An evaluation of the benefits and harms of antenatal corticosteroid treatment for women at risk of imminent preterm birth or prior to elective Caesarean-section: an individual participant data meta-analysis.:Study protocol

Background: Antenatal corticosteroid treatment (ACT) has been widely accepted as a safe, beneficial treatment which improves outcomes following preterm birth. It has been shown to reduce respiratory distress syndrome and neonatal mortality and is commonly used in threatened or planned preterm delivery, as well as prior to elective Caesarean-section at term. There are some concerns however, that in some cases, ACT is used in patients where clinical benefit has not been established, or may potentially increase harm. Many women who receive ACT do not deliver preterm and the long-term consequences of ACT treatment are unclear. This study aims to evaluate the benefits and harms of ACT using latest trial evidence to allow refinement of current practice. Methods: This study will compare ACT with placebo or non-treatment. Inclusion criteria are: Randomised Controlled Trials (RCT) comparing ACT vs. no ACT (with or without placebo) in all settings. Exclusion criteria are: non-randomised or quasi-randomised studies and studies comparing single vs. multiple courses of ACT. Main outcomes are to evaluate, for women at risk of preterm birth or undergoing planned Caesarean- section, the benefits and harms of ACT, on maternal, fetal, newborn, and long-term offspring health outcomes. The individual participant data (IPD) of identified RCTs will be collected and consecutively synthesised using meta-analysis with both a one-stage model where all IPD is analysed together and a two-stage model where treatment effect estimates are calculated for each trial individually first and thereafter pooled in a meta-analysis. Sub-group analysis will be performed to identify heterogeneous effects of ACT across predefined risk groups. Discussion: Co-opt is the Consortium for the Study of Pregnancy Treatments and aims to complete a robust evaluation of the benefits and harms of ACT. This IPD meta-analysis will contribute to this by allowing detailed interrogation of existing trial datasets. PROSPERO registration: CRD42020167312 (03/02/2020

Characterization of MCF mammary epithelial cells overexpressing the Arylhydrocarbon receptor (AhR)

<p>Abstract</p> <p>Background</p> <p>Recent reports indicate the existence of breast cancer cells expressing very high levels of the Arylhydrocarbon receptor (AhR), a ubiquitous intracellular receptor best known for mediating toxic action of dioxin and related pollutants. Positive correlation between the degree of AhR overexpression and states of increasing transformation of mammary epithelial cells appears to occur in the absence of any exogenous AhR ligands. These observations have raised many questions such as why and how AhR is overexpressed in breast cancer and its physiological roles in the progression to advanced carcinogenic transformation. To address those questions, we hypothesized that AhR overexpression occurs in cells experiencing deficiencies in normally required estrogen receptor (ER) signaling, and the basic role of AhR in such cases is to guide the affected cells to develop orchestrated cellular changes aimed at substituting the normal functions of ER. At the same time, the AhR serves as the mediator of the cell survival program in the absence of ER signaling.</p> <p>Methods</p> <p>We subjected two lines of Michigan Cancer Foundation (MCF) mammary epithelial cells to 3 different types ER interacting agents for a number of passages and followed the changes in the expression of AhR mRNA. The resulting sublines were analyzed for phenotypical changes and unique molecular characteristics.</p> <p>Results</p> <p>MCF10AT1 cells continuously exposed to 17-beta-estradiol (E2) developed sub-lines that show AhR overexpression with the characteristic phenotype of increased proliferation, and distinct resistance to apoptosis. When these chemically selected cell lines were treated with a specific AhR antagonist, 3-methoxy-4-nitroflavone (MNF), both of the above abnormal cellular characteristics disappeared, indicating the pivotal role of AhR in expressing those cellular phenotypes. The most prominent molecular characteristics of these AhR overexpressing MCF cells were found to be overexpression of ErbB2 and COX-2. Furthermore, we could demonstrate that suppression of AhR functions through anti-AhR siRNA or MNF causes the recovery of ERalpha functions.</p> <p>Conclusion</p> <p>One of the main causes for AhR overexpression in these MCF breast cancer cells appears to be the loss of ERalpha functions. This phenomenon is likely to be based on the mutually antagonistic relationship between ER and AhR.</p

Evolutionary explanations in medical and health profession courses: are you answering your students' "why" questions?

BACKGROUND: Medical and pre-professional health students ask questions about human health that can be answered in two ways, by giving proximate and evolutionary explanations. Proximate explanations, most common in textbooks and classes, describe the immediate scientifically known biological mechanisms of anatomical characteristics or physiological processes. These explanations are necessary but insufficient. They can be complemented with evolutionary explanations that describe the evolutionary processes and principles that have resulted in human biology we study today. The main goal of the science of Darwinian Medicine is to investigate human disease, disorders, and medical complications from an evolutionary perspective. DISCUSSION: This paper contrasts the differences between these two types of explanations by describing principles of natural selection that underlie medical questions. Thus, why is human birth complicated? Why does sickle cell anemia exist? Why do we show symptoms like fever, diarrhea, and coughing when we have infection? Why do we suffer from ubiquitous age-related diseases like arteriosclerosis, Alzheimer's and others? Why are chronic diseases like type II diabetes and obesity so prevalent in modern society? Why hasn't natural selection eliminated the genes that cause common genetic diseases like hemochromatosis, cystic fibrosis, Tay sachs, PKU and others? SUMMARY: In giving students evolutionary explanations professors should underscore principles of natural selection, since these can be generalized for the analysis of many medical questions. From a research perspective, natural selection seems central to leading hypotheses of obesity and type II diabetes and might very well explain the occurrence of certain common genetic diseases like cystic fibrosis, hemochromatosis, Tay sachs, Fragile X syndrome, G6PD and others because of their compensating advantages. Furthermore, armed with evolutionary explanations, health care professionals can bring practical benefits to patients by treating their symptoms of infection more specifically and judiciously. They might also help curtail the evolutionary arms race between pathogens and antibiotic defenses

Safety of bazedoxifene in a randomized, double-blind, placebo- and active-controlled phase 3 study of postmenopausal women with osteoporosis

Background. We report the safety findings from a 3-year phase 3 study (NCT00205777) of bazedoxifene, a novel selective estrogen receptor modulator under development for the prevention and treatment of postmenopausal osteoporosis. Methods. Healthy postmenopausal osteoporotic women (N = 7,492; mean age, 66.4 years) were randomized to daily doses of bazedoxifene 20 or 40 mg, raloxifene 60 mg, or placebo for 3 years. Safety and tolerability were assessed by adverse event (AE) reporting and routine physical, gynecologic, and breast examination. Results. Overall, the incidence of AEs, serious AEs, and discontinuations due to AEs in the bazedoxifene groups was not different from that seen in the placebo group. The incidence of hot flushes and leg cramps was higher with bazedoxifene or raloxifene compared with placebo. The rates of cardiac disorders and cerebrovascular events were low and evenly distributed among groups. Venous thromboembolic events, primarily deep vein thromboses, were more frequently reported in the active treatment groups compared with the placebo group; rates were similar with bazedoxifene and raloxifene. Bazedoxifene showed a neutral effect on the breast and an excellent endometrial safety profile. The incidence of fibrocystic breast disease was lower with bazedoxifene 20 and 40 mg versus raloxifene or placebo. Reductions in total and low-density lipoprotein levels and increases in high-density lipoprotein levels were seen with bazedoxifene versus placebo; similar results were seen with raloxifene. Triglyceride levels were similar among groups. Conclusion. Bazedoxifene showed a favorable safety and tolerability profile in women with postmenopausal osteoporosis. © 2010 Christiansen et al; licensee BioMed Central Ltd.link_to_subscribed_fulltex

The Diagnostic Potential of Fe Lines Applied to Protostellar Jets

We investigate the diagnostic capabilities of iron lines for tracing the physical conditions of shock-excited gas in jets driven by pre-main sequence stars. We have analyzed the 3000-25000 \uc5, X-shooter spectra of two jets driven by the pre-main sequence stars ESO-H\u3b1 574 and Par-Lup 3-4. Both spectra are very rich in [Fe II] lines over the whole spectral range; in addition, lines from [Fe III] are detected in the ESO-H\u3b1 574 spectrum. Non-local thermal equilibrium codes solving the equations of the statistical equilibrium along with codes for the ionization equilibrium are used to derive the gas excitation conditions of electron temperature and density and fractional ionization. An estimate of the iron gas-phase abundance is provided by comparing the iron lines emissivity with that of neutral oxygen at 6300 \uc5. The [Fe II] line analysis indicates that the jet driven by ESO-H\u3b1 574 is, on average, colder (T e 3c 9000 K), less dense (n e 3c 2 7 104 cm-3), and more ionized (x e 3c 0.7) than the Par-Lup 3-4 jet (T e 3c 13,000 K, n e 3c 6 7 104 cm-3, x e < 0.4), even if the existence of a higher density component (n e 3c 2 7 105 cm-3) is probed by the [Fe III] and [Fe II] ultra-violet lines. The physical conditions derived from the iron lines are compared with shock models suggesting that the shock at work in ESO-H\u3b1 574 is faster and likely more energetic than the Par-Lup 3-4 shock. This latter feature is confirmed by the high percentage of gas-phase iron measured in ESO-H\u3b1 574 (50%-60% of its solar abundance in comparison with less than 30% in Par-Lup 3-4), which testifies that the ESO-H\u3b1 574 shock is powerful enough to partially destroy the dust present inside the jet. This work demonstrates that a multiline Fe analysis can be effectively used to probe the excitation and ionization conditions of the gas in a jet without any assumption on ionic abundances. The main limitation on the diagnostics resides in the large uncertainties of the atomic data, which, however, can be overcome through a statistical approach involving many line

Pyrosequencing of Bacterial Symbionts within Axinella corrugata Sponges: Diversity and Seasonal Variability

Background: Marine sponge species are of significant interest to many scientific fields including marine ecology, conservation biology, genetics, host-microbe symbiosis and pharmacology. One of the most intriguing aspects of the sponge ‘‘holobiont’’ system is the unique physiology, interaction with microbes from the marine environment and the development of a complex commensal microbial community. However, intraspecific variability and temporal stability of sponge-associated bacterial symbionts remain relatively unknown. Methodology/Principal Findings: We have characterized the bacterial symbiont community biodiversity of seven different individuals of the Caribbean reef sponge Axinella corrugata, from two different Florida reef locations during variable seasons using multiplex 454 pyrosequencing of 16 S rRNA amplicons. Over 265,512 high-quality 16 S rRNA sequences were generated and analyzed. Utilizing versatile bioinformatics methods and analytical software such as the QIIME and CloVR packages, we have identified 9,444 distinct bacterial operational taxonomic units (OTUs). Approximately 65,550 rRNA sequences (24%) could not be matched to bacteria at the class level, and may therefore represent novel taxa. Differentially abundant classes between seasonal Axinella communities included Gammaproteobacteria, Flavobacteria, Alphaproteobacteria, Cyanobacteria, Acidobacter and Nitrospira. Comparisons with a proximal outgroup sponge species (Amphimedon compressa), and the growing sponge symbiont literature, indicate that this study has identified approximately 330 A. corrugata-specific symbiotic OTUs, many of which are related to the sulfur-oxidizing Ectothiorhodospiraceae. This family appeared exclusively within A. corrugata, comprising \u3e34.5% of all sequenced amplicons. Other A. corrugata symbionts such as Deltaproteobacteria, Bdellovibrio, and Thiocystis among many others are described. Conclusions/Significance: Slight shifts in several bacterial taxa were observed between communities sampled during spring and fall seasons. New 16 S rDNA sequences and concomitant identifications greatly expand the microbial community profile for this model reef sponge, and will likely be useful as a baseline for any future comparisons regarding sponge microbial community dynamics

Degradation of a benzene–toluene mixture by hydrocarbon-adapted bacterial communities

We examined the rate of degradation of a benzene–toluene mixture in aerobic microcosms prepared with samples of an aquifer that lies below a petrochemical plant (SIReN, UK). Five samples exposed to different concentrations of benzene (from 0.6 to 317 mg l−1) were used. Fast degradation (approx. 1–6 mg l−1 day−1) of both contaminants was observed in all groundwater samples and complete degradation was recorded by the seventh day except for one sample. We also identified the microbial community in each of the samples by culture-independent techniques. Two of the less impacted samples harbour the aerobic benzene degrader Pseudomonas fluorescens, while Acidovorax and Arthrobacter spp. were found in the most polluted sample and are consistent with the population observed in situ. Hydrogenophaga was found in the deepest sample while Rhodoferax spp. were recovered in an alkaline sample (pH 8.4) and may also be implicated in benzene degradation. Time series analysis shows that each of the samples has a different community but they remain stable over the degradation period. This study provides new information on a well not previously studied (no. 309s) and confirms that adapted communities have the ability to degrade hydrocarbon mixtures and could be used in further bioaugmentation approaches in contaminated sites

IGFBP3 Colocalizes with and Regulates Hypocretin (Orexin)

Background: The sleep disorder narcolepsy is caused by a vast reduction in neurons producing the hypocretin (orexin) neuropeptides. Based on the tight association with HLA, narcolepsy is believed to result from an autoimmune attack, but the cause of hypocretin cell loss is still unknown. We performed gene expression profiling in the hypothalamus to identify novel genes dysregulated in narcolepsy, as these may be the target of autoimmune attack or modulate hypocretin gene expression. Methodology/Principal Findings: We used microarrays to compare the transcriptome in the posterior hypothalamus of (1) narcoleptic versus control postmortem human brains and (2) transgenic mice lacking hypocretin neurons versus wild type mice. Hypocretin was the most downregulated gene in human narcolepsy brains. Among many additional candidates, only one, insulin-like growth factor binding protein 3 (IGFBP3), was downregulated in both human and mouse models and coexpressed in hypocretin neurons. Functional analysis indicated decreased hypocretin messenger RNA and peptide content, and increased sleep in transgenic mice overexpressing human IGFBP3, an effect possibly mediated through decrease

Neurocognitive functioning in school-aged cystinosis patients

Contains fulltext : 89600.pdf (publisher's version ) (Closed access)INTRODUCTION: Cystinosis is an autosomal recessive disorder leading to intralysosomal cystine accumulation in various tissues. It causes renal Fanconi syndrome and end stage renal failure around the age of 10 years if not treated with cysteamine. Children with cystinosis seem to have a normal intelligence but frequently show learning difficulties. These problems may be due to specific neurocognitive deficits rather than impaired renal function. Whether cysteamine treatment can improve cognitive functioning of cystinosis patients is thus far unknown. We aim to analyze neurocognitive functioning of school-aged cystinosis patients treated with cysteamine in order to identify specific deficits that can lead to learning difficulties. PATIENTS AND METHODS: Fourteen Dutch and Belgian school-aged cystinosis patients were included. Glomerular filtration rate was estimated using the Schwartz formula. Children were tested for general intelligence, visual-motor integration, inhibition, interference, sustained attention, accuracy, planning, visual memory, processing speed, motor planning, fluency and speed, and behavioural and emotional functioning using standardized methods. RESULTS: Glomerular filtration rate ranged from 22 to 120 ml min(-1) 1.73 m(-2). Median full-scale intelligence was below the average of a normal population (87, range 60-132), with a discrepancy between verbal (median 95, range 60-125) and performance (median 87, range 65-130) intelligence. Over 50% of the patients scored poorly on visual-motor integration, sustained attention, visual memory, planning, or motor speed. The other tested areas showed no differences between patients' and normal values. CONCLUSION: Neurocognitive diagnostics are indicated in cystinosis patients. Early recognition of specific deficits and supervision from special education services might reduce learning difficulties and improve school careers.1 december 201

Acquisition vs. Memorization Trade-Offs Are Modulated by Walking Distance and Pattern Complexity in a Large-Scale Copying Paradigm

In a “block-copying paradigm”, subjects were required to copy a configuration of colored blocks from a model area to a distant work area, using additional blocks provided at an equally distant resource area. Experimental conditions varied between the inter-area separation (walking distance) and the complexity of the block patterns to be copied. Two major behavioral strategies were identified: in the memory-intensive strategy, subjects memorize large parts of the pattern and rebuild them without intermediate visits at the model area. In the acquisition-intensive strategy, subjects memorize one block at a time and return to the model after having placed this block. Results show that the frequency of the memory-intensive strategy is increased for larger inter-area separations (larger walking distances) and for simpler block patterns. This strategy-shift can be interpreted as the result of an optimization process or trade-off, minimizing combined, condition-dependent costs of the two strategies. Combined costs correlate with overall response time. We present evidence that for the memory-intensive strategy, costs correlate with model visit duration, while for the acquisition-intensive strategy, costs correlate with inter-area transition (i.e., walking) times