Foam-in-Vein: Rheological Characterisation of Liquid Sclerosing Foams Using a Pipe Viscometer

Sclerotherapy is one of the most common and least-invasive treatment methods for varicose veins. While bench-top properties of sclerosing foams (e.g., bubble size distribution and foam half-life) have been studied previously, their flow behaviour and its relationship to therapeutic efficacy remain largely uncharacterised. To address this research gap, the present study reports on a novel approach for the rheological characterisation of sclerosing foams aimed at obtaining clinically-applicable data. A pipe viscometry apparatus was employed under conditions that mimic the end-point therapeutic application of foams. Polidocanol (1% v/v) foams of various liquid-to-gas volume ratios (1:3, 1:4 and 1:5) were formulated manually using the Tessari and DSS (double syringe system) methods across a clinically-relevant range of shear rates (≈ 7 s^{-1} – 400 s^{-1}), in polytetrafluoroethylene pipes of different diameters (2.48 mm and 4.48 mm). Additionally, end-effect and wall-slip correction methods were utilised to model the nominal rheology of sclerosing foams. The rheological data were fitted into a power-law model to obtain fluid flow index (n) and fluid consistency index (K) of sclerosing foams, followed by an in-depth statistical analysis of the power-law indices. The observed rheological behaviour of sclerosing foams is shown to be dependent on vessel diameter and liquid-to-gas ratio, while the type of manual formulation technique used appears to be statistically insignificant towards foam rheology. Sclerosing foams behaved as shear-thinning fluids with observed flow indices ranging 0.238 < n < 0.445, while the observed consistency indices ranged 2.977 < K < 12.49. The nominal (end-effect corrected) rheology of foams was shown to follow similar trends concerning liquid-to-gas ratio and formulation technique, independent of the tube diameter. The power-law characterisation of sclerosing foam rheology provided evidence of a quasi-static drainage effect that affected foam viscosity during slower injections. Wall-slip correction failed to provide physically meaningful results and statistical analysis suggested that the type of manual formulation technique used has no impact on the outcome of sclerotherapy on larger varicosities. Overall, results suggest a direct correlation between foam dryness and viscosity. Based on the developed rheological model, this work also demonstrates that low injection flowrates could yield higher therapeutic efficacy in dilated varicose veins

Direct Imaging in Reflected Light: Characterization of Older, Temperate Exoplanets With 30-m Telescopes

Direct detection, also known as direct imaging, is a method for discovering and characterizing the atmospheres of planets at intermediate and wide separations. It is the only means of obtaining spectra of non-transiting exoplanets. Characterizing the atmospheres of planets in the <5 AU regime, where RV surveys have revealed an abundance of other worlds, requires a 30-m-class aperture in combination with an advanced adaptive optics system, coronagraph, and suite of spectrometers and imagers - this concept underlies planned instruments for both TMT (the Planetary Systems Imager, or PSI) and the GMT (GMagAO-X). These instruments could provide astrometry, photometry, and spectroscopy of an unprecedented sample of rocky planets, ice giants, and gas giants. For the first time habitable zone exoplanets will become accessible to direct imaging, and these instruments have the potential to detect and characterize the innermost regions of nearby M-dwarf planetary systems in reflected light. High-resolution spectroscopy will not only illuminate the physics and chemistry of exo-atmospheres, but may also probe rocky, temperate worlds for signs of life in the form of atmospheric biomarkers (combinations of water, oxygen and other molecular species). By completing the census of non-transiting worlds at a range of separations from their host stars, these instruments will provide the final pieces to the puzzle of planetary demographics. This whitepaper explores the science goals of direct imaging on 30-m telescopes and the technology development needed to achieve them.Comment: (March 2018) Submitted to the Exoplanet Science Strategy committee of the NA

Prognostic interaction between expression of p53 and estrogen receptor in patients with node-negative breast cancer: results from IBCSG Trials VIII and IX

Introduction: The prognostic significance of p53 protein expression in early breast cancer remains uncertain, with some but not all studies finding an association with poorer outcomes. Estrogen receptor (ER) expression is both a positive prognostic marker and predictive of response to endocrine therapies. The relationship between these biomarkers is unknown. Methods: We constructed tissue microarrays (TMAs) from available pathological material from 1113 patients participating in two randomized clinical trials comparing endocrine therapy alone versus chemo-endocrine therapy in node-negative breast cancer. Expression of p53 defined as >10% positive nuclei was analyzed together with prior immunohistochemical assays of ER performed at central pathological review of whole tumor sections. Results: ER was present (i.e. >1% positive tumor cell nuclei) in 80.1% (880/1092). p53 expression was significantly more frequent when ER was absent, 125/212 (59%) than when ER was present, 171/880 (19%), p <0.0001. A significant qualitative interaction was observed such that p53 expression was associated with better disease-free survival (DFS) and overall survival (OS) among patients whose tumors did not express ER, but worse DFS and OS among patients whose tumors expressed ER. The interaction remained significant after allowance for pathologic variables, and treatment. Similar effects were seen when luminal and non-luminal intrinsic subtypes were compared. Conclusions: Interpretation of the prognostic significance of p53 expression requires knowledge of concurrent expression of ER. The reason for the interaction between p53 and ER is unknown but may reflect qualitatively different p53 mutations underlying the p53 expression in tumors with or without ER expression. Trial registration Current Controlled Trials ACTRN12607000037404 (Trial VIII) and ACTRN12607000029493 (Trial IX)

"Pathogen Eradication" and "Emerging Pathogens": Difficult Definitions in Cystic Fibrosis.

Infection is a common complication of cystic fibrosis (CF) airway disease. Current treatment approaches include early intervention with the intent to eradicate pathogens in the hope of delaying the development of chronic infection and the chronic use of aerosolized antibiotics to suppress infection. The use of molecules that help restore CFTR (cystic fibrosis transmembrane conductance regulator) function, modulate pulmonary inflammation, or improve pulmonary clearance may also influence the microbial communities in the airways. As the pipeline of these new entities continues to expand, it is important to define when key pathogens are eradicated from the lungs of CF patients and, equally important, when new pathogens might emerge as a result of these novel therapies

Developmental profile and sexually dimorphic expression of kiss1 and kiss1r in the fetal mouse brain

The hypothalamic-pituitary-gonadal axis (HPG) is a complex neuroendocrine circuit involving multiple levels of regulation. Kisspeptin neurons play essential roles in controlling the HPG axis from the perspectives of puberty onset, oscillations of gonadotropin releasing hormone (GnRH) neuron activity and the pre-ovulatory LH surge. The current studies focus on the expression of kisspeptin during murine fetal development using in situ hybridization (ISH), quantitative reverse transcription real-time PCR (QPCR) and immunocytochemistry. Expression of mRNA coding for kisspeptin (KISS1) and its receptor KISS1R was observed at embryonic (E) day 13 by ISH. At E13 and other later ages examined, Kiss1 signal in individual cells within the arcuate nucleus (ARC) appeared stronger in females than males. ISH examination of agonadal steroidogenic factor-1 (Sf1) knockout mice revealed that E17 XY knockouts resembled wild-type XX females. These findings raise the possibility that gonadal hormones modulate the expression of Kiss1 in the ARC prior to birth. The sex and genotype differences were tested quantitatively by QPCR experiments in dissected hypothalami from mice at E17 and adulthood. Females had significantly more Kiss1 than males at both ages, even though the number of cells detected by ISH was similar. In addition, QPCR revealed a significant difference in the amount of Kiss1 mRNA in Sf1 mice with wild-type (WT) XY mice expressing less than XY knockouts (KO) and XX mice of both genotypes. The detection of immunoreactive KISS1 in perikarya of the ARC at E17 indicates that early mRNA is translated to peptide. The functional significance of this early expression of Kiss1 awaits elucidation

What the disjunctivist is right about

There is a traditional conception of sensory experience on which the experiences one has looking at, say, a cat could be had by someone merely hallucinating a cat. Disjunctivists take issue with this conception on the grounds that it does not enable us to understand how perceptual knowledge is possible. In particular, they think, it does not explain how it can be that experiences gained in perception enable us to be in ‘cognitive contact’ with objects and facts. I develop this chal- lenge to the traditional conception and then show that it is possible to accommo- date an adequate account of cognitive contact in keeping with the traditional conception. One upshot of the discussion is that experiences do not bear the explanatory burden placed upon them by disjunctivists

Impact of the Location of CpG Methylation within the GSTP1 Gene on Its Specificity as a DNA Marker for Hepatocellular Carcinoma

Hypermethylation of the glutathione S-transferase π 1 (GSTP1) gene promoter region has been reported to be a potential biomarker to distinguish hepatocellular carcinoma (HCC) from other liver diseases. However, reports regarding how specific a marker it is have ranged from 100% to 0%. We hypothesized that, to a large extent, the variation of specificity depends on the location of the CpG sites analyzed. To test this hypothesis, we compared the methylation status of the GSTP1 promoter region of the DNA isolated from HCC, cirrhosis, hepatitis, and normal liver tissues by bisulfite–PCR sequencing. We found that the 5′ region of the position −48 nt from the transcription start site of the GSTP1 gene is selectively methylated in HCC, whereas the 3′ region is methylated in all liver tissues examined, including normal liver and the HCC tissue. Interestingly, when DNA derived from fetal liver and 11 nonhepatic normal tissue was also examined by bisulfite-PCR sequencing, we found that methylation of the 3′ region of the promoter appeared to be liver-specific. A methylation-specific PCR assay targeting the 5′ region of the promoter was developed and used to quantify the methylated GSTP1 gene in various diseased liver tissues including HCC. When we used an assay targeting the 3′ region, we found that the methylation of the 5′-end of the GSTP1 promoter was significantly more specific than that of the 3′-end (97.1% vs. 60%, p<0.0001 by Fisher's exact test) for distinguishing HCC (n = 120) from hepatitis (n = 35) and cirrhosis (n = 35). Encouragingly, 33.8% of the AFP-negative HCC contained the methylated GSTP1 gene. This study clearly demonstrates the importance of the location of CpG site methylation for HCC specificity and how liver-specific DNA methylation should be considered when an epigenetic DNA marker is studied for detection of HCC

The role of steroids in the management of brain metastases: a systematic review and evidence-based clinical practice guideline

Do steroids improve neurologic symptoms in patients with metastatic brain tumors compared to no treatment? If steroids are given, what dose should be used? Comparisons include: (1) steroid therapy versus none. (2) comparison of different doses of steroid therapy. Target population These recommendations apply to adults diagnosed with brain metastases. Recommendations Steroid therapy versus no steroid therapy Asymptomatic brain metastases patients without mass effect Insufficient evidence exists to make a treatment recommendation for this clinical scenario. Brain metastases patients with mild symptoms related to mass effect Level 3 Corticosteroids are recommended to provide temporary symptomatic relief of symptoms related to increased intracranial pressure and edema secondary to brain metastases. It is recommended for patients who are symptomatic from metastatic disease to the brain that a starting dose of 4–8 mg/day of dexamethasone be considered. Brain metastases patients with moderate to severe symptoms related to mass effect Level 3 Corticosteroids are recommended to provide temporary symptomatic relief of symptoms related to increased intracranial pressure and edema secondary to brain metastases. If patients exhibit severe symptoms consistent with increased intracranial pressure, it is recommended that higher doses such as 16 mg/day or more be considered. Choice of Steroid Level 3 If corticosteroids are given, dexamethasone is the best drug choice given the available evidence. Duration of Corticosteroid Administration Level 3 Corticosteroids, if given, should be tapered slowly over a 2 week time period, or longer in symptomatic patients, based upon an individualized treatment regimen and a full understanding of the long-term sequelae of corticosteroid therapy. Given the very limited number of studies (two) which met the eligibility criteria for the systematic review, these are the only recommendations that can be offered based on this methodology. Please see “Discussion” and “Summary” section for additional details

Analysis of conserved microRNAs in floral tissues of sexual and apomictic Boechera species

<p>Abstract</p> <p>Background</p> <p>Apomixis or asexual seed formation represents a potentially important agronomic trait whose introduction into crop plants could be an effective way to fix and perpetuate a desirable genotype through successive seed generations. However, the gene regulatory pathways underlying apomixis remain unknown. In particular, the potential function of microRNAs, which are known to play crucial roles in many aspects of plant growth and development, remains to be determined with regards to the switch from sexual to apomictic reproduction.</p> <p>Results</p> <p>Using bioinformatics and microarray validation procedures, 51 miRNA families conserved among angiosperms were identified in <it>Boechera</it>. Microarray assay confirmed 15 of the miRNA families that were identified by bioinformatics techniques. 30 cDNA sequences representing 26 miRNAs could fold back into stable pre-miRNAs. 19 of these pre-miRNAs had miRNAs with <it>Boechera</it>-specific nucleotide substitutions (NSs). Analysis of the Gibbs free energy (ΔG) of these pre-miRNA stem-loops with NSs showed that the <it>Boechera</it>-specific miRNA NSs significantly (p ≤ 0.05) enhance the stability of stem-loops. Furthermore, six transcription factors, the Squamosa promoter binding protein like SPL6, SPL11 and SPL15, Myb domain protein 120 (MYB120), RELATED TO AP2.7 DNA binding (RAP2.7, TOE1 RAP2.7) and TCP family transcription factor 10 (TCP10) were found to be expressed in sexual or apomictic ovules. However, only SPL11 showed differential expression with significant (p ≤ 0.05) up-regulation at the megaspore mother cell (MMC) stage of ovule development in apomictic genotypes.</p> <p>Conclusions</p> <p>This study constitutes the first extensive insight into the conservation and expression of microRNAs in <it>Boechera </it>sexual and apomictic species. The miR156/157 target squamosa promoter binding protein-like 11 (SPL11) was found differentially expressed with significant (p ≤ 0.05) up-regulation at the MMC stage of ovule development in apomictic genotypes. The results also demonstrate that nucleotide changes in mature miRNAs significantly (p ≤ 0.05) enhance the thermodynamic stability of pre-miRNA stem-loops.</p