Productivity, carbon dioxide uptake and net energy return of microalgal bubble column photobioreactors

This work examined the energy return of Chlorella vulgaris and Dunaliella tertiolecta cultivated in a gas-sparged photobioreactor design where the power input for sparging was manipulated (10, 20, and 50 W m⁻³). Dry weight, organic carbon and heating values of the biomass were measured, plus a suite of variables including Fv/Fm and dissolved oxygen. A model for predicting the higher heating value of microalgal biomass was developed and used to measure the energetic performance of batch cultivations. High power inputs enhanced maximum biomass yields, but did not improve the energy return. Cultivation in 10 W m⁻³ showed up to a 39% higher cumulative net energy return than 50 W m⁻³, and increased the cumulative net energy ratio up to fourfold. The highest net energy ratio for power input was 19.3 (D. tertiolecta, 12% CO₂, 10 W m⁻³). These systems may be a sustainable method of biomass production, but their effectiveness is sensitive to operational parameters.     

Transient changes in transpiration, and stem and soil CO2 efflux in longleaf pine (Pinus palustris Mill.) following fire-induced leaf area reduction

In 20-year-old longleaf pine, we examined short-term effects of reduced live leaf area (A _L) via canopy scorching on sap flow (Q; kg H₂O h⁻¹), transpiration per unit leaf area (E _L; mm day⁻¹), stem CO₂ efflux (R _stem; μmol m⁻² s⁻¹) and soil CO₂ efflux (R _soil; μmol m⁻² s⁻¹) over a 2-week period during early summer. R _stem and Q were measured at two positions (1.3-m or BH, and base of live crown—BLC), and R _soil was measured using 15 open-system chambers on each plot. E _L before and after treatment was estimated using Q measured at BLC with estimates of A _L before and after scorching. We expected Q to decrease in scorched trees compared with controls resulting from reduced A _L. We expected R _stem at BLC and BH and R _soil to decrease following scorching due to reduced leaf area, which would decrease carbon supply to the stem and roots. Scorching reduced A _L by 77%. Prior to scorching, Q at BH was similar between scorch and control trees. Following scorching, Q was not different between control and scorch trees; however, E _L increased immediately following scorching by 3.5-fold compared to control trees. Changes in E _L in scorched trees corresponded well with changes in VPD (D), whereas control trees appeared more decoupled over the 5-day period following treatment. By the end of the study, R _stem decreased to 15–25% in scorched trees at both stem positions compared to control trees. Last, we found that scorching resulted in a delayed and temporary increase in R _soil rather than a decrease. No change in Q and increased E _L following scorching indicates a substantial adjustment in stomatal conductance in scorched trees. Divergence in R _stem between scorch and control trees suggests a gradual decline in stem carbohydrates following scorching. The absence of a strong R _soil response is likely due to non-limiting supplies of root starch during early summer.     

Cerebral gene expression and neurobehavioural development after perinatal exposure to an environmentally relevant polybrominated diphenylether (BDE47)

Nutrients in seafood are known to be beneficial for brain development. Effects of maternal exposure to 2,2′,4,4′ tetrabromo diphenylether (BDE47) was investigated, alongside the potential ameliorating impact of seafood nutrients, through assessment of neurobehaviour and gene expression in brain and liver. Developing mice were exposed during gestation and lactation via dams dosed through casein- or salmon-based feed, spiked with BDE47. Two concentrations were used: a low level (6 μg/kg feed) representing an environmentally realistic concentration and a high level (1,900 μg/kg feed) representing a BDE47 intake much higher than expected from frequents consumption of contaminated seafood. Experimental groups were similar with respect to reproductive success, growth and physical development. Minor, transient changes in neurobehavioural metrics were observed in groups given the highest dose of BDE47. No significant differences in behaviour or development were seen on postnatal day 18 among maternally exposed offspring. Cerebral gene expression investigated by microarray analyses and validated by RT-qPCR showed low fold changes for all genes, despite dose-dependent accumulation of BDE47 in brain tissue. The gene for glutamate ammonia ligase was upregulated compared to control in the casein-based high BDE47diet, suggesting potential impacts on downstream synaptic transmission. The study supported a previously observed regulation of Igfbp2 in brain with BDE47 exposure. Genes for hepatic metabolic enzymes were not influenced by BDE47. Potential neurotoxic effects and neurobehavioural aberrations after perinatal exposure to high levels of BDE47 were not readily observed in mice pups with the present experimental exposure regimes and methods of analysis.     

Cost-effectiveness of second-line antihyperglycemic therapy in patients with type 2 diabetes mellitus inadequately controlled on metformin

Background:

Metformin is widely accepted as first-line pharmacotherapy for patients with type 2 diabetes mellitus when glycemic control cannot be achieved by lifestyle interventions alone. However, uncertainty exists regarding the optimal second-line therapy for patients whose diabetes is inadequately controlled by metformin monotherapy. Increased use of newer, more costly agents, along with the rising incidence of type 2 diabetes, carries significant budgetary implications for health care systems. We conducted this analysis to determine the relative costs, benefits and cost-effectiveness of options for second-line treatment of type 2 diabetes.

Methods:

We used the United Kingdom Prospective Diabetes Study Outcomes Model to forecast diabetes-related complications, quality-adjusted life-years and costs of alternative second-line therapies available in Canada for adults with type 2 diabetes inadequately controlled by metformin. We obtained clinical data from a systematic review and mixed treatment comparison meta-analysis, and we obtained information on costs and utilities from published sources. We performed extensive sensitivity analyses to test the robustness of results to variation in inputs and assumptions.

Results:

Sulphonylureas, when added to metformin, were associated with the most favourable cost-effectiveness estimate, with an incremental cost of $12 757 per quality-adjusted life-year gained, relative to continued metformin monotherapy. Treatment with other agents, including thiazolidinediones and dipeptidyl peptidase-4 inhibitors, had unfavourable cost-effectiveness estimates compared with sulphonylureas. These results were robust to extensive sensitivity analyses.

Interpretation:

For most patients with type 2 diabetes that is inadequately controlled with metformin monotherapy, the addition of a sulphonylurea represents the most cost-effective second-line therapy.Type 2 diabetes mellitus is a progressive disease typically treated in a stepwise fashion, beginning with lifestyle modification, followed by the addition of one or more oral antihyperglycemic drugs and, finally, administration of exogenous insulin. Metformin monotherapy is widely recommended as first-line pharmacotherapy,^1,2 given its favourable effects in controlling blood glucose and body weight, low risk of hypoglycemia, low cost and association with mortality benefit.³ Multiple second-line treatment strategies are available for patients in whom glycemic control has become inadequate. These approaches are typically used in addition to continued metformin therapy.^4,5 Numerous second-line agents are available in Canada, including older oral agents, such as sulphonylureas, and more recently introduced agents, such as thiazolidinediones and dipeptidyl peptidase-4 inhibitors.The large number of choices for second-line therapy has increased uncertainty regarding the optimal treatment pathway. Recent clinical practice guidelines, including those produced by the Canadian Diabetes Association¹ and by the American Diabetes Association and the European Association for the Study of Diabetes,² have suggested selecting from among several agents on the basis of their respective advantages and disadvantages. There has been a considerable increase in the use of newer, more costly oral antihyperglycemic agents, which has resulted in substantial increases in associated costs to patients and both public and private drug plans in Canada.⁴ In light of current therapeutic uncertainty, the large proportion of patients requiring second-line therapy over time^3,6 and the increasing prevalence of type 2 diabetes,⁷ the utilization and cost of second-line therapy are likely to continue to grow.Informed decisions regarding optimal prescribing and reimbursement of second-line agents by public and private health care payers requires information about clinical benefits, costs and cost-effectiveness.⁸ As part of a larger initiative to determine optimal prescribing of antihyperglycemic agents, we sought to determine the incremental cost-effectiveness of treatment with alternative second-line agents added to metformin in patients with type 2 diabetes no longer adequately controlled by metformin monotherapy.     

Selective non zinc binding inhibitors of MMP13

Directed screening has identified a novel series of MMP13 inhibitors that possess good levels of activity whilst possessing excellent selectivity over related MMPs. The binding mode of the series has been solved by co-crystallisation and demonstrates an interesting mode of inhibition without interaction with the catalytic zinc atom.     

Design and synthesis of pyridin-2-yloxymethylpiperidin-1-ylbutyl amide CCR5 antagonists that are potent inhibitors of M-tropic (R5) HIV-1 replication

A novel series of CCR5 antagonists were identified based on the redesign of Schering C. An SAR was established based on inhibition of CCR5 (RANTES) binding and these compounds exhibited potent inhibition of R5 HIV-1 replication in peripheral blood mononuclear cells.     

Azaindoles as potent CRTH2 receptor antagonists

A new class of 7-azaindole analogs of MK-7246 as potent and selective CRTH2 antagonists is reported. The SAR leading to the identification of the optimal azaindole regioisomer as well as the pharmacokinetics and off-target activities of the most potent antagonists are disclosed.