A Novel In Vitro Model for Determining the Optimum pH and Dose Volume of New Liquid Alginate for Infant Reflux Suppression.

BACKGROUND: Gastroesophageal reflux frequently occurs in infants from birth to 2 years and is characterised by reflux and regurgitation often occurring during or immediately after feeds. These reflux events can range in both frequency and severity, and as the reflux events increase, they become increasingly distressing for both the infant and the parent. The study aimed to characterise the properties of a new infant liquid alginate product, determining the optimum gastric pH and dose volume for maximum reflux suppressant activity. METHODS: An in vitro infant stomach model was designed and developed that allowed products to be assessed for their reflux suppression activity. The validation of the model was completed by three independent operators comparing a milk control with infant Gaviscon to evaluate the models' robustness, reproducibility, and ease of use. The model was used to establish reflux suppression activity of a new liquid alginate infant formulation in comparison with a milk control. Suppression activity was assessed at varying doses and pH within a physiological range. RESULTS: The validation study demonstrated no significant difference in refluxate volumes for the milk control within each reflux event when comparing across the three individual operators. Similarly, no statistical differences were seen during the infant Gaviscon experiments, confirming the robustness and reproducibility of the model. Significant reflux suppression was seen across the pH range (except at pH 5.75); the pH most advantageous for reflux suppression was pH 5.25. The optimum dose volume for consistently suppressing reflux was shown to be 5 ml. An infant stomach model was designed for evaluating reflux suppression activity of a formulation of liquid alginate. The optimum gastric pH and dose volume for demonstrating significant reflux suppression and the thickening of formula milk by the infant liquid alginate formulation were established. CONCLUSION: This study confirms the mode of action of the alginate formula, demonstrating a superior reduction in the retrograde movement of in vitro gastric contents and volume of regurgitation. The study also demonstrates that optimal performance occurs in conditions that are in line physiologically with the target patient. Both actions compliment and support the efficacy of the alginate formulation as a reflux therapy agent.

Guard Cells Integrate Light and Temperature Signals to Control Stomatal Aperture.

High temperature promotes guard cell expansion, which opens stomatal pores to facilitate leaf cooling. How the high-temperature signal is perceived and transmitted to regulate stomatal aperture is, however, unknown. Here, we used a reverse-genetics approach to understand high temperature-mediated stomatal opening in Arabidopsis (Arabidopsis thaliana). Our findings reveal that high temperature-induced guard cell movement requires components involved in blue light-mediated stomatal opening, suggesting cross talk between light and temperature signaling pathways. The molecular players involved include phototropin photoreceptors, plasma membrane H+-ATPases, and multiple members of the 14-3-3 protein family. We further show that phototropin-deficient mutants display impaired rosette evapotranspiration and leaf cooling at high temperatures. Blocking the interaction of 14-3-3 proteins with their client proteins severely impairs high temperature-induced stomatal opening but has no effect on the induction of heat-sensitive guard cell transcripts, supporting the existence of an additional intracellular high-temperature response pathway in plants.

Detecting and coping with disruptive shocks in Arctic marine systems: a resilience approach to place and people.

It seems inevitable that the ongoing and rapid changes in the physical environment of the marine Arctic will push components of the region's existing social-ecological systems-small and large-beyond tipping points and into new regimes. Ongoing changes include warming, freshening, acidification, and alterations to food web structure. In anticipation we pose three distinct but interrelated challenges: (1) to explore existing connectivities within components of the marine system; (2) to seek indicators (if they exist) of approaching regime change through observation and modeling; and (3) to build functional resilience into existing systems through adaptation-oriented policy and to have in hand transformative options when tipping points are crossed and new development trajectories are required. Each of the above challenges is scale dependent, and each requires a much deeper understanding than we currently have of connectivity within existing systems and their response to external forcing. Here, we argue from a global perspective the need to understand the Arctic's role in an increasingly nonlinear world; then describe emerging evidence from new observations on the connectivity of processes and system components from the Canada Basin and subarctic seas surrounding northern North America; and finally posit an approach founded in "resilience thinking" to allow northern residents living in small coastal communities to participate in the observation, adaption and-if necessary-transformation of the social-ecological system with which they live.

Aragonite undersaturation in the Arctic Ocean: effects of ocean acidification and sea ice melt.

The increase in anthropogenic carbon dioxide emissions and attendant increase in ocean acidification and sea ice melt act together to decrease the saturation state of calcium carbonate in the Canada Basin of the Arctic Ocean. In 2008, surface waters were undersaturated with respect to aragonite, a relatively soluble form of calcium carbonate found in plankton and invertebrates. Undersaturation was found to be a direct consequence of the recent extensive melting of sea ice in the Canada Basin. In addition, the retreat of the ice edge well past the shelf-break has produced conditions favorable to enhanced upwelling of subsurface, aragonite-undersaturated water onto the Arctic continental shelf. Undersaturation will affect both planktonic and benthic calcifying biota and therefore the composition of the Arctic ecosystem.

Smallest algae thrive as the Arctic Ocean freshens.

As climate changes and the upper Arctic Ocean receives more heat and fresh water, it becomes more difficult for mixing processes to deliver nutrients from depth to the surface for phytoplankton growth. Competitive advantage will presumably accrue to small cells because they are more effective in acquiring nutrients and less susceptible to gravitational settling than large cells. Since 2004, we have discerned an increase in the smallest algae and bacteria along with a concomitant decrease in somewhat larger algae. If this trend toward a community of smaller cells is sustained, it may lead to reduced biological production at higher trophic levels.

A major ecosystem shift in the northern Bering Sea.

Until recently, northern Bering Sea ecosystems were characterized by extensive seasonal sea ice cover, high water column and sediment carbon production, and tight pelagic-benthic coupling of organic production. Here, we show that these ecosystems are shifting away from these characteristics. Changes in biological communities are contemporaneous with shifts in regional atmospheric and hydrographic forcing. In the past decade, geographic displacement of marine mammal population distributions has coincided with a reduction of benthic prey populations, an increase in pelagic fish, a reduction in sea ice, and an increase in air and ocean temperatures. These changes now observed on the shallow shelf of the northern Bering Sea should be expected to affect a much broader portion of the Pacific-influenced sector of the Arctic Ocean.

Histone deacetylase inhibitors open new doors in cancer therapy.

Cancer drug development has moved from conventional cytotoxic chemotherapeutics to a more mechanism-based targeted approach towards the common goal of tumour growth arrest. The rapid progress in chromatin research has supplied a plethora of potential targets for intervention in cancer. Here, we focus on the histone deacetylase (HDAC) inhibitors, together with their current status of clinical development and potential utility in cancer therapy. HDACs have been widely implicated in growth and transcriptional control, and inhibition of HDAC activity using small molecules causes apoptosis in tumour cells. We discuss the rationale for the development of HDAC inhibitors as novel anti-cancer agents, the potential clinical application and explore ideas on how we may move towards patient stratification with the possibility of increasing efficacy in the clinic.

Histone deacetylase inhibitors in psoriasis therapy.

Psoriasis is recognised as a multifactorial disease with inflammatory, proliferative, angiogenic and genetic components contributing to the pathology. The disease, which may vary in intensity, remains clinically unmet although there have been several recent advances that have had a substantial impact on suffering. Histone deacetylase inhibitors represent a new class of therapeutic agent, initially developed for oncology, which prevent cell proliferation and induce differentiation. Here we discuss the possible application of HDAC inhibitors to psoriasis, focussing particularly on their anti-proliferative and anti-inflammatory activity. Our view, based upon the emerging clinical properties of HDAC inhibitors, reflects the growing recognition that HDAC inhibitors will be important therapeutic agents in diseases other than cancer.

The cell cycle, chromatin and cancer: mechanism-based therapeutics come of age.

Tumour cells grow and divide in an uncontrolled fashion. Recent advances in the cell cycle have uncovered new mechanisms that integrate growth and division with chromatin and gene expression control. Small-molecule drugs that target key enzyme classes involved in these pathways, the cyclin-dependent kinases (Cdk) in the cell cycle and histone deacetylases (HDAC) in chromatin control, have entered clinical studies, with emerging clinical efficacy. These new mechanism-based approaches could provide significant improvements over many current chemotherapeutics.