Intercalated theophylline-smectite hybrid for pH-mediated delivery

On the basis of their large specific surface areas, high adsorption and cation exchange capacities, swelling potential and low toxicity, natural smectite clays are attractive substrates for the gastric protection of neutral and cationic drugs. Theophylline is an amphoteric xanthine derivative that is widely used as a bronchodilator in the treatment of asthma and chronic obstructive pulmonary disease. This study considers the in vitro uptake and release characteristics of the binary theophylline-smectite system. The cationic form of theophylline was readily ion exchanged into smectite clay at pH 1.2 with a maximum uptake of 67±2 mg g−1. Characterisation of the drug-clay hybrid system by powder X-ray diffraction analysis, Fourier transform infrared spectroscopy, differential scanning calorimetry and scanning electron microscopy confirmed that the theophylline had been exclusively intercalated into the clay system in an amorphous form. The drug remained bound within the clay under simulated gastric conditions at pH 1.2; and the prolonged release of approximately 40% of the drug was observed in simulated intestinal fluid at pH 6.8 and 7.4 within a 2-h timeframe. The incomplete reversibility of the intercalation process was attributed to chemisorption of the drug within the clay lattice. These findings indicate that smectite clay is a potentially suitable vehicle for the safe passage of theophylline into the duodenum. Protection from absorption in the stomach and subsequent prolonged release in the small intestine are advantageous in reducing fluctuations in serum concentration which may impact therapeutic effect and toxicit

Antimicrobial lubricant formulations containing poly(hydroxybenzene)-trimethoprim conjugates synthesized by tyrosinase

Poly(hydroxybenzene)-trimethoprim conjugates were prepared using methylparaben as substrate of the oxida- tive enzyme tyrosinase. MALDI-TOF MS analysis showed that the enzymatic oxidation of methylparaben alone leads to the poly(hydroxybenzene) formation. In the presence of tri- methoprim, the methylparaben tyrosinase oxidation leads poly(hydroxybenzene)-trimethoprim conjugates. All of these compounds were incorporated into lubricant hydroxyethyl cellulose/glycerol mixtures. Poly(hydroxybenzene)-trimetho- prim conjugates were the most effective phenolic structures against the bacterial growth reducing by 96 and 97 % of Escherichia coli and Staphylococcus epidermidis suspen- sions, respectively (after 24 h). A novel enzymatic strategy to produce antimicrobial poly(hydroxybenzene)-antibiotic conjugates is proposed here for a wide range of applications on the biomedical field.The authors Idalina Gonçalves and Cláudia Botelho would like to acknowledge the NOVO project (FP7-HEALTH- 2011.2.3.1- 5) for funding. Loïc Hilliou acknowledges the financial support by FCT – Foundation for Science and Technology, Portugal (501100001871), through Grant PEst-C/CTM/LA0025/2013 - Strategic Project - LA 25 - 2013–2014, and by Programa Operacional Regional do Norte (ON.2) through the project BMatepro – Optimizing Materials and Processes^, with reference NORTE-07-0124-FEDER-000037 FEDER COMPETE

Age-related delay in information accrual for faces: Evidence from a parametric, single-trial EEG approach

Background: In this study, we quantified age-related changes in the time-course of face processing by means of an innovative single-trial ERP approach. Unlike analyses used in previous studies, our approach does not rely on peak measurements and can provide a more sensitive measure of processing delays. Young and old adults (mean ages 22 and 70 years) performed a non-speeded discrimination task between two faces. The phase spectrum of these faces was manipulated parametrically to create pictures that ranged between pure noise (0% phase information) and the undistorted signal (100% phase information), with five intermediate steps. Results: Behavioural 75% correct thresholds were on average lower, and maximum accuracy was higher, in younger than older observers. ERPs from each subject were entered into a single-trial general linear regression model to identify variations in neural activity statistically associated with changes in image structure. The earliest age-related ERP differences occurred in the time window of the N170. Older observers had a significantly stronger N170 in response to noise, but this age difference decreased with increasing phase information. Overall, manipulating image phase information had a greater effect on ERPs from younger observers, which was quantified using a hierarchical modelling approach. Importantly, visual activity was modulated by the same stimulus parameters in younger and older subjects. The fit of the model, indexed by R2, was computed at multiple post-stimulus time points. The time-course of the R2 function showed a significantly slower processing in older observers starting around 120 ms after stimulus onset. This age-related delay increased over time to reach a maximum around 190 ms, at which latency younger observers had around 50 ms time lead over older observers. Conclusion: Using a component-free ERP analysis that provides a precise timing of the visual system sensitivity to image structure, the current study demonstrates that older observers accumulate face information more slowly than younger subjects. Additionally, the N170 appears to be less face-sensitive in older observers

Whole genome sequence and manual annotation of Clostridium autoethanogenum, an industrially relevant bacterium

Clostridium autoethanogenum is an acetogenic bacterium capable of producing high value commodity chemicals and biofuels from the C1 gases present in synthesis gas. This common industrial waste gas can act as the sole energy and carbon source for the bacterium that converts the low value gaseous components into cellular building blocks and industrially relevant products via the action of the reductive acetyl-CoA (Wood-Ljungdahl) pathway. Current research efforts are focused on the enhancement and extension of product formation in this organism via synthetic biology approaches. However, crucial to metabolic modelling and directed pathway engineering is a reliable and comprehensively annotated genome sequence

HIF1α drives chemokine factor pro-tumoral signaling pathways in acute myeloid leukemia

Approximately 80% of patients diagnosed with acute myeloid leukemia (AML) die as a consequence of failure to eradicate the tumor from the bone marrow microenvironment. We have recently shown that stroma-derived interleukin-8 (IL-8) promotes AML growth and survival in the bone marrow in response to AML-derived macrophage migration inhibitory factor (MIF). In the present study we show that high constitutive expression of MIF in AML blasts in the bone marrow is hypoxia-driven and, through knockdown of MIF, HIF1α and HIF2α, establish that hypoxia supports AML tumor proliferation through HIF1α signaling. In vivo targeting of leukemic cell HIF1α inhibits AML proliferation in the tumor microenvironment through transcriptional regulation of MIF, but inhibition of HIF2α had no measurable effect on AML blast survival. Functionally, targeted inhibition of MIF in vivo improves survival in models of AML. Here we present a mechanism linking HIF1α to a pro-tumoral chemokine factor signaling pathway and in doing so, we establish a potential strategy to target AML

Structured models of cell migration incorporating molecular binding processes

The dynamic interplay between collective cell movement and the various molecules involved in the accompanying cell signalling mechanisms plays a crucial role in many biological processes including normal tissue development and pathological scenarios such as wound healing and cancer. Information about the various structures embedded within these processes allows a detailed exploration of the binding of molecular species to cell-surface receptors within the evolving cell population. In this paper we establish a general spatio-temporal-structural framework that enables the description of molecular binding to cell membranes coupled with the cell population dynamics. We first provide a general theoretical description for this approach and then illustrate it with two examples arising from cancer invasion

Lung epithelial stem cells and their niches : Fgf10 takes center stage

Throughout life adult animals crucially depend on stem cell populations to maintain and repair their tissues to ensure life-long organ function. Stem cells are characterized by their capacity to extensively self-renew and give rise to one or more differentiated cell types. These powerful stem cell properties are key to meet the changing demand for tissue replacement during normal lung homeostasis and regeneration after lung injury. Great strides have been made over the last few years to identify and characterize lung epithelial stem cells as well as their lineage relationships. Unfortunately, knowledge on what regulates the behavior and fate specification of lung epithelial stem cells is still limited, but involves communication with their microenvironment or niche, a local tissue environment that hosts and influences the behaviors or characteristics of stem cells and that comprises other cell types and extracellular matrix. As such, an intimate and dynamic epithelial-mesenchymal cross-talk, which is also essential during lung development, is required for normal homeostasis and to mount an appropriate regenerative response after lung injury. Fibroblast growth factor 10 (Fgf10) signaling in particular seems to be a well-conserved signaling pathway governing epithelial-mesenchymal interactions during lung development as well as between different adult lung epithelial stem cells and their niches. On the other hand, disruption of these reciprocal interactions leads to a dysfunctional epithelial stem cell-niche unit, which may culminate in chronic lung diseases such as chronic obstructive pulmonary disease (COPD), chronic asthma and idiopathic pulmonary fibrosis (IPF)

Characterization of Diffusion Bonds Using an Acoustic Microscope

Solid state bonding is now being used in aircraft fabrication. As a result of this, various groups have considered the destructive examination of such bonds and categorized them in terms of characteristics seen in the examination of micrographic sections [1,2]. A range of studies which employ ultrasonic non-destructive techniques for bond-line characterization have also been undertaken [1,3,4]

Perspectives from deductible plan enrollees: plan knowledge and anticipated care-seeking changes

<p>Abstract</p> <p>Background</p> <p>Consumer directed health care proposes that patients will engage as informed consumers of health care services by sharing in more of their medical costs, often through deductibles. We examined knowledge of deductible plan details among new enrollees, as well as anticipated care-seeking changes in response to the deductible.</p> <p>Methods</p> <p>In a large integrated delivery system with a range of deductible-based health plans which varied in services included or exempted from deductible, we conducted a mixed-method, cross-sectional telephone interview study.</p> <p>Results</p> <p>Among 458 adults newly enrolled in a deductible plan (71% response rate), 51% knew they had a deductible, 26% knew the deductible amount, and 6% knew which medical services were included or exempted from their deductible. After adjusting for respondent characteristics, those with more deductible-applicable services and those with lower self-reported health status were significantly more likely to know they had a deductible. Among those who knew of their deductible, half anticipated that it would cause them to delay or avoid medical care, including avoiding doctor's office visits and medical tests, even services that they believed were medically necessary. Many expressed concern about their costs, anticipating the inability to afford care and expressing the desire to change plans.</p> <p>Conclusion</p> <p>Early in their experience with a deductible, patients had limited awareness of the deductible and little knowledge of the details. Many who knew of the deductible reported that it would cause them to delay or avoid seeking care and were concerned about their healthcare costs.</p

International phase I study protocol to develop a patient-reported outcome measure for adolescents and adults receiving gender-affirming treatments (the GENDER-Q)

Introduction A critical barrier to outcome assessment in gender-affirming healthcare is the lack of a specific patient-reported outcome measure (PROM). This phase I protocol describes an international collaboration between investigators in Canada, Denmark, the Netherlands and the USA who have coalesced to develop a new PROM (ie, the GENDER-Q) to evaluate outcomes of psychological, hormonal and surgical gender-affirming treatments. Methods and analysis This phase I study uses an interpretive description approach. Participants aged 16 years and older seeking any form of gender-affirming treatments in centres located in Canada, Denmark, the Netherlands and the USA will be invited to take part in qualitative interviews. Participants will review BREAST-Q and FACE-Q scales hypothesised to contain content relevant to specific gender-affirming treatments. Interviews will elicit new concepts for additional scale development. Each interview will be digitally recorded, transcribed and coded. The main outcome of this phase I study will be the development of a conceptual framework and set of scales to measure outcomes important to evaluating gender-affirming treatments. To this end, analysis will be used to add/drop/revise items of existing scales to achieve content validity. For new concepts, coding will assign top-level domains and themes/subthemes to participant quotes. Codes will be used to develop an item pool to inform scale development. Draft scales will be shown to transgender and gender diverse persons and experts to obtain feedback that will be used to refine and finalise the scales. The field-test version of the GENDER-Q will be translated by following rigorous methods to prepare for the international field-test study. Ethics and dissemination This study is coordinated at McMaster University (Canada). Ethics board approval was received from the Hamilton Integrated Ethics Board (Canada), the Medical Ethical Committee at VUmc (The Netherlands) and Advarra (USA). Findings will be published in peer-reviewed journals and presented at national and international conferences and meetings