally develop a UV upturn within a reasonable time scale - less than a Hubble time - without the presence of young stars. The most likely stars to dominate the UV flux of such populations are low mass, core helium burning (HB and evolved HB) stars. Metal-poor populations produce a higher ratio of UV-to-V flux, due to opacity effects, but only metal-rich stars develop a UV upturn, in which the flux increases towards shorter UV wavelengths. Model color-magnitude diagrams and corresponding integrated spectra (for various values of age, metallicity, helium enrichment, mass loss efficiency, initial mass function, and the HB mass dispersion factor) are available on S.Y.'s world wide web site http://shemesh.gsfc.nasa.gov/model.html.Comment: LaTeX, 38p text. 19 postscript Figures and 11 gif figures. PS file also at http://shemesh.gsfc.nasa.gov/astronomy.html. ApJ, vol 486, in pres

Can incontinence be cured? A systematic review of cure rates

Background Incontinence constitutes a major health problem affecting millions of people worldwide. The present study aims to assess cure rates from treating urinary (UI) or fecal incontinence (FI) and the number of people who may remain dependent on containment strategies. Methods Medline, Embase, PsycINFO, Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL, and PEDro were searched from January 2005 to June 2015. Supplementary searches included conference abstracts and trials registers (2013–2015). Included studies had patients ≥ 18 years with UI or FI, reported treatment cure or success rates, had ≥ 50 patients treated with any intervention recognized in international guideline algorithms, a follow-up ≥ 3 months, and were published from 2005 onwards. Title and abstract screening, full paper screening, data extraction and risk-of-bias assessment were performed independently by two reviewers. Disagreements were resolved through discussion or referral to a third reviewer where necessary. A narrative summary of included studies is presented. Results Most evidence was found for UI: Surgical interventions for stress UI showed a median cure rate of 82.3% (interquartile range (IQR), 72–89.5%); people with urgency UI were mostly treated using medications (median cure rate for antimuscarinics = 49%; IQR, 35.6–58%). Pelvic floor muscle training and bulking agents showed lower cure rates for UI. Sacral neuromodulation for FI had a median cure rate of 38.6% (IQR, 35.6–40.6%). Conclusions Many individuals were not cured and hence may continue to rely on containment. No studies were found assessing success of containment strategies. There was a lack of data in the disabled and in those with neurological diseases, in the elderly and those with cognitive impairment. Surgical interventions were effective for stress UI. Other interventions for UI and FI showed lower cure rates. Many individuals are likely to be reliant on containment strategies

Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study

Background: Serum neurofilament light chain (sNfL) is a biomarker of neuronal damage that is used not only to monitor disease activity and response to drugs and to prognosticate disease course in people with multiple sclerosis on the group level. The absence of representative reference values to correct for physiological age-dependent increases in sNfL has limited the diagnostic use of this biomarker at an individual level. We aimed to assess the applicability of sNfL for identification of people at risk for future disease activity by establishing a reference database to derive reference values corrected for age and body-mass index (BMI). Furthermore, we used the reference database to test the suitability of sNfL as an endpoint for group-level comparison of effectiveness across disease-modifying therapies. Methods: For derivation of a reference database of sNfL values, a control group was created, comprising participants with no evidence of CNS disease taking part in four cohort studies in Europe and North America. We modelled the distribution of sNfL concentrations in function of physiological age-related increase and BMI-dependent modulation, to derive percentile and Z score values from this reference database, via a generalised additive model for location, scale, and shape. We tested the reference database in participants with multiple sclerosis in the Swiss Multiple Sclerosis Cohort (SMSC). We compared the association of sNfL Z scores with clinical and MRI characteristics recorded longitudinally to ascertain their respective disease prognostic capacity. We validated these findings in an independent sample of individuals with multiple sclerosis who were followed up in the Swedish Multiple Sclerosis registry. Findings: We obtained 10 133 blood samples from 5390 people (median samples per patient 1 [IQR 1–2] in the control group). In the control group, sNfL concentrations rose exponentially with age and at a steeper increased rate after approximately 50 years of age. We obtained 7769 samples from 1313 people (median samples per person 6·0 [IQR 3·0–8·0]). In people with multiple sclerosis from the SMSC, sNfL percentiles and Z scores indicated a gradually increased risk for future acute (eg, relapse and lesion formation) and chronic (disability worsening) disease activity. A sNfL Z score above 1·5 was associated with an increased risk of future clinical or MRI disease activity in all people with multiple sclerosis (odds ratio 3·15, 95% CI 2·35–4·23; p<0·0001) and in people considered stable with no evidence of disease activity (2·66, 1·08–6·55; p=0·034). Increased Z scores outperformed absolute raw sNfL cutoff values for diagnostic accuracy. At the group level, the longitudinal course of sNfL Z score values in people with multiple sclerosis from the SMSC decreased to those seen in the control group with use of monoclonal antibodies (ie, alemtuzumab, natalizumab, ocrelizumab, and rituximab) and, to a lesser extent, oral therapies (ie, dimethyl fumarate, fingolimod, siponimod, and teriflunomide). However, longitudinal sNfL Z scores remained elevated with platform compounds (interferons and glatiramer acetate; p<0·0001 for the interaction term between treatment category and treatment duration). Results were fully supported in the validation cohort (n=4341) from the Swedish Multiple Sclerosis registry. Interpretation: The use of sNfL percentiles and Z scores allows for identification of individual people with multiple sclerosis at risk for a detrimental disease course and suboptimal therapy response beyond clinical and MRI measures, specifically in people with disease activity-free status. Additionally, sNfL might be used as an endpoint for comparing effectiveness across drug classes in pragmatic trials. Funding: Swiss National Science Foundation, Progressive Multiple Sclerosis Alliance, Biogen, Celgene, Novartis, Roche

Sex Pheromone Evolution Is Associated with Differential Regulation of the Same Desaturase Gene in Two Genera of Leafroller Moths

Chemical signals are prevalent in sexual communication systems. Mate recognition has been extensively studied within the Lepidoptera, where the production and recognition of species-specific sex pheromone signals are typically the defining character. While the specific blend of compounds that makes up the sex pheromones of many species has been characterized, the molecular mechanisms underpinning the evolution of pheromone-based mate recognition systems remain largely unknown. We have focused on two sets of sibling species within the leafroller moth genera Ctenopseustis and Planotortrix that have rapidly evolved the use of distinct sex pheromone blends. The compounds within these blends differ almost exclusively in the relative position of double bonds that are introduced by desaturase enzymes. Of the six desaturase orthologs isolated from all four species, functional analyses in yeast and gene expression in pheromone glands implicate three in pheromone biosynthesis, two Δ9-desaturases, and a Δ10-desaturase, while the remaining three desaturases include a Δ6-desaturase, a terminal desaturase, and a non-functional desaturase. Comparative quantitative real-time PCR reveals that the Δ10-desaturase is differentially expressed in the pheromone glands of the two sets of sibling species, consistent with differences in the pheromone blend in both species pairs. In the pheromone glands of species that utilize (Z)-8-tetradecenyl acetate as sex pheromone component (Ctenopseustis obliquana and Planotortrix octo), the expression levels of the Δ10-desaturase are significantly higher than in the pheromone glands of their respective sibling species (C. herana and P. excessana). Our results demonstrate that interspecific sex pheromone differences are associated with differential regulation of the same desaturase gene in two genera of moths. We suggest that differential gene regulation among members of a multigene family may be an important mechanism of molecular innovation in sex pheromone evolution and speciation

Mesenchymal Stem Cells Induce T-Cell Tolerance and Protect the Preterm Brain after Global Hypoxia-Ischemia

Hypoxic-ischemic encephalopathy (HIE) in preterm infants is a severe disease for which no curative treatment is available. Cerebral inflammation and invasion of activated peripheral immune cells have been shown to play a pivotal role in the etiology of white matter injury, which is the clinical hallmark of HIE in preterm infants. The objective of this study was to assess the neuroprotective and anti-inflammatory effects of intravenously delivered mesenchymal stem cells (MSC) in an ovine model of HIE. In this translational animal model, global hypoxia-ischemia (HI) was induced in instrumented preterm sheep by transient umbilical cord occlusion, which closely mimics the clinical insult. Intravenous administration of 2 x 106MSC/kg reduced microglial proliferation, diminished loss of oligodendrocytes and reduced demyelination, as determined by histology and Diffusion Tensor Imaging (DTI), in the preterm brain after global HI. These anti-inflammatory and neuroprotective effects of MSC were paralleled by reduced electrographic seizure activity in the ischemic preterm brain. Furthermore, we showed that MSC induced persistent peripheral T-cell tolerance in vivo and reduced invasion of T-cells into the preterm brain following global HI. These findings show in a preclinical animal model that intravenously administered MSC reduced cerebral inflammation, protected against white matter injury and established functional improvement in the preterm brain following global HI. Moreover, we provide evidence that induction of T-cell tolerance by MSC might play an important role in the neuroprotective effects of MSC in HIE. This is the first study to describe a marked neuroprotective effect of MSC in a translational animal model of HIE

The Milky Way Tomography with SDSS: I. Stellar Number Density Distribution

Abridged: We estimate the distances to ~48 million stars detected by the Sloan Digital Sky Survey and map their 3D number density distribution in 100 < D < 20 kpc range over 6,500 deg^2 of sky. The data show strong evidence for a Galaxy consisting of an oblate halo, a disk component, and a number of localized overdensities with exponential disk parameters (bias-corrected for an assumed 35% binary fraction) H_1 = 300 pc, L_1 = 2600 pc, H_2 = 900 pc, L_2 = 3600 pc, and local density normalization of 12%. We find the halo to be oblate, with best-fit axis ratio c/a = 0.64, r^{-2.8} profile, and the local halo-to-thin disk normalization of 0.5%. We estimate the errors of derived model parameters to be no larger than ~20% (disk scales) and ~10% (thick disk normalization). While generally consistent with the above model, the density distribution shows a number of statistically significant localized deviations. We detect two overdensities in the thick disk region at (R, Z) ~ (6.5, 1.5)kpc and (R, Z) ~ (9.5, 0.8) kpc, and a remarkable density enhancement in the halo covering >1000deg^2 of sky towards the constellation of Virgo, at distances of ~6-20 kpc. Compared to a region symmetric with respect to the l=0 line, the Virgo overdensity is responsible for a factor of 2 number density excess and may be a nearby tidal stream or a low-surface brightness dwarf galaxy merging with the Milky Way. After removal of the resolved overdensities, the remaining data are consistent with a smooth density distribution; we detect no evidence of further unresolved clumpy substructure at scales ranging from ~50pc in the disk, to ~1 - 2 kpc in the halo.Comment: 60 pages, 46 figures (reduced resolution; see the ApJ for hi-res version

Predictive Genes in Adjacent Normal Tissue Are Preferentially Altered by sCNV during Tumorigenesis in Liver Cancer and May Rate Limiting

Background: In hepatocellular carcinoma (HCC) genes predictive of survival have been found in both adjacent normal (AN) and tumor (TU) tissues. The relationships between these two sets of predictive genes and the general process of tumorigenesis and disease progression remains unclear. Methodology/Principal Findings: Here we have investigated HCC tumorigenesis by comparing gene expression, DNA copy number variation and survival using ~250 AN and TU samples representing, respectively, the pre-cancer state, and the result of tumorigenesis. Genes that participate in tumorigenesis were defined using a gene-gene correlation meta-analysis procedure that compared AN versus TU tissues. Genes predictive of survival in AN (AN-survival genes) were found to be enriched in the differential gene-gene correlation gene set indicating that they directly participate in the process of tumorigenesis. Additionally the AN-survival genes were mostly not predictive after tumorigenesis in TU tissue and this transition was associated with and could largely be explained by the effect of somatic DNA copy number variation (sCNV) in cis and in trans. The data was consistent with the variance of AN-survival genes being rate-limiting steps in tumorigenesis and this was confirmed using a treatment that promotes HCC tumorigenesis that selectively altered AN-survival genes and genes differentially correlated between AN and TU. Conclusions/Significance: This suggests that the process of tumor evolution involves rate-limiting steps related to the background from which the tumor evolved where these were frequently predictive of clinical outcome. Additionally treatments that alter the likelihood of tumorigenesis occurring may act by altering AN-survival genes, suggesting that the process can be manipulated. Further sCNV explains a substantial fraction of tumor specific expression and may therefore be a causal driver of tumor evolution in HCC and perhaps many solid tumor types. © 2011 Lamb et al.published_or_final_versio